Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@H:2]([C:10]([OH:12])=O)[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:9])[NH2:8].Cl.Cl.[NH:25]1[CH2:65][CH2:64][CH2:63][C@H:26]1[C:27]([NH:29][C@H:30]([C:42]([N:44]1[CH2:62][CH2:61][CH2:60][C@H:45]1[C:46]([NH:48][C@H:49]([C:57]([NH2:59])=[O:58])[CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)=[O:47])=[O:43])[CH2:31][C:32](=[O:41])[O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:28].CN1CCOCC1.C(P(=O)(OCC)OCC)#N>CC(N(C)C)=O>[NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@H:2]([C:10]([N:25]1[CH2:65][CH2:64][CH2:63][C@H:26]1[C:27]([NH:29][C@H:30]([C:42]([N:44]1[CH2:62][CH2:61][CH2:60][C@H:45]1[C:46]([NH:48][C@H:49]([C:57]([NH2:59])=[O:58])[CH2:50][C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1)=[O:47])=[O:43])[CH2:31][C:32](=[O:41])[O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:28])=[O:12])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:9])[NH2:8]
Reactant: N=C(N)NCCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H]1CCCN1C(=O)[C@H](CC(=O)OCc1ccccc1)NC(=O)[C@@H]1CCCN1
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: CN1CCOCC1
Product: N=C(N)NCCC[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)N[C@@H](Cc1ccccc1)C(N)=O
Reaction time: 4 h

Procedure:
To a stirred solution of Z-Arg.HCl (5.17 g, 15 mmoles) in dimethylacetamide (25 mL) at 25° C. was added a solution of HCl.Pro-Asp(OBzl)-Pro-Phe-NH2 and N-methylmorpholine (1.65 mL, 15 mmoles) in dimethylacetamide (25 mL). To the resulting solution, diethyl cyanophosphonate (2.45 g, 15 mmoles) and N-methylmorpholine (1.65 mL, 15 mmoles) were added and the mixture stirred for 4 hours. The reaction was quenched by the addition of 10% aqueous acetic acid (10 mL) and the solvents were removed on a rotary evaporator under reduced pressure. The resulting solid was triturated with 10% potassium carbonate and then with water and filtered.
Reaction SMILES: [Cl:1][C:2]1[S:6][N:5]=[C:4]([OH:7])[CH:3]=1.[CH:8]([C:10]([CH3:12])=[O:11])=[CH2:9]>C1(C)C=CC=CC=1>[O:11]=[C:10]([CH3:12])[CH2:8][CH2:9][N:5]1[C:4](=[O:7])[CH:3]=[C:2]([Cl:1])[S:6]1
Reactant: Oc1cc(Cl)sn1
Reactant: C=CC(C)=O
Solvent: Cc1ccccc1
Product: CC(=O)CCn1sc(Cl)cc1=O

Procedure:
A solution of 0.5 g (0.0037 mole) of 5-chloro-3-hydroxyisothiazole and methyl vinyl ketone (1.0 g, 0.014 mole) in 15 ml of toluene was heated at 80° C. for 24 hours. After cooling and removal of toluene and excess reagent by rotary evaporation, the residual oil was purified by column chromatography on silica gel, using diethyl ether/methanol (9/1) as eluant. Compound 1 was obtained as an oil; 0.65 g (85%); IR (neat) 1725,1650 cm-1 ; NMR (CDCl3) δ6.25 (s,1H); 4.0 (t,2H); 2.9 (t,2H); 2.2 (s,3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][NH:9][C:10]([NH2:26])=[N:11][C:12](=[O:25])[CH2:13][C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20](OC)[CH:21]=3)[NH:16][CH:15]=2)[CH:5]=[C:4]([Cl:27])[C:3]=1[NH:28]C(=O)C.N1C2C(=CC=CC=2)C(C(C)C(O)=O)=[CH:33]1.ClC1C=C(C=C(Cl)C=1N)CN>>[NH2:28][C:3]1[C:4]([Cl:27])=[CH:5][C:6]([CH2:8][NH:9][C:10]([NH2:26])=[N:11][C:12](=[O:25])[CH:13]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][CH:15]=2)[CH3:33])=[CH:7][C:2]=1[Cl:1]
Reactant: COc1ccc2[nH]cc(CC(=O)N=C(N)NCc3cc(Cl)c(NC(C)=O)c(Cl)c3)c2c1
Reactant: CC(C(=O)O)c1c[nH]c2ccccc12
Agent: NCc1cc(Cl)c(N)c(Cl)c1
Product: CC(C(=O)N=C(N)NCc1cc(Cl)c(N)c(Cl)c1)c1c[nH]c2ccccc12

Procedure:
In a manner similar to that used in the preparation of the compound of example 2, but using 2-(1H-indol-3-yl)propionic acid in step 8 (A) and 3,5-dichloro-4-aminobenzylamine (preparation A) in step 8 (B), the title compound was prepared. MS (ESI) (M+H)+=404.03 1H-NMR (500 MHz, CD3OD) δ 7.55 (d, J=7.93 Hz, 1 H), 7.40 (d, J=7.93 Hz, 1 H), 7.28 (s, 1 H), 7.19 (s, 2 H), 7.12-7.17 (m, 1 H), 7.02-7.08 (m, 1 H), 4.31 (s, 2 H), 4.14 (m, 1 H), 1.63 (d, J=7.02 Hz, 3 H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].C(=O)([O-])[O-].[K+].[K+].[CH2:16](Br)[CH:17]=[CH2:18]>CN(C=O)C>[CH2:18]([O:9][C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Br:1])[CH:17]=[CH2:16]
Reactant: Oc1ccc(Cl)cc1Br
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCOc1ccc(Cl)cc1Br
Temperature: 50 °C
Reaction time: 15 h
Yield: 101.1 %

Procedure:
To a solution of 2-Bromo-4-chlorophenol (7.7897 g, 37.549 mmol) in 20 mL DMF was added potassium carbonate (5.784 g, 41.85 mmol) and allyl bromide (3.30 mL, 38.1 mmol). The reaction mixture was stirred at 50° C. for 15 hours. The reaction mixture was partitioned between ethyl acetate and water, and the organic layer washed with brine, dried over magnesium sulfate, and evaporated in vacuo to yield 9.4 g (100%) of 1-(allyloxy)-2-bromo-4-chlorobenzene, which was carried forward without further purification. 1H NMR (400 MHz, CDCl3) δ: 7.54 (d, J=2.5, 1H), 7.21 (dd, J=8.8, 2.5, 1H), 6.81 (d, J=8.8, 1H), 6.10-5.98 (m, 1H), 5.46 (dd, J=17.3, 1.4, 1H), 5.31 (dd, J=10.6, 1.3, 1H), 4.59 (d, J=5.0, 2H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[CH:3]=[CH:2]1.CCN(C(C)C)C(C)C.Cl[C:20]1[N:25]=[CH:24][N:23]=[C:22]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][C:34]([F:37])([F:36])[F:35])=[CH:29][CH:28]=2)[CH:21]=1>C(O)(CC)C>[N:1]1([C:20]2[N:25]=[CH:24][N:23]=[C:22]([NH:26][C:27]3[CH:28]=[CH:29][C:30]([O:33][C:34]([F:35])([F:36])[F:37])=[CH:31][CH:32]=3)[CH:21]=2)[C:9]2=[N:8][CH:7]=[CH:6][CH:5]=[C:4]2[CH:3]=[CH:2]1
Reactant: FC(F)(F)Oc1ccc(Nc2cc(Cl)ncn2)cc1
Reactant: c1cnc2[nH]ccc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC(C)O
Product: FC(F)(F)Oc1ccc(Nc2cc(-n3ccc4cccnc43)ncn2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 40 %

Procedure:
To a solution of compound 7-azaindole (18 mg, 0.15 mmol) in sec-BuOH (5 mL) was added DIEA (0.20 mL) and the reaction mixture was stirred for 15 min at RT. 6-Chloro-N-(4-(trifluoromethoxy)phenyl)pyrimidin-4-amine (29 mg, 0.1 mmol) was then added and the temperature was raised to 90° C. and continued stirring for another 16 h. The solvent was removed and the title compound was purified by prep. HPLC (15 mg, 40% Yield). MS m/z 372.10 (M+1).
Reaction SMILES: C(=O)(OCC)[O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([Br:22])[CH:20]=3)[NH:15][C:14](=[O:23])[C@@H:13]2[CH2:24][CH3:25])(=[O:11])=[O:10])=[CH:5][CH:4]=1.IC.[CH2:32]([C@@H]1N(S(C2C=CC(O)=CC=2)(=O)=O)C2C(=CC=C(F)C=2)N(CCC)C1=O)C>>[Br:22][C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH3:32])[C:14](=[O:23])[C@H:13]([CH2:24][CH3:25])[N:12]2[S:9]([C:6]1[CH:7]=[CH:8][C:3]([OH:2])=[CH:4][CH:5]=1)(=[O:10])=[O:11]
Reactant: CCOC(=O)Oc1ccc(S(=O)(=O)N2c3cc(Br)ccc3NC(=O)[C@@H]2CC)cc1
Reactant: CCCN1C(=O)[C@H](CC)N(S(=O)(=O)c2ccc(O)cc2)c2cc(F)ccc21
Solvent: CI
Product: CC[C@H]1C(=O)N(C)c2ccc(Br)cc2N1S(=O)(=O)c1ccc(O)cc1

Procedure:
4-{[(2S)-7-Bromo-2-ethyl-3-oxo-3,4-dihydroquinoxalin-1 (2H)-yl]sulfonyl}phenyl ethyl carbonate (see Example 33) was treated with iodomethane according to the procedure for the preparation of (3S)-3-ethyl-6-fluoro-4-[(4-hydroxyphenyl)sulfonyl]-1-propyl-3,4-dihydroquinoxalin-2(1H)-one (see Example 20) to yield (3S)-6-bromo-3-ethyl-4-[(4-hydroxyphenyl)sulfonyl]-1-methyl-3,4-dihydroquinoxalin-2(1H)-one. MS (ESI) m/z 425/427 ([M+H]+); MS (ESI) m/z 423/425 ([M−H]−); Anal. Calcd for C17H17BrN2O4S: C, 48.01; H, 4.03; N, 6.59. Found: C, 48.07; H, 4.27; N, 6.37.
Reaction SMILES: [H-].[Na+].[CH3:3][CH2:4][O:5][C:6]([CH:8](P(OCC)(OCC)=O)[CH3:9])=[O:7].[CH:18](=O)[C:19]1[CH:26]=[CH:25][C:22]([CH:23]=[O:24])=[CH:21][CH:20]=1.O>COC(OC)C>[CH:23]([C:22]1[CH:25]=[CH:26][C:19]([CH:18]=[C:8]([CH3:9])[C:6]([O:5][CH2:4][CH3:3])=[O:7])=[CH:20][CH:21]=1)=[O:24]
Reactant: CCOC(=O)C(C)P(=O)(OCC)OCC
Reactant: O=Cc1ccc(C=O)cc1
Agent: COC(C)OC
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)C(C)=Cc1ccc(C=O)cc1

Procedure:
To a suspension of 10.0 g of 50% sodium hydride (dispersion in mineral oil) in freshly distilled dimethyoxyethane (DME, 350 ml) stirred under nitrogen at 10° is added 53.6 ml of triethyl 2-phosphonopropionate in ca. 40 minutes. The mixture is stirred for 0.5 hour at 10° and for an additional 1.5 hours during which time the temperature is allowed to rise to room temperature. This solution is transferred under nitrogen by cannula to a 500 ml addition funnel and is added dropwise to a solution of terephthalaldehyde (33.53 g) in dry DME (475 ml) over a period of 1 hour at 22-341. After addition is complete the reaction mixture is stirred mechanically at room temperature for 2 hours, poured into 1L of water and extracted with 4×500 ml of ether. The ether extract is washed with a saturated sodium chloride solution (700 ml), dried over magnesium sulfate, filtered, and concentrated in vacuo to give a yellow oil which partially crystallizes on standing. This crude mixture is purified by suspending in petroleum ether and ethyl acetate (93:7). The filtrate, after removal of unreacted dialdehyde, is concentrated in vacuo to give a mixture which is further purified by high pressure liquid chromatography (using petroleum ether/ethyl acetate 93:7). There is obtained pure ethyl 4-formyl-α-methylcinnamate. A solution of the aldehyde (34.80 g) in 820 ml of absolute ethanol is treated with 12.11 g of granular sodium borohydride at room temperature under nitrogen. The resulting mixture is stirred at room temperature for 3 hours (or until all borohydride has dissolved) and then concentrated to ca. 200 ml volume, diluted with 400 ml of water, and extracted with 3×200 ml of ether. The ether extract is washed with 100 ml of water and brine (100 ml), is dried over magnesium sulfate, filtered, and the filtrate concentrated in vacuo to give ethyl 3-(p-hydroxymethylphenyl)-2-methylacrylate. To a solution of this product in 350 ml of methylene chloride is added at room temperature 11.53 ml of thionyl chloride dropwise over 25 minutes. The clear, colorless solution is stirred for 2 hours. The solution is washed with 100 ml of water, 200 ml of saturated sodium bicarbonate, 100 ml of water, and 100 ml of brine. The organic layer after drying and removal of solvent yields ethyl 3-(p-chloromethylphenyl)-2-methylacrylate which can be used without further purification.
Reaction SMILES: N[C:2]1[CH:3]=[C:4](/[CH:11]=[CH:12]/[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:5]=[CH:6][C:7]=1[CH:8]([CH3:10])[CH3:9].[ClH:18].N([O-])=O.[Na+].C(OCC)(=O)C>C(O)(=O)C>[Cl:18][C:2]1[CH:3]=[C:4](/[CH:11]=[CH:12]/[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:5]=[CH:6][C:7]=1[CH:8]([CH3:10])[CH3:9]
Reactant: Cl
Reactant: CCOC(=O)/C=C/c1ccc(C(C)C)c(N)c1
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCOC(=O)/C=C/c1ccc(C(C)C)c(Cl)c1
Reaction time: 0.5 h

Procedure:
4.67 g of ethyl (E)-3-(3-amino-4-isopropylphenyl)acrylate was dissolved in 46.7 ml of acetic acid. To the solution was added 46.7 ml of 2N hydrochloric acid with ice-cooling. To the mixture was dropwise added 10 ml of an aqueous solution containing 1.52 g of sodium nitrite. The mixture was stirred for 30 minutes at the same temperature. The reaction mixture was added to 30 ml of 6N hydrochloric acid solution containing 2.18 g of cuprous chloride, with ice-cooling. The mixture was stirred for 1 hour at the same temperature and then for 2 hours at room temperature. To the reaction mixture was added 100 ml of ethyl acetate. The organic layer was separated and washed with water. Thereto was added 50 ml of water. The mixture was adjusted to about pH 7 with sodium hydrogencarbonate. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was purified by a column chromatography (eluant: n-hexane/ethyl acetate=20/1) to obtain 3.57 g of colorless oily ethyl (E)-3-(3-chloro-4-isopropylphenyl)acrylate.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]2[CH2:14][O:13][C:12](=[O:15])[CH:11]=2)=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:19][CH:20]=[C:21]([Cl:23])[Cl:22].CO>O1CCCC1>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]([CH2:19][CH:20]=[C:21]([Cl:23])[Cl:22])[C:10]2[CH2:14][O:13][C:12](=[O:15])[CH:11]=2)=[CH:4][CH:3]=1
Reactant: ClC(Cl)=CCBr
Reactant: O=C1C=C(NCc2ccc(Cl)nc2)CO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: O=C1C=C(N(CC=C(Cl)Cl)Cc2ccc(Cl)nc2)CO1
Temperature: 25 °C
Yield: 50.7 %

Procedure:
350 mg (1.56 mmol) of 4-[[(6-chloropyridin-3-yl)methyl]amino]furan-2(5H)-one (Ia-1; cf. EP 0539588 A1) and 124 mg (3.12 mmol) of a 60% dispersion of sodium hydride in mineral oil in 100 ml of tetrahydrofuran are heated under reflux for 3 h. After cooling to room temperature, 592 mg (3.12 mmol) of 3-bromo-1,1-dichloroprop-1-ene (cf. WO 8800183 A1) are added and the mixture is heated under reflux for a further 5 h. After cooling of the reaction mixture to room temperature and addition of methanol, the mixture is concentrated under reduced pressure. The residue is taken up in ethyl acetate and the mixture is washed successively twice with 1 N aqueous hydrochloric acid, twice with 1 N aqueous sodium hydroxide solution and once with saturated sodium chloride solution. The organic phase is then dried over sodium sulphate and concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel (silica gel 60—Merck, particle size: 0.04 to 0.063 mm) using the mobile phase mixture ethyl acetate:cyclohexane (2:1) gives 264 mg (50% of theory) of 4-[[(6-chloropyridin-3-yl)methyl](3,3-dichloroprop-2-en-1-yl)amino]furan-2(5H)-one.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:14])([CH2:12][OH:13])[CH2:10][OH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:15](OC=C)(=[O:21])[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>C(OC(C)C)(C)C>[C:1]([O:5][C:6]([NH:8][C@@:9]([CH3:14])([CH2:10][O:11][C:15](=[O:21])[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:12][OH:13])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=COC(=O)CCCCC
Reactant: CC(CO)(CO)NC(=O)OC(C)(C)C
Solvent: CC(C)OC(C)C
Product: CCCCCC(=O)OC[C@@](C)(CO)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.6 %

Procedure:
2-t-Butoxycarbonylamino-2-methylpropane-1,3-diol (20.0 g, 97.4 mmol) was suspended in isopropyl ether (200 mL), and 16.3 mL (0.100 mol) of vinyl hexanoate and lipase [Immobilized lipase from Pseudomonas sp., manufactured by TOYOBO Co., Inc., 0.67 U/mg] (0.8 g) were added thereto, followed by stirring of the mixture at room temperature for 2 hours. After the reaction mixture was filtered, the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate, 10:1-2:1) to obtain the title compound (25.0 g, yield: 85%).
Reaction SMILES: [CH2:1]([C:3]1([CH:16]=[O:17])[CH2:15][CH:6]2[CH2:7][N:8]([C:10]([N:12]([CH3:14])[CH3:13])=[O:11])[CH2:9][CH:5]2[CH2:4]1)[CH3:2].O.O.P([O-])(O)(O)=[O:21].[Na+].Cl([O-])=O.[Na+].CC(=CC)C>O1CCCC1.O>[CH2:1]([C:3]1([C:16]([OH:21])=[O:17])[CH2:15][CH:6]2[CH2:7][N:8]([C:10](=[O:11])[N:12]([CH3:13])[CH3:14])[CH2:9][CH:5]2[CH2:4]1)[CH3:2]
Reactant: O=P([O-])(O)O
Reactant: CCC1(C=O)CC2CN(C(=O)N(C)C)CC2C1
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: C1CCOC1
Solvent: O
Product: CCC1(C(=O)O)CC2CN(C(=O)N(C)C)CC2C1
Yield: 99.7 %

Procedure:
5-Ethyl-5-formyl-N,N-dimethyl-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acid dimethylamide 19b (0.4 g, 1.68 mmol) was dissolved in the solvent mixture of 18 mL of tetrahydrofuran and 9 mL of water, followed by addition of sodium dihydrogenphosphate dihydrate (787 mg, 5.04 mmol), sodium chlorite (0.454 g, 5.04 mmol) and 2-methyl-2-butene (354 mg, 5.06 mmol) at 0° C. The reaction mixture was reacted at 0° C. for 2 hours under nitrogen atmosphere. The reaction was monitored by TLC until the disappearance of the starting materials. The mixture was extracted with ethyl acetate. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain the title compound 5-ethyl-2-dimethylcarbamoyl-hexahydro-cyclopenta[c]pyrrole-5-carboxylic acid 19c (0.426 g, yield 100%) as a yellow solid which was directly used in the next step.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([OH:13])[CH:7]=[CH:6]2.C(N(CC)CC)C.[C:21](Cl)(=[O:25])[C:22]([CH3:24])=[CH2:23]>ClCCl>[C:21]([O:13][C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([CH2:2][OH:1])[CH:4]=2)[CH:9]=1)(=[O:25])[C:22]([CH3:24])=[CH2:23]
Reactant: OCc1ccc2cc(O)ccc2c1
Reactant: C=C(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(C)C(=O)Oc1ccc2cc(CO)ccc2c1
Temperature: 5 °C
Reaction time: 8 h
Yield: 64.9 %

Procedure:
To a 3-necked, 500-mL round bottomed flask equipped with a digital thermometer, 50-mL constant-pressure addition funnel with a nitrogen inlet and a magnetic stir bar was added 25 g (0.14 mol) of 6-hydroxymethyl-2-naphthol, 200 mL of dichloromethane and 14.5 g (0.14 mol) of triethylamine. The addition funnel was charged with a solution of 14.9 g (0.15 mol) of methacryloyl chloride in 30 mL of dichloromethane. The flask was cooled to 5° C. and the acid chloride added slowly dropwise while maintaining a temperature of less than 10° C. The reaction mixture was stirred at room temperature overnight after which it was washed with water and brine, dried over MgSO4, evaporated and the residue chromatographed on silica gel with 35% ethyl acetate in hexane. The fractions containing the pure product were combined and evaporated to yield 22 g (65%) of the title compound as an off-white solid. Approximately 8 g of starting material can be recovered from the column by increasing the percentage of ethyl acetate in the mobile phase.
Reaction SMILES: [N:1]1([C:13]2([CH2:23][OH:24])[CH2:22][CH2:21][C:16]3(OCC[O:17]3)[CH2:15][CH2:14]2)[C:5]2=[C:6]3[S:12][CH:11]=[CH:10][C:7]3=[N:8][CH:9]=[C:4]2[N:3]=[CH:2]1.Cl.O.[OH-].[Na+]>CC(C)=O>[OH:24][CH2:23][C:13]1([N:1]2[C:5]3=[C:6]4[S:12][CH:11]=[CH:10][C:7]4=[N:8][CH:9]=[C:4]3[N:3]=[CH:2]2)[CH2:22][CH2:21][C:16](=[O:17])[CH2:15][CH2:14]1
Reactant: OCC1(n2cnc3cnc4ccsc4c32)CCC2(CC1)OCCO2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: O=C1CCC(CO)(n2cnc3cnc4ccsc4c32)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 48.9 %

Procedure:
A mixture of [8-(1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl)-1,4-dioxaspiro[4.5]dec-8-yl]methanol (0.13 g, 0.38 mmol) and 3.0 M hydrogen chloride in water (2.0 mL, 6.0 mmol) in acetone (5 mL) was stirred at room temperature for 5 h and then at 60° C. for 1 h. After cooling, the mixture was made slightly basic by the addition of 2.0 N NaOH. The mixture was extracted with EtOAc (3×). The combined extracts were dried (Na2SO4), filtered, and concentrated. The crude was purified on silica gel, eluted with 0-15% MeOH in dichloromethane to give 56 mg (49%) of the desired product. LCMS calculated for C15H16N3O2S (M+H)+: m/z=302.1. Found: 302.1.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[C:8]1[CH:23]=[CH:22][C:11]([O:12][CH2:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:10][CH:9]=1.Cl[CH2:25][CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>CN(C=O)C.O>[N:28]1([CH2:27][CH2:26][CH2:25][N:3]2[CH:7]=[CH:6][CH:5]=[C:4]2[C:8]2[CH:23]=[CH:22][C:11]([O:12][CH2:13][CH2:14][CH2:15][N:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[CH:10][CH:9]=2)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: c1c[nH]c(-c2ccc(OCCCN3CCCCC3)cc2)c1
Reactant: ClCCCN1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: c1cc(-c2ccc(OCCCN3CCCCC3)cc2)n(CCCN2CCCCC2)c1
Reaction time: 0.33 h
Yield: 89.2 %

Procedure:
To a stirred suspension of sodium hydride (0.051 g) in DMF (3 mL) at RT was added dropwise the product of Example 18 (0.2 g) in DMF (4 mL). After 20 min, 1-(3-chloro-propyl)-piperdine (0.139 g) was added dropwise and the mixture stirred for 12 h. The mixture was diluted with water and extracted several times with diethyl ether. The combined organic layers were washed with brine, dried (sodium sulfate), filtered and concentrated under reduced pressure, giving the title compound as a dark red oil (0.257 g). 1H NMR (400 MHz, C6D6): 7.35 (d, J=8.8 Hz, 2H), 6.90 (d, J=8.8 Hz, 2H), 6.72 (t, J=2.5 Hz, 1H), 6.44 (d, J=2.5 Hz), 3.82 (m, 4H), 2.37–2.16 (m, 8H), 2.06 (br s, 4H), 1.96 (t, J=6.6 Hz, 2H), 1.87–1.81 (m, 2H), 1.59–1.22 (m, 16H).
Reaction SMILES: [CH:1]1([C:7]2[CH:31]=[CH:30][C:10]([C:11]([N:13]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[CH2:17][N:16]4[C:24]([C:27](Cl)=[O:28])=[CH:25][CH:26]=[C:15]4[CH2:14]3)=[O:12])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.Cl.[C:42]1(C)[C:43]([C:48]([N:50]2[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]2)=O)=[CH:44][CH:45]=[CH:46][CH:47]=1>CN(C)C1C=CN=CC=1.ClCCl>[CH:1]1([C:7]2[CH:31]=[CH:30][C:10]([C:11]([N:13]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[CH2:17][N:16]4[C:24]([C:27]([N:53]5[CH2:52][CH2:51][N:50]([C:48]6[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=6[CH3:42])[CH2:55][CH2:54]5)=[O:28])=[CH:25][CH:26]=[C:15]4[CH2:14]3)=[O:12])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1ccccc1C(=O)N1CCNCC1
Reactant: O=C(Cl)c1ccc2n1Cc1ccccc1N(C(=O)c1ccc(C3CCCCC3)cc1)C2
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccccc1N1CCN(C(=O)c2ccc3n2Cc2ccccc2N(C(=O)c2ccc(C4CCCCC4)cc2)C3)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The crude 10-(4-cyclohexyl-benzoyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carbonyl chloride prepared in the manner of Example 23 (0.5 g) was added to a stirred mixture of N,N-diisopropylethyl amine (0.47 g), 4-(2-toluoyl)piperazine hydrochloride (0.51 g) and 4-(dimethylamino)pyridine (0.05 g) in dichloromethane (25 mL). After stirring overnight at room temperature the reaction mixture was washed with water and saturated aqueous sodium bicarbonat, and dried over anhydrous sodium sulfate. The solution was filtered through a short column of Magnesol®. Refluxing the eluate with the gradual addition of hexane resulted in crystallization of the desired title compound (0.46 g) as colorless crystals, m.p. 141–143° C.
Reaction SMILES: Br.[F:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10]1[S:11][CH:12]=[C:13]([C:15]2[C:19](=[CH2:20])[S:18][CH:17]([C:21]([O:23][CH3:24])=[S:22])[CH:16]=2)[N:14]=1.[Br:25]CC(C1C=C(C(OC)=S)SC=1C)=O.FC1C=CC=CC=1NC(N)=S>>[BrH:25].[F:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10]1[S:11][CH:12]=[C:13]([C:15]2[CH:16]=[C:17]([C:21]([O:23][CH3:24])=[S:22])[S:18][C:19]=2[CH3:20])[N:14]=1
Reactant: COC(=S)c1cc(C(=O)CBr)c(C)s1
Reactant: C=C1SC(C(=S)OC)C=C1c1csc(Nc2ccccc2F)n1
Agent: Br
Agent: NC(=S)Nc1ccccc1F
Product: COC(=S)c1cc(-c2csc(Nc3ccccc3F)n2)c(C)s1
Yield: 70 %

Procedure:
Methyl 4-{2-[(2-fluorophenyl)amino](1,3-thiazol-4-yl)}-5-methlylthiothiophene-2-carboxylate hydrobromide: Methyl 4-(2-bromoacetyl)-5-methylthiothiophene-2-carboxylate (60 mg, 0.19 mmol) was allowed to react with 2-fluorophenyl thiourea as described in Example 154, step (a) to give 55.6 mg (70% yield) of methyl 4-{2-[(2-fluorophenyl)amino](1,3-thiazol-4-yl)}-5-methylthiothiophene-2-carboxylate hydrobromide. 1H NMR (DMSO-d6, 300 MHz) δ 2.68 (s, 3H), 3.83 (s, 3H), 6.96-7.04 (m, 1H), 7.14-7.29 (m, 3H), 7.35 (s, 1H), 8.06, 8.14 (s, 1H rotomer), 8.61 (td, 1H rotomer, J=1.5, 8.5 Hz), 10.14, 10.30 (s, 1H rotomer); Mass Spectrum (ESI) m/z calcd. for C16H13FN2O2S3, 380.48 (M+H), found 381.1.