Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:3][CH:4]=[CH:5][C:6]=1[SH:7].[CH2:8]([SH:15])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C(=O)([O-])[O-].[Na+].[Na+].II>C(OCC)C.O>[CH2:8]([S:15][S:7][C:6]1[CH:5]=[CH:4][O:3][C:2]=1[CH3:1])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: Cc1occc1S
Reactant: CCCCCCCS
Agent: II
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: CCCCCCCSSc1ccoc1C
Reaction time: 0.33 h

Procedure:
0.57 Grams (0.0050 moles) of 2-methyl-3-furanthiol and 1.32 grams (0.01 moles) of n-heptylmercaptan are dissolved in 12 ml of diethyl ether. 0.8 Grams (0.0075 moles) of sodium carbonate dissolved in 8 ml water is added to the reaction mass. Over a period of 20 minutes, a solution of 1.9 grams (0.0075 moles) of iodine dissolved in 6 ml diethyl ether is added to the reaction mass with stirring until the iodine color remains. The reaction mass is then stirred over a period of 35 minutes.
Reaction SMILES: O[C:2]1[C:6]2[CH:7]=[CH:8][C:9]([O:11][CH3:12])=[CH:10][C:5]=2[O:4][N:3]=1.O=P(Cl)(Cl)Cl.[NH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>C(N(CC)CC)C>[CH3:12][O:11][C:9]1[CH:8]=[CH:7][C:6]2[C:2]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[N:3][O:4][C:5]=2[CH:10]=1
Reactant: C1CNCCN1
Reactant: COc1ccc2c(O)noc2c1
Solvent: CCN(CC)CC
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc2c(N3CCNCC3)noc2c1
Temperature: 30 °C

Procedure:
Prepare 4-(6-methoxybenzo[d]isoxzaol-3-yl)piperazine by slowly adding a solution of hydroxylamine hydrochloride (57.2 g, 0.823 mol) and water (600 mL) to a solution of sodium hydroxide (76.9 g, 1.92 mol) and water (300 mL). Then add a solution of methyl 4-methoxysalicylate (100 g, 0.55 mol, Aldrich Chemical Co.) and ether (800 mL), stir overnight, evaporate the ether, acidify with dilute hydrochloric acid, cool to 0° C., and filter. Recrystallize the filter cake from methanol to afford the 2-hydroxy-p-anisohydroxamic acid (78 g). Treat a warm (50° C.) solution of the hydroxamic acid (78 g) and tetrahydrofuran (500 mL) under nitrogen with a solution of carbonyldiimidazole (138.1 g, 0.85 mol) and tetrahydrofuran (500 mL), reflux for 3.5 hours, quench by addition of water (1000 mL), acidify to pH 3, add water (1000 mL) and refrigerate overnight. Collect the solid, wash with water and recrystallize from methanol to afford 54 g of 3-hydroxy-6-methoxy-1,2-benzisoxazole. Heat a stirred mixture of 3-hydroxy-6-methoxy-1,2-benzisoxazole (54 g) and POCl3 (100.3 g, d 1.645) at 95° C. under nitrogen, cool to 30° C., add triethylamine (33 g), heat at 140° C. overnight, quench with stirring into ice water and filter. Dissolve the filter cake in cyclohexane (2000 mL), filter, concentrate and recrystallize the residue from petroleum ether to give 3-chloro-6-methoxy-1,2-benzisoxzole (33 g). Treat this product with piperazine as described in U.S. Pat. No. 5,852,022, the contents of which are herein incorporated by reference, to afford 6-methoxy-3-(1-piperazinyl)-1,2-benzisoxazole.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[OH:10].F[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[O:10][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1
Reactant: COc1ccc(C)c(O)c1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(C)c(Oc2ccc([N+](=O)[O-])cc2)c1
Yield: 96.4 %

Procedure:
To a solution of 2-methyl-5-(methyloxy)phenol (Intermediate 12, 1.5 g) and 1-fluoro-4-nitrobenzene (1.4 g, 10.0 mmol) in acetonitrile (100 mL) was added potassium carbonate (2.1 g, 15.2 mmol) and the mixture was stirred at reflux for 5 hours. The resulting mixture was concentrated and partitioned between ethyl acetate (3 times 30 mL) and water (100 mL). The combined ethyl acetate layers were dried over sodium sulphate, filtered and concentrated under vacuum. The crude product thus obtained was purified by column chromatography on silica gel (EtOAc: PE=1:20) to afford the title compound as a solid (2.5 g).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:7][C:8]([Cl:12])=[N:9]2)=[CH:4][CH:3]=1.[CH3:19][S:20]([C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1)(=[O:22])=[O:21].C(=O)([O-])[O-].[Na+].[Na+].CN(C=O)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[Cl:12][C:8]1[N:7]=[C:6]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[C:10](=[CH:11][C:2]([C:27]3[CH:26]=[CH:25][CH:24]=[C:23]([S:20]([CH3:19])(=[O:22])=[O:21])[CH:28]=3)=[CH:3][CH:4]=2)[N:9]=1
Reactant: Clc1nc(N2CCOCC2)c2ccc(Br)cc2n1
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)(=O)c1cccc(-c2ccc3c(N4CCOCC4)nc(Cl)nc3c2)c1
Temperature: 95 °C
Reaction time: 2 h
Yield: 55 %

Procedure:
To a 50 mL round bottom flask, 7-bromo-2-chloro-4-morpholin-4-yl-quinazoline (0.65 g, 0.0019 mol), 3-methylsulfonylphenylboronic acid (0.35 g, 0.0018 mol), sodium carbonate (0.314 g, 0.0029 mol), DMF (25 mL) and water (6 mL) were added and degassed the reaction vessel with nitrogen for 5-10 min. To the same reaction mixture, Pd(PPh3)2Cl2 (0.069 g, 0.00099 mol) was added and again degassed with nitrogen for 5-10 min. The reaction mixture was stirred at 95° C. for 2 h. The reaction mixture was cooled and diluted with ethyl acetate. The organic layer was washed with water, brine and dried over sodium sulfate. The solvent was removed under reduced pressure to afford the crude product. The crude product was purified; using column chromatography (60-120 silica gel, 50% ethyl acetate in hexane) to yield the desired product [400 mg, 80%]. LC-MS (ESI): Calculated mass: 403.1; Observed mass: 404.0 [M+H]+ (RT: 1.36 min).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]2[O:6][C:7]3[CH:19]=[CH:18][CH:17]=[CH:16][C:8]=3[C@H:9]3[CH2:13][N:12]([CH3:14])[C:11](=[O:15])[C@H:10]3[C:4]=2[CH:3]=1.[OH-].[K+].C(OCC)(=[O:26])C>C(O)C>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]2[O:6][C:7]3[CH:19]=[CH:18][CH:17]=[CH:16][C:8]=3[C@@H:9]([CH2:13][NH:12][CH3:14])[C@H:10]([C:11]([OH:15])=[O:26])[C:4]=2[CH:3]=1
Reactant: CCOC(C)=O
Reactant: CN1C[C@@H]2c3ccccc3Oc3ccc(Cl)cc3[C@@H]2C1=O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CNC[C@@H]1c2ccccc2Oc2ccc(Cl)cc2[C@H]1C(=O)O
Yield: 52 %

Procedure:
To a solution of cis-1′-chloro-2,3,3a,12b-tetrahydro-2-methyl-1H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrol-1-one (V) (2 gram, 6.7 mmol) in ethanol (20 mL), was added potassium hydroxide (3.8 g, 67 mmol). The reaction mixture was heated to reflux for 5 hours. The reaction mixture was evaporated and water was added (50 mL). The water phase was washed with diethyl ether (2×25 mL). The aqueous phase was acidified with concentrated hydrochloric acid to a pH between 5 and 6, resulting in a gum precipitate. Ethyl acetate was added (25 mL), which slowly dissolved the gum and resulted in the formation of fine crystals of the product. The crystals were filtered and dried to give trans-8-chloro-10,11-dihydro-11-[(methylamino)-methyl]-dibenz[b,f]oxepin-10-carboxylic acid (I) (1.1 g, 52%); mp 154.4° C.; 1H-NMR (399.87 MHz in MeOD relative to TMS) δ 2.09 (s, 3H), 2.45 and 2.66 (2×m, 2H), 3.23 (s, 1H), 3.50 (m, 1H), 3.92 (d, 1H), 6.96-7.20 (m, 6H).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.N1C=CC=CC=1.Cl[C:14]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:15].C(=O)(O)[O-].[Na+]>ClCCl>[S:3]1[CH:4]=[CH:5][N:6]=[C:2]1[NH:1][C:14](=[O:15])[O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Nc1nccs1
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1nccs1)Oc1ccccc1
Reaction time: 0.5 h
Yield: 75 %

Procedure:
To a stirred mixture of 2-aminothiazole (2 g, 20 mmol), pyridine (10 mL), and anhydrous dichloromethane (20 mL) was added phenyl chloroformate (3 mL, 24 mmol) under argon at 0° C. The mixture was stirred at the same temperature for 5 min and at rt overnight before saturated aqueous sodium bicarbonate solution (30 mL) was added slowly. After mixed with heptanes (30 mL), the mixture was stirred for 30 min. The solid was filtered, washed with water (3×3 mL) and then diethylether (3×3 mL), and dried to give phenyl thiazol-2-ylcarbamate (3.4 g, 15 mmol, 75% yield) as an off-white solid.
Reaction SMILES: [NH2:1][C:2]1[O:3][CH2:4][C@@:5]2([N:22]=1)[C:18]1[CH:17]=[C:16]([OH:19])[CH:15]=[C:14]([F:20])[C:13]=1[O:12][C:11]1[C:6]2=[CH:7][C:8](Br)=[CH:9][CH:10]=1.C([Sn](CCCC)(CCCC)[C:28]1[CH:33]=[N:32][CH:31]=[CH:30][N:29]=1)CCC>CN(C=O)C.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[O:3][CH2:4][C@@:5]2([N:22]=1)[C:18]1[CH:17]=[C:16]([OH:19])[CH:15]=[C:14]([F:20])[C:13]=1[O:12][C:11]1[C:6]2=[CH:7][C:8]([C:28]2[CH:33]=[N:32][CH:31]=[CH:30][N:29]=2)=[CH:9][CH:10]=1
Reactant: NC1=N[C@@]2(CO1)c1cc(Br)ccc1Oc1c(F)cc(O)cc12
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: NC1=N[C@@]2(CO1)c1cc(-c3cnccn3)ccc1Oc1c(F)cc(O)cc12
Temperature: 110 °C

Procedure:
Pd(PPh3)4 (0.506 g, 0.438 mmol), (S)-2-amino-7′-bromo-4′-fluoro-5H-spiro[oxazole-4,9′-xanthen]-2′-ol (1.6 g, 4.38 mmol), and 2-(tributylstannyl)pyrazine (2.426 g, 6.57 mmol) were combined in 10 ml of DMF and heated in the microwave at 110° C. for two hours. The solution was diluted with ethyl acetate (50 mL) and washed twice with water. The organic layer was washed with brine and dried over anhydrous sodium sulfate, filtered and concentrated. The product was purified via silica gel column chromatography (RediSep 40 g column) using 10-100% 90/10/1 (CH2Cl2/MeOH/ammonia) in CH2Cl2 to afford (S)-2-amino-4′-fluoro-7′-(pyrazin-2-yl)-5H-spiro[oxazole-4,9′-xanthen]-2′-ol as a white solid. MS m/z=365.0 [M+H].
Reaction SMILES: [I:1][CH2:2][C:3]([NH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[O:4].[B-](F)(F)(F)F.CN(C(O[N:33]1[C:38](=[O:39])[CH2:37][CH2:36][C:34]1=[O:35])=[N+](C)C)C.CCN(C(C)C)C(C)C.Cl>C1COCC1>[O:35]=[C:34]1[CH2:36][CH2:37][C:38](=[O:39])[N:33]1[O:18][C:17](=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][NH:5][C:3](=[O:4])[CH2:2][I:1]
Reactant: O=C(O)CCCCCCCCCCCNC(=O)CI
Reactant: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(CI)NCCCCCCCCCCCC(=O)ON1C(=O)CCC1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 12-(2-Iodoacetylamino)dodecanoic acid (460 mg) in THF (10 ml) was added TSTU (415 mg) and DIPEA (0.315 ml). After stirring at room temperature for 2 h, the mixture was pored in to 0.5 N HCl (200 ml) and was extracted with ethyl acetate (2×200 ml). The combined organic layers was washed with 0.1 N HCl and brine, dried with magnesium sulphate and concentrated. The residue was used without further purification. Yield, 99% (575 mg). LC-MS, M/z: 481.2 (M+1).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[O:22][C@H:21]([CH2:23]O)[C@@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:6]1[O:7][C:8](=[O:10])[CH3:9])(=[O:3])[CH3:2].C(N(CC)CC)C.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>ClCCl>[C:1]([O:4][C@@H:5]1[O:22][C@H:21]([CH2:23][S:33]([CH3:32])(=[O:35])=[O:34])[C@@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:6]1[O:7][C:8](=[O:10])[CH3:9])(=[O:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)O[C@@H]1O[C@H](CO)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)O[C@@H]1O[C@H](CS(C)(=O)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.8 %

Procedure:
In a 100 mL round bottom flask containing 50 mL dichloromethane at 0° C. was placed 1,2,3,4-tetra-O-acetyl-β-D-glucopyranose (4.62 g, 13.26 mmol). To this solution was added triethylamine (2.77 mL, 19.90 mmol) followed by dropwise addition of methanesulfonyl chloride (1.23 mL, 15.9 mmol). The reaction was then warmed to room temperature and stirred for 3 hours at which time the reaction was diluted with 100 mL dichloromethane. The organic layer was then washed two times each with 50 mL of water, 1N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate and brine. The organic layer was dried over magnesium sulfate, filtered and the solvent removed in vacuo to yield 4.45 g of crude title compound as a white solid which was used directly in Preparation 2. (79%).
Reaction SMILES: [Cl:1][C:2]1[C:10]([CH3:11])=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.Cl.[NH:13]1[CH2:16][CH2:15][CH2:14]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.Cl>ClCCl>[N:13]1([C:6]([C:5]2[CH:9]=[C:10]([CH3:11])[C:2]([Cl:1])=[N:3][CH:4]=2)=[O:8])[CH2:16][CH2:15][CH2:14]1
Reactant: Cc1cc(C(=O)O)cnc1Cl
Reactant: C1CNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(C(=O)N2CCC2)cnc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.9 %

Procedure:
Commercially available 6-chloro-5-methylnicotinic acid (200 mg, 1.29 mmol) was dissolved in dichloromethane (7.0 mL), and azetidine hydrochloride (160 mg, 1.71 mmol), HATU (1000 mg, 2.63 mmol) and N,N-diisopropylethylamine (0.69 mL, 3.96 mmol) were added, followed by stirring at room temperature overnight under nitrogen atmosphere. 0.5N hydrochloric acid (30 mL) was added, and extraction was carried out with dichloromethane (30 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=60%-75%) to afford the desired compound (160 mg, yield 64%) as a colorless liquid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=O.[NH2:12][C:13]1[CH:14]=[C:15]2[C:19]3=[C:20]([CH2:22][O:23][CH2:24][CH2:25][N:18]3[C@H:17]3[CH2:26][CH2:27][N:28](C(OC(C)(C)C)=O)[CH2:29][C@@H:16]23)[CH:21]=1>>[CH3:11][O:10][C:9]1[CH:8]=[CH:7][C:4]([CH2:5][NH:12][C:13]2[CH:14]=[C:15]3[C:19]4=[C:20]([CH2:22][O:23][CH2:24][CH2:25][N:18]4[C@H:17]4[CH2:26][CH2:27][NH:28][CH2:29][C@@H:16]34)[CH:21]=2)=[CH:3][C:2]=1[CH3:1]
Reactant: COc1ccc(C=O)cc1C
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(N)cc3c1N2CCOC3
Product: COc1ccc(CNc2cc3c4c(c2)[C@@H]2CNCC[C@@H]2N4CCOC3)cc1C

Procedure:
Using 3-methyl-4-methoxybenzaldehyde and following the procedures described in EXAMPLE 126, tert-butyl (7bR,11aS)-6-amino-1,2,7b,10,11,11a-hexahydro-4H-[1,4]oxazepino[6,5,4-hi]pyrido[4,3-b]indole-9(8H)-carboxylate from EXAMPLE 56, Part B was converted into the title compound of EXAMPLE 136. 1H NMR(CDCl3) δ: 7.18-7.10 (m, 2H), 6.78 (d, 1H, J=9.2 Hz), 6.42 (d, 1H, J=1.9 Hz), 6.25 (d, 1H, J=2.2 Hz), 4.59 (ABq, 2H, JAB=14.1 Hz), 4.20-4.10 (m, 1H), 4.13 (s, 2H), 3.83 (s, 3H), 3.74 (app t, 1H), 3.30-3.23 (m, 1H), 3.22-3.10 (m, 2H), 3.09-3.01 (m, 1H), 2.95-2.88 (m, 2H), 2.62 (app t, 1H), 2.48 (app t, 1H), 2.21 (s, 3H), 2.00-1.80 (m, 2H). LRMS (ES)+: 380.4 (M+H)+.
Reaction SMILES: [O:1]1[C@H:3]2[CH:4]=[C:5]3[C@@H:21]([C@@:22]4([CH3:28])[CH2:23][CH2:24][C@H:25]([OH:27])[CH2:26][C:2]124)[CH2:20][CH2:19][C@@:18]1([CH3:29])[C@H:6]3[CH2:7][CH2:8][C@@H:9]1[C@H:10]([CH3:17])[CH2:11][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15].[NH2:30][CH2:31][CH2:32][C:33]1[N:37]=[CH:36][NH:35][CH:34]=1.C(O)CCC>COC(C)(C)C>[OH:1][C@:2]12[CH2:26][C@@H:25]([OH:27])[CH2:24][CH2:23][C@:22]1([CH3:28])[C@@H:21]1[C:5]([C@H:6]3[C@:18]([CH3:29])([CH2:19][CH2:20]1)[C@@H:9]([C@H:10]([CH3:17])[CH2:11][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:8][CH2:7]3)=[CH:4][C@H:3]2[NH:30][CH2:31][CH2:32][C:33]1[N:37]=[CH:36][NH:35][CH:34]=1
Reactant: NCCc1c[nH]cn1
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2C3=C[C@@H]4OC45C[C@@H](O)CC[C@]5(C)[C@H]3CC[C@]12C
Solvent: CCCCO
Solvent: COC(C)(C)C
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2C3=C[C@@H](NCCc4c[nH]cn4)[C@@]4(O)C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Yield: 18 %

Procedure:
5,6α-epoxicholest-7-en-3β-ol (8.9 g, 22.1 mmol, 1 eq) and histamine (4.9 g, 44.1 mmol, 2 eq) were charged in a round-bottomed flask equipped with a magnetic stirrer bar. 1-Butanol (70 ml, 5 vol) was added and the mixture heated to reflux for 40 h. The reaction mixture was cooled at r.t., diluted with methyl-tertbutyl-ether (5 vol) and washed with water (5 vol) and with brine (5 vol). The organic layer was passed through a silica pad (40 g) eluted with methyl-tertbutyl-ether (3 vol) then 10% Methanol/ethyl acetate (60 vol). Fractions of interest were pooled and the solvent was removed under reduced pressure to give 5α-Hydroxy-6β-[2-(1H-imidazol-4-yl)-ethylamino]-cholest-7-en-3β-ol) as a white solid (7.2 g, 64%). In same conditions, use of ethanol as solvent (40 vol) and Ca(OTf)2 as catalyst gave a 18% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[C:16]([NH:18][CH:19]([CH3:21])[CH3:20])[C:5]([C:6]([NH:8][NH:9][C:10](=O)[C:11]([O:13][CH3:14])=[O:12])=O)=[CH:4][N:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:31])=CC=1>C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:6]2[S:31][C:10]([C:11]([O:13][CH3:14])=[O:12])=[N:9][N:8]=2)=[C:16]([NH:18][CH:19]([CH3:21])[CH3:20])[CH:17]=1
Reactant: COC(=O)C(=O)NNC(=O)c1cnc(Cl)cc1NC(C)C
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1nnc(-c2cnc(Cl)cc2NC(C)C)s1

Procedure:
To a stirred solution of methyl 2-(2-(6-chloro-4-(isopropylamino)nicotinoyl)hydrazinyl)-2-oxoacetate (11) (1 g, 3.1 mmol) in THF (30 mL), Lawesson's reagent (6.3 mmol, 2 equiv) was added and heated to reflux for 3 h. The reaction mixture was diluted with EtOAc and washed twice with 10% NaHCO3 solution. The organic layer was collected, dried over Na2SO4, filtered and concentrated. The crude material obtained was purified by column chromatography through silica gel and MeOH: DCM as eluent afford methyl 5-(6-chloro-4-(isopropylamino)pyridin-3-yl)-1,3,4-thiadiazole-2-carboxylate.
Reaction SMILES: [OH-:1].[Na+].Cl.[Cl-].[CH3:5][O:6][CH2:7][CH2:8][N:9]1[C:13]2[C:14](=[O:23])[C:15]3[C:20]([C:21](=[O:22])[C:12]=2[N+:11]([CH2:24][C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)=[C:10]1[CH3:31])=[CH:19][CH:18]=[CH:17][CH:16]=3.O>C(O)C>[CH3:5][O:6][CH2:7][CH2:8][NH:9][C:13]1[C:14](=[O:23])[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:21](=[O:22])[C:12]=1[N:11]([CH2:24][C:25]1[CH:26]=[CH:27][N:28]=[CH:29][CH:30]=1)[C:10](=[O:1])[CH3:31]
Reactant: [OH-]
Reactant: COCCn1c2c([n+](Cc3ccncc3)c1C)C(=O)c1ccccc1C2=O
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COCCNC1=C(N(Cc2ccncc2)C(C)=O)C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1 M Sodium hydroxide aqueous solution (5.0 ml) was added to a solution of 1-(2-methoxyethyl)-2-methyl-3-(4-pyridylmethyl)-4,9-dihydro-4,9-dioxo-1H-naphtho[2,3-d]imidazol-3-ium chloride monohydrochloride (1.1 g) in ethanol (30 ml) and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine and then dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography (fraction A: elution with ethyl acetate-hexane 1:1 solution, fraction B: elution with ethyl acetate). The fraction A was crystallized from diethyl ether to give N-[3-(2-methoxyethyl)amino-1,4-dihydro-1,4-dioxo-2-naphthalenyl]-N-(4-pyridylmethyl)acetamide (0.2 g) as a red powder. In this connection, the fraction B was crystallized from ethyl acetate to give a yellow powder (0.31 g) which was found to be the same compound, N-(2-methoxyethyl)-N-[3-(4-pyridylmethyl)amino-1,4-dihydro-1,4-dioxo-2-naphthalenyl]acetamide that will be described later in Example 37.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14](=[O:20])[C:15]([O:17]CC)=[O:16])[CH:5]=[CH:4][C:3]1=2.C(O)C.[OH-].[Na+]>O>[CH3:1][C:2]1([CH3:21])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C:14](=[O:20])[C:15]([OH:17])=[O:16])[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)C(=O)c1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC1(C)CCC(C)(C)c2cc(C(=O)C(=O)O)ccc21

Procedure:
16 g (55.6 mmol) of the ester obtained above in (a) and 50 ml of ethyl alcohol are introduced into a round-bottomed flask. A solution of 2.5 g (58.5 mmol) of sodium hydroxide in 50 ml of water is added and the mixture is heated to reflux for one hour. The reaction medium is evaporated to dryness, the residue is taken up with water, the mixture is extracted with ethyl ether, the aqueous phase is separated after settling has taken place, acidified to pH 1 with concentrated hydrochloric acid and extracted with ethyl ether, and the organic phase is separated after settling has taken place, dried over magnesium sulphate and evaporated. 14 g (97%) of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylglyoxylic acid are collected in the form of a colorless oil.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:19](=[O:20])[NH:18][CH2:17][CH2:16][C:15]=2[C:14]=34)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:21][C:22]1[CH:37]=[CH:36][C:25]([O:26]C2C=C(B(O)O)C=CC=2)=[CH:24][CH:23]=1>>[F:21][C:22]1[CH:37]=[CH:36][C:25]([O:26][C:5]2[CH:6]=[C:1]([C:7]3[NH:8][C:9]4[CH:10]=[CH:11][CH:12]=[C:13]5[C:19](=[O:20])[NH:18][CH2:17][CH2:16][C:15]=3[C:14]=45)[CH:2]=[CH:3][CH:4]=2)=[CH:24][CH:23]=1
Reactant: OB(O)c1cccc(Oc2ccc(F)cc2)c1
Reactant: O=C1NCCc2c(-c3ccccc3)[nH]c3cccc1c23
Product: O=C1NCCc2c(-c3cccc(Oc4ccc(F)cc4)c3)[nH]c3cccc1c23

Procedure:
In a manner similar to that described for Compound 12, the tricyclic bromide (200 mg, 0.75 mmol) and 3-(4-fluoro-phenoxy)-phenylboronic acid (213 mg, 0.83 mmol) were coupled to yield 2-[3-(4-fluoro-phenoxy)-phenyl]-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one, 170 mg (60%) as a yellow crystalline solid: m.p. 240-241° C.; 1H NMR (300 MHz, d6-DMSO) δ3.01 (m, 2H), 3.38 (m, 2H), 6.99 (m, 2H), 7.21 (m, 6H), 7.42 (m, 1H), 7.54 (m, 2H), 7.68 (m, 1H), 8.09 (br t, 1H), 11.60 (br s, 1H). MS (FAB, MH+) 373. Anal. (C23H17N2O2 F.0.5 H2O) C, H, N.
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH2:6][CH2:5][N:4]([S:8]([NH2:11])(=[O:10])=[O:9])[CH2:3]1.Cl[C:13]1[CH:18]=[C:17]([O:19][CH3:20])[N:16]=[C:15]([S:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:24]=2[F:30])[N:14]=1>CCOC(C)=O>[F:30][C:24]1[C:25]([F:29])=[CH:26][CH:27]=[CH:28][C:23]=1[CH2:22][S:21][C:15]1[N:14]=[C:13]([NH:11][S:8]([N:4]2[CH2:5][CH2:6][NH:7][C:2](=[O:1])[CH2:3]2)(=[O:10])=[O:9])[CH:18]=[C:17]([O:19][CH3:20])[N:16]=1
Reactant: COc1cc(Cl)nc(SCc2cccc(F)c2F)n1
Reactant: NS(=O)(=O)N1CCNC(=O)C1
Solvent: CCOC(C)=O
Product: COc1cc(NS(=O)(=O)N2CCNC(=O)C2)nc(SCc2cccc(F)c2F)n1

Procedure:
The title compound was prepared from 3-oxopiperazine-1-sulfonamide (the product of step i) (0.22 g) and 4-chloro-2-[[(2,3-difluorophenyl)methyl]thio]-6-methoxypyrimidine (the product of Example 35, step i) (0.25 g) according to the procedure outlined in Example 1, step iv). The crude material was purified by column chromatography using EtOAc/isohexane (1:1) as eluent to give a white solid. This solid was dissolved in EtOAc and Et2O and extracted with 1N sodium hydroxide. The basic solution was washed with Et2O, acidified with dilute hydrochloric acid and extracted with EtOAc. The organic solution was washed with H2O, dried (MgSO4) and the solvent evaporated in vacuo to give the product as a yellow foam.