Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[OH:13])[N:9]=[CH:8][CH:7]=[C:6]2[O:14][C:15]1[C:16]([CH3:25])=[N:17][C:18]2[C:23]([CH:24]=1)=[CH:22][CH:21]=[CH:20][CH:19]=2.Br[CH2:27][CH2:28][Cl:29].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:29][CH2:28][CH2:27][O:13][C:12]1[CH:11]=[C:10]2[C:5]([C:6]([O:14][C:15]3[C:16]([CH3:25])=[N:17][C:18]4[C:23]([CH:24]=3)=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1O
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1OCCCl
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.3 %

Procedure:
6-Methoxy-4-(2-methyl-quinolin-3-yloxy)-quinolin-7-ol (compound 352) (200 mg) was dissolved in N,N-dimethylformamide (10 ml) to prepare a solution. 1-Bromo-2-chloroethane (432 mg) and potassium carbonate (416 mg) were added to the solution, and the mixture was stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (186 mg, yield 78%).
Reaction SMILES: CN[OH:3].Cl.C[O-].[Na+].[Br:8][C:9]1[CH:17]=[C:16]2[C:12]([CH2:13][C:14]3([CH2:34][CH2:33][CH:32]([O:35][CH3:36])[CH2:31][CH2:30]3)[C:15]2([NH:23][S:24]([C:26]([CH3:29])([CH3:28])[CH3:27])=[O:25])[C:18]([O:20][CH2:21][CH3:22])=C)=[CH:11][CH:10]=1>CO>[Br:8][C:9]1[CH:17]=[C:16]2[C:12]([CH2:13][C:14]3([CH2:34][CH2:33][CH:32]([O:35][CH3:36])[CH2:31][CH2:30]3)[C:15]2([NH:23][S:24]([C:26]([CH3:28])([CH3:29])[CH3:27])=[O:25])[C:18]([O:20][CH2:21][CH3:22])=[O:3])=[CH:11][CH:10]=1
Reactant: CNO
Reactant: C=C(OCC)C1(NS(=O)C(C)(C)C)c2cc(Br)ccc2CC12CCC(OC)CC2
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)C1(NS(=O)C(C)(C)C)c2cc(Br)ccc2CC12CCC(OC)CC2
Reaction time: 0.08 h
Yield: 56.7 %

Procedure:
To a solution of MeNHOH.HCl (24.4 mg, 0.29 mmol) in MeOH (5 mL) was added NaOMe (10 wt % in MeOH, 141 mg, 0.26 mmol) and the mixture was stirred for 5 min. Then to a solution of compound 5 (104 mg, 0.29 mmol) in MeOH (8 mL) was added to above solution. Then final reaction mixture was stirred at room temperature for 45 min. Then the solution was concentrated and the residue was purified, which was purified preparative TLC to give compound 6 (80 mg, 68%) as a white solid.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[OH:7][N:8]=[C:9]([C:15]1[N:16]=[C:17]([CH3:20])[S:18][CH:19]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11].S(OC)(OC)(=O)=O>CC(C)=O>[CH3:1][O:7][N:8]=[C:9]([C:15]1[N:16]=[C:17]([CH3:20])[S:18][CH:19]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)C(=NO)c1csc(C)n1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Product: CCOC(=O)C(=NOC)c1csc(C)n1
Yield: 93.9 %

Procedure:
Pulverized potassium carbonate (0.33 g.) was suspended in a solution of ethyl 2-hydroxyimino-2-(2-methyl-1,3-thiazol-4-yl)acetate (syn isomer) (0.5 g.) in acetone (20 ml.). A solution of dimethyl sulfate (0.3 g.) in acetone (5 ml.) was dropwise added thereto with stirring at 40° to 45° C. After stirring for 2 hours at the same temperature, an insoluble material was filtered off. The filtrate was concentrated and water was added to the residue. The resulting mixture was extracted with ethyl acetate. The extract was in turn washed with water, a sodium bicarbonate aqueous solution and a saturated sodium chloride aqueous solution and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to give pale yellow oil of ethyl 2-methoxyimino-2-(2-methyl-1,3-thiazol-4-yl)acetate (syn isomer) (0.5 g.).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[C:9]([Br:11])[C:8](=[O:12])[N:7]([C@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:14])[C:6]=1[CH2:21][N:22]([CH2:33][C:34]([O:36][CH3:37])=[O:35])S(C1C=CC(C)=CC=1)(=O)=O)=O.C[O-].[Na+].Cl>CO>[CH3:37][O:36][C:34]([C:33]1[C:3]([OH:2])=[C:5]2[C:6](=[CH:21][N:22]=1)[N:7]([C@H:13]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH3:14])[C:8](=[O:12])[C:9]([Br:11])=[CH:10]2)=[O:35]
Reactant: COC(=O)CN(Cc1c(C(=O)OC)cc(Br)c(=O)n1[C@@H](C)c1ccccc1)S(=O)(=O)c1ccc(C)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ncc2c(cc(Br)c(=O)n2[C@@H](C)c2ccccc2)c1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 65.6 %

Procedure:
(S)-5-Bromo-2-{[methoxycarbonylmethyl-(toluene-4-sulfonyl)-amino]-methyl}-6-oxo-1-(1-phenyl-ethyl)-1,6-dihydro-pyridine-3-carboxylic acid methyl ester (2.26 g, 3.82 mmol) was dissolved in 80 mL of MeOH and placed in ice bath. NaOMe solution (2.6 mL, 11.5 mmol, 4.375 M in MeOH) was added and the mixture was stirred for 16 h at r.t. 1 M HCl was added to acidify the mixture, and the resulting suspension was extracted with CH2Cl2. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (30-100% CH2Cl2/hexanes) to give 1.01 g of the title compound as a pale yellow solid. MS: (−) m/z 401.24, 403.19 (M-1, 79/81Br).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:10].[NH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1.CC1C2C(=O)OC(=O)[NH:31]C=2C=CC=1>>[NH:16]1[CH2:20][CH2:19][N:31]=[C:17]1[CH2:18][NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:10]
Reactant: Cc1cccc2[nH]c(=O)oc(=O)c12
Reactant: C1CCNC1
Reactant: Cc1cccc(N)c1C(=O)N1CCCC1
Product: Cc1cccc(NCC2=NCCN2)c1C(=O)N1CCCC1

Procedure:
{2-Amino-6-methylphenyl}(1-pyrrolidinyl)methanone (prepared from pyrrolidine and 5-methyl-2H-3,1-benzoxazine-2,4(1H)-dione using the methods described in Example 17) and CMI were reacted using conditions described in the general procedure for CMI coupling to give {2-[(4,5-dihydro-1H-imidazol-2-ylmethyl)amino]-6-methylphenyl}(1-pyrrolidinyl)methanone.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[N:11][CH:12]=[C:13]([OH:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:16].[K+].[C:18]([C@@H:25]1[CH2:28][CH2:27][N:26]1[CH2:29][O:30]S(C1C(C)=CC=CC=1)(=O)=O)(OC(C)(C)C)=O>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:18][C@@H:25]2[CH2:28][CH2:27][N:26]2[C:29]([O:30][C:2]([CH3:7])([CH3:3])[CH3:1])=[O:16])[CH:12]=[N:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccccc1S(=O)(=O)OCN1CC[C@H]1C(=O)OC(C)(C)C
Reactant: [OH-]
Reactant: Oc1cncc(OCc2ccccc2)c1
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc(OCc2ccccc2)c1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 178.4 %

Procedure:
Next, a solution of 3-benzyloxy-5-hydroxypyridine (350 mg, 1.74 mmol, from step 120d) in DMF (20 mL) was treated with ground KOH (154 mg, 2.74 mmol) and stirred for 30 minutes at 80° C. To this mixture was rapidly added the Boc-(S)-toluensulfonyloxymethylazetidine (585 mg, 1.74 mmol) dissolved in DMF (5 mL), and the mixture was stirred for 16 hours at 80° C. The mixture was concentrated under vacuum to remove the DMF, and the residue was diluted with water and extracted with EtOAc. The organic extracts were combined, dried (Na2SO4), filtered, and concentrated under vacuum to give 800 mg of crude product. This material was purified by chromatography (silica gel; hexane/EtOAc, 10:1) to give the title compound (575 mg, 90%): 1H NMR (CDCl3, 300 MHz) δ 1.40 (s, 9H), 2.26-2.30 (m, 2H), 3.90-2.94 (m, 2H), 4.16 (m, 1H), 4.35 (m, 1H), 4.54 (m, 1H), 5.10 (s, 2H), 6.95 (s, 1H), 7.40-7.46 (m, 5H), 8.20 (br s, (2H): MS (CI/NH3) m/z: 371 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]([CH2:5][CH2:6][C:7]1[C:12]([CH3:14])([CH3:13])[CH2:11][CH2:10][CH2:9][C:8]=1[CH3:15])[CH:3]=O.[C:16]([O:24][CH2:25][CH3:26])(=[O:23])[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]>O1CCCC1.ClC(Cl)(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[CH3:1][CH:2]([CH2:5][CH2:6][C:7]1[C:12]([CH3:14])([CH3:13])[CH2:11][CH2:10][CH2:9][C:8]=1[CH3:15])[CH:3]=[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:16]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CC1=C(CCC(C)C=O)C(C)(C)CCC1
Reactant: CCOC(=O)CC(=O)OCC
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: CCOC(=O)C(=CC(C)CCC1=C(C)CCCC1(C)C)C(=O)OCC

Procedure:
Under the conditions described in example 1, titanium(IV) chloride (91 g, 0.5 mol), 2-methyl-4-(2,6,6-trimethylcyclohex-1-enyl)butanal 4 (50 g, 0.24 mol) and diethyl malonate (39.7 g, 0.24 mol) in tetrahydrofuran and tetrachloromethane are reacted which each other to give after work-up and short-path-distillation 70.1 g (83%) of 3b. Analytical data: 1H-NMR (400 MHz, CDCl3): δ 0.97 (s, 6 H), 1.1 (d, 3 H), 1.25-1.6 (6 H), 1.3 (2t, 6 H), 1.58 (s, 3 H), 1.8-2.0 (2 H), 2.55 (m, 1 H), 4.15-4.35 (2q, 4 H), 6.8 (d, 1 H) ppm. 13C-NMR (400 MHz, CDCl3): δ 14.0 (q), 14.15 (q), 19.5 (t), 19.6 (q), 19.8 (q), 26.5 (t), 28.5 (q), 32.7 (t), 34.85 (s), 35.6 (d), 36.9 (t), 39.8 (t), 61.1 (t), 61.15 (t), 127.0 (s), 127.5 (s), 136.9 (s), 153.9 (d), 164.0 (s), 165.7 (s). MS (EI): m/z (%) 350 (M+, 4), 335 ([M-15]+, 3), 305 (4), 289 (5), 259 (9), 243 (11), 215 (8), 200 (98), 190 (18), 187 (11), 175 (16), 173 (27), 167 (18), 154 (100), 135 (30), 123 (42), 122 (30), 121 (39), 109 (19), 108 (60), 107 (32), 105 (19), 95 (52), 93 (34), 91 (25), 81 (40), 79 (30), 77 (15), 69 (21), 67 (26), 55 (36), 41 (32), 29 (28). JR (film): 2950 (m), 2960 (m), 2930 (m), 2862 (m), 1725 (s), 1645 (w), 1455 (m), 1375 (m), 1325 (w), 1250 (s), 1222 (s), 1205 (s), 1180 (m), 1170 (m), 1100 (m), 1050 (m), 1030 (m), 950 (w), 865 (w), 800 (w), 765 (w).
Reaction SMILES: Cl.[C:2]([CH2:8][NH2:9])(=[O:7])[CH2:3][CH:4]([CH3:6])[CH3:5].C(=O)(O)[O-].[Na+].[F:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1>>[F:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([NH:9][CH2:8][C:2](=[O:7])[CH2:3][CH:4]([CH3:6])[CH3:5])=[O:21])=[CH:18][CH:17]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CC(C)CC(=O)CN
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(C)CC(=O)CNC(=O)c1ccc(F)cc1
Yield: 93 %

Procedure:
2.75 g of isovalerylmethylamine hydrochloride, 3.8 g of sodium bicarbonate and 3.16 g of 4-fluorobenzoyl chloride are treated in the same manner as described in Preparation 1-(4). 4.0 g of N-(4-fluorobenzoyl)isovalerylmethylamine are thereby obtained. Yield: 82.9%.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[C:8]([S:10]([Cl:13])(=[O:12])=[O:11])[CH:7]=[CH:6][C:5]=1[C:14]1[NH:15][C:16]2[C:17]([N:22]=1)=[N:18][CH:19]=[CH:20][CH:21]=2.COC1C=C(S(Cl)(=O)=O)C=CC=1C(O)=O.[CH3:38][NH:39][CH3:40]>>[ClH:13].[CH3:2][O:3][C:4]1[CH:9]=[C:8]([S:10]([N:39]([CH3:40])[CH3:38])(=[O:12])=[O:11])[CH:7]=[CH:6][C:5]=1[C:14]1[NH:15][C:16]2[C:17]([N:22]=1)=[N:18][CH:19]=[CH:20][CH:21]=2
Reactant: CNC
Reactant: COc1cc(S(=O)(=O)Cl)ccc1-c1nc2ncccc2[nH]1
Agent: COc1cc(S(=O)(=O)Cl)ccc1C(=O)O
Agent: Cl
Product: COc1cc(S(=O)(=O)N(C)C)ccc1-c1nc2ncccc2[nH]1
Temperature: 0 °C

Procedure:
The crude 2-(2'-methoxy-4'-chlorosulfonyl-phenyl)-imidazo[4,5-b]pyridine hydrochloride prepared from 2.5 gm of 2-methoxy-4-chlorosulfonyl-benzoic acid according to Example C was added to 150 ml of a saturated aqueous dimethylamine solution at 10° C., under stirring, and a light-colored precipitate formed slowly. After stirring for 20 hours at ambient temperature, 200 ml of ice water were added. The precipitate was dried and then taken up in 60 ml of methanol, and 10 ml of methanolic hydrochloric acid were added. After filtering over active charcoal, the solvent was eliminated, and the residue remaining was digested with acetone and ether, subjected to suction filtration, and washed with ether.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[CH3:38][N:39]([CH3:45])[CH:40]1[CH2:44][CH2:43][NH:42][CH2:41]1>>[CH3:38][N:39]([CH3:45])[CH:40]1[CH2:44][CH2:43][N:42]([C:21]2[N:20]=[C:19]([O:18][C:11]3[C:12]4[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:8]([NH:7][C:5](=[O:6])[C:4]4[CH:29]=[C:30]([N:32]5[CH2:37][CH2:36][O:35][CH2:34][CH2:33]5)[CH:31]=[C:2]([F:1])[CH:3]=4)=[CH:9][CH:10]=3)[CH:24]=[CH:23][N:22]=2)[CH2:41]1
Reactant: CN(C)C1CCNC1
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)c3ccccc23)n1
Product: CN(C)C1CCN(c2nccc(Oc3ccc(NC(=O)c4cc(F)cc(N5CCOCC5)c4)c4ccccc34)n2)C1

Procedure:
Compound is prepared from 3-fluoro-N-(4-{[2-(methylsulfonyl)pyrimidin-4-yl]oxy}-1-naphthyl)-5-morpholin-4-ylbenzamide and dimethyl-pyrrolidin-3-yl-amine according to conditions described in general procedure C. Mp: 106-108° C.; 1H NMR (400 MHz, DMSO-d6) δ 2.07-2.17 (m, 10 H), 2.45-3.15 (m, 3 H), 3.27 (t, J=4.4 Hz, 4 H), 3.77 (t, J=5.1 Hz, 4H), 6.15 (m, 1 H), 7.05 (d, J=12.1 Hz, 1 H), 7.27 (d, J=9.5 Hz, 1 H), 7.42-7.62 (m, 5 H), 7.85-7.87 (m, 1 H), 8.00 (d, J=7.7 Hz, 1 H), 8.23 (d, J=5.5 Hz, 1 H), 10.47 (s, 1 H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].Br[C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[CH2:30][OH:31]>>[F:15][C:12]([F:14])([F:13])[C:11]1[N:6]2[N:5]=[CH:4][C:3]([C:1]#[C:2][C:27]3[CH:28]=[C:29]([CH2:30][OH:31])[CH:32]=[CH:33][CH:34]=3)=[C:7]2[N:8]=[C:9]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH:10]=1
Reactant: OCc1cccc(Br)c1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: OCc1cccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (355 g, 1.0 mmol) and commercially available 3-bromobenzyl alcohol (243 mg, 1.3 mmol) according to general procedure II. Obtained as a brown solid (60 mg, 13%). MS (ISP) 462.2 [(M+H)+]; mp 177° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH2:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([CH2:11][CH:12]3[CH2:21][CH2:20][C:15]4(OCC[O:16]4)[CH2:14][CH2:13]3)[C:4]=2[O:3]1.O>C(O)(=O)C>[CH3:1][C:2]1([CH3:22])[CH2:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([CH2:11][CH:12]3[CH2:21][CH2:20][C:15](=[O:16])[CH2:14][CH2:13]3)[C:4]=2[O:3]1
Reactant: CC1(C)Cc2cccc(CC3CCC4(CC3)OCCO4)c2O1
Solvent: CC(=O)O
Solvent: O
Product: CC1(C)Cc2cccc(CC3CCC(=O)CC3)c2O1

Procedure:
This compound is prepared in a manner analogous to that of Step D of Example 2, using 5.4 grams (0.018 mole) of 8-(2,3-dihydro-2,2-dimethylbenzofuran-7-ylmethyl)-1,4-dioxaspiro[4.5]decane and 25 mL of water in 100 mL of acetic acid, yielding 4-(2,3-dihydro-2,2-dimethylbenzofuran-7-ylmethyl)cyclohexanone.
Reaction SMILES: Cl[C:2]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[Cl:17])[C:7]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:6][C:3]=1[C:4]#[N:5].C([O-])([O-])=O.[Cs+].[Cs+].[F:31][C:32]1[CH:37]=[CH:36][C:35]([SH:38])=[CH:34][CH:33]=1>C1(C)C=CC=CC=1>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([C:7]2[C:8]([C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=3[Cl:17])=[N:9][C:2]([S:38][C:35]3[CH:36]=[CH:37][C:32]([F:31])=[CH:33][CH:34]=3)=[C:3]([CH:6]=2)[C:4]#[N:5])=[CH:19][CH:20]=1
Reactant: N#Cc1cc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)nc1Cl
Reactant: Fc1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Product: N#Cc1cc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)nc1Sc1ccc(F)cc1
Temperature: 100 °C

Procedure:
An oven-dried round bottom flask was charged with 60.0 mg (0.152 mmol) of the product of Example 36 and Cs2CO3 (250.0 mg, 0.767 mmol), toluene (1.0 mL) and 4-fluorobenzene thiol (97.5 mg, 0.761 mmol) were added sequentially. The reaction was heated to 100° C. for 23 hours and then allowed to cool to room temperature at which point the reaction was filtered and concentrated. The residue was purified by preparative thin layer chromatography (20 cm×20 cm, 1000 μm, silica gel) eluting with 10:90 EtOAc-hexane affording a white solid). MS (electrospray) m/e 487 MH+.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[CH3:32][O:33][C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1>>[CH3:32][O:33][C:34]1[CH:39]=[CH:38][C:37]([C:12]2[N:13]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:14]=[C:15]3[C:11]=2[CH2:10][CH2:9][NH:8][CH2:17][CH2:16]3)=[CH:36][CH:35]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CCc2nn(-c3ccccc3)c(OS(=O)(=O)C(F)(F)F)c2CC1
Product: COc1ccc(-c2c3c(nn2-c2ccccc2)CCNCC3)cc1
Yield: 31.8 %

Procedure:
The title compound (43.6 mg) was prepared from 198.3 mg of 2-phenyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 176, Step B) and 94.7 mg of 4-methoxyphenylboronic acid as described in Example 199. MS (ESI): exact mass calculated for C20H21N3O, 319.17. found, m/z 320.2 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.28-7.24 (m, 2H), 7.21-7.17 (m, 3H), 7.07 (d, J=8.8 Hz, 2H), 6.87 (d, J=8.8 Hz, 2H), 3.81 (s, 3H), 3.11-3.08 (m, 2H), 3.04-3.01 (m, 2H), 3.00-2.97 (m, 2H), 2.68-2.65 (m, 2H).
Reaction SMILES: [ClH:1].[C:2]1([N:8]2[C:12]3([CH2:17][CH2:16][N:15]([CH:18]4[C:27]5[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=5)[CH2:21][CH2:20][CH2:19]4)[CH2:14][CH2:13]3)[C:11](=[O:28])[NH:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29]I>>[ClH:1].[CH3:29][N:10]1[C:11](=[O:28])[C:12]2([CH2:17][CH2:16][N:15]([CH:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:21][CH2:20][CH2:19]3)[CH2:14][CH2:13]2)[N:8]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9]1
Reactant: O=C1NCN(c2ccccc2)C12CCN(C1CCCc3ccccc31)CC2
Reactant: CI
Agent: Cl
Product: CN1CN(c2ccccc2)C2(CCN(C3CCCc4ccccc43)CC2)C1=O

Procedure:
The title compound, m.p. 232-234° C. was prepared in accordance with the general method of example 4 from 1-phenyl-8-(1,2,3,4-tetrahydro-1-naphthyl)-1,3,8-triaza-spiro[4.5]decan-4-one hydrochloride (1:1) and methyl iodide.
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:20])[NH:6][C:7](=[O:19])[NH:8][C:9]=1[S:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].C1(C)C(S(O[CH:31]2[CH2:35][CH2:34][CH2:33][CH2:32]2)(=O)=O)=CC=CC=1.[C:37](=O)(O)[O-].[Na+]>CN(C)C=O>[CH:31]1([CH2:37][N:8]2[C:9]([S:10][C:11]3[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=3)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:20])[NH:6][C:7]2=[O:19])[CH2:32][CH2:33][CH2:34][CH2:35]1
Reactant: Cc1cc(C)cc(Sc2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Reactant: Cc1ccccc1S(=O)(=O)OC1CCCC1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(C)cc(Sc2c(C(C)C)c(=O)[nH]c(=O)n2CC2CCCC2)c1
Yield: 50.3 %

Procedure:
A mixture of 5-isopropyl-6-(3,5-dimethylphenylthio)-2,4-pyrimidinedione (0.10 g, 0.40 mmol) and cyclopentyl toluenesulfonate (0.1 g, 0.4 mmol) in dimethylformamide (10 ml) were heated at 100° C. for overnight in the presence of sodium bicarbonate (41 mg, 0.48 mmol). After the concentration of dimethylformamide, the desirable product was obtained by the separation of the column chromatography to give a desirable product as a white solid (75 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[NH:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:5]([OH:7])=[O:6].Cl.[N:17]([O-])=O.[Na+]>O>[CH2:12]([N:11]1[C:10]2[CH:9]=[CH:8][C:4]([C:5]([OH:7])=[O:6])=[CH:3][C:2]=2[N:1]=[N:17]1)[CH2:13][CH2:14][CH3:15]
Reactant: O=N[O-]
Reactant: CCCCNc1ccc(C(=O)O)cc1N
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CCCCn1nnc2cc(C(=O)O)ccc21
Yield: 72.6 %

Procedure:
To a stirred and cooled mixture of 43.7 parts of 3-amino-4-(butylamino)benzoic acid and 200 parts of a hydrochloric acid solution 6N was added dropwise a solution of 22 parts of sodium nitrite in a small amount of water. Upon complete addition, the reaction mixture was stirred for 4 hours at 10°-20° C. The product was filtered off, washed with 30 parts of water and crystallized from a mixture of 2-propanone and ethyl acetate. The product was filtered off and dried, yielding 33.3 parts (72.6%) of 1-butyl-1H-benzotriazole-5-carboxylic acid; mp. 192.5° C. (int. 9).
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)[N:15]=1)#[N:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:27][C:24]1[CH:23]=[CH:22][C:21]([S:20][C:16]2[N:15]=[C:14]([C:12]3[S:4][C:3]4[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=4[C:1](=[O:10])[N:13]=3)[CH:19]=[CH:18][CH:17]=2)=[CH:26][CH:25]=1
Reactant: Cc1ccc(Sc2cccc(C#N)n2)cc1
Reactant: COC(=O)c1ccccc1S
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1ccc(Sc2cccc(-c3nc(=O)c4ccccc4s3)n2)cc1
Yield: 12.5 %

Procedure:
A mixture of methyl thiosalicylate (0.37 g, 2.2 mmol), 2-cyano-6-(4-methylphenyl)thiopyridine (0.50 g, 2.2 mmol), triethylamine (0.46 ml, 3.3 mmol) and toluene (30 ml) was refluxed for 48 hrs as described in Example 1. The solvent was concentrated under reduced pressure. The residue was recrystallized from ethanol to give the titled compound (0.10 g, 13%) as crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[C:5]([Cl:7])[S:4][C:3]=1[CH:8]1[CH2:17][C:16]2[N:15]=[CH:14][CH:13]=[C:12]([CH3:18])[C:11]=2[C:10](=O)[CH2:9]1.[C:20]([NH:23][NH2:24])([NH2:22])=[NH:21].Cl.Cl.O>C(O)C>[ClH:1].[Cl:1][C:2]1[CH:6]=[C:5]([Cl:7])[S:4][C:3]=1[CH:8]1[CH2:17][C:16]2[N:15]=[CH:14][CH:13]=[C:12]([CH3:18])[C:11]=2[C:10](=[N:24][NH:23][C:20]([NH2:22])=[NH:21])[CH2:9]1
Reactant: N=C(N)NN
Reactant: Cc1ccnc2c1C(=O)CC(c1sc(Cl)cc1Cl)C2
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1ccnc2c1C(=NNC(=N)N)CC(c1sc(Cl)cc1Cl)C2
Yield: 123.4 %

Procedure:
A mixture of 7-(3,5-dichlorothiophen-2-yl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (0.5 g), aminoguanidine hydrochloride (0.21 g), concentrated hydrochloric acid (0.4 ml), water (0.4 ml) and ethanol (15 ml) was refluxed for 4 hours. Under reduced pressure, the solvent was evaporated. To the residue was added water, and the mixture was washed with ethyl acetate. Under reduced pressure, the solvent was evaporated, and the residue was recrystallized from water. The resulting crystals were washed with ethanol to give 7-(3,5-dichlorothiophen-2-yl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 121) (0.40 g) as colorless crystals.
Reaction SMILES: [C:1](Cl)(=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][S:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](Cl)=[O:13].[NH2:21][C:22]1[CH:26]=[CH:25][S:24][C:23]=1[C:27]([O:29][CH3:30])=[O:28]>ClCCl.N1C=CC=CC=1>[C:11]1([C:12]([NH:21][C:22]2[CH:26]=[CH:25][S:24][C:23]=2[C:27]([O:29][CH3:30])=[O:28])=[O:13])[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=1[S:9][S:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:1]([NH:21][C:22]1[CH:26]=[CH:25][S:24][C:23]=1[C:27]([O:29][CH3:30])=[O:28])=[O:19]
Reactant: COC(=O)c1sccc1N
Reactant: O=C(Cl)c1ccccc1SSc1ccccc1C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1sccc1NC(=O)c1ccccc1SSc1ccccc1C(=O)Nc1ccsc1C(=O)OC
Temperature: 23 °C
Reaction time: 18 h
Yield: 59 %

Procedure:
A solution of 2,2'-dithiobisbenzoyl chloride (2.00 g, 5.83 mmol) in 50 mL of dichloromethane was added to a solution of methyl 3-amino-2-thiophenecarboxylate (1.82 g, 11.6 mmol) in 14 mL of pyridine at 23° C. The reaction mixture was stirred for 18 hours at 23° C. under nitrogen atmosphere. The precipitate formed was collected by filtration, then triturated with 5% aqueous HCl and washed with water to yield the crude product. The crude material was recrystallized first from ethanol, then from acetonitrile-DMF to yield 2.0 g of the title compound, mp 250°-252° C.