Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[C:11]([CH:18]([CH3:20])[CH3:19])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:21](I)[CH3:22].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([O:15][CH2:21][CH3:22])=[O:14])=[C:11]([CH:18]([CH3:20])[CH3:19])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)c1cc(OCc2ccccc2)ccc1C(=O)O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(OCc2ccccc2)cc1C(C)C
Temperature: 25 °C

Procedure:
A mixture of N-methylformanilide (9.92 g) and phosphoryl chloride (11.3 g) was stirred at room temperature for 30 minutes, and benzyloxy-3-isopropylbenzene (16.6 g) was added to the mixture. After being stirred at room temperature overnight, ice was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to afford 4-benzyloxy-2-isopropylbenzaldehyde (19.4 g) as a crude product. An aqueous solution (200 mL) of sodium chlorite (33.2 g) was added dropwise to an ice-cooled suspension of the crude 4-benzyloxy-2-isopropylbenzaldehyde and potassium dihydrogenphosphate (50.0 g) in tert-butylalcohol (200 mL)/2-methyl-2-butene (100 mL) with stirring. The mixture was stirred at room temperature for 3 hrs. To the resulting mixture was added water, and the insoluble materials were removed by filtration. The filtrate was extracted with ethyl acetate. The organic layer was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to afford 4-benzyloxy-2-isopropylbenzoic acid (23.3 g) as a crude product. A suspension of the crude 4-benzyloxy-2-isopropylbenzoic acid, ethyl iodide (13.7 g) and potassium carbonate (15.2 g) in N,N-dimethylformamide (300 mL) was stirred at room temperature for30 minutes. The reaction mixture was partitioned between diethyl ether and water. The organic layer was washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/5) to afford ethyl 4-benzyloxy-2-isopropylbenzoate (16.8 g). A suspension of ethyl 4-benzyloxy-2-isopropylbenzoate and 10% palladium-carbon (0.1 g) in ethanol (100 mL) was stirred at room temperature for 30 minutes under an atmosphere of hydrogen. The catalyst was removed by filtration, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/5) to afford the title compound (1.1 g).
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[C:9]([C:17](O)=[O:18])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)(Cl)=O.[CH3:24][NH:25][CH:26]([CH2:28][CH3:29])[CH3:27]>N1C=CC=CC=1>[CH3:24][N:25]([CH:26]([CH3:27])[CH2:28][CH3:29])[C:17]([C:9]1[CH:8]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1)=[O:18]
Reactant: CCC(C)NC
Reactant: O=C(O)c1cc(-c2ccccc2)c2ccccc2c1
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: CCC(C)N(C)C(=O)c1cc(-c2ccccc2)c2ccccc2c1
Yield: 54.9 %

Procedure:
Operations are carried out as for Example 1, starting from 4.3 g of 4-phenyl naphthalene 2-carboxylic acid, 20 ml of thionyl chloride and then 1.5 g of N-methyl 2-butanamine in 20 ml of pyridine. 3 g of N-methyl N(1-methyl propyl) 4-phenyl naphthalene 2-carboxamide, melting at 108° C., are obtained.
Reaction SMILES: C1(PC2C=CC=CC=2)C=CC=CC=1.[C:14]([NH:17][C:18](=[CH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:19]([OH:21])=[O:20])(=[O:16])[CH3:15].[H][H]>C1COCC1>[C:14]([NH:17][C@H:18]([C:19]([OH:21])=[O:20])[CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)(=[O:16])[CH3:15]
Reactant: CC(=O)NC(=Cc1ccccc1)C(=O)O
Reactant: [H][H]
Agent: c1ccc(Pc2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 97 %

Procedure:
110 μmol of the optically active diphenylphosphine ligand of Example 3 were dissolved in 5 ml of THF and, after addition of 100 μmol of Rh(COD)2BF4, stirred at RT for 20 min. 100 mmol of α-acetamidocinnamic acid and 250 ml of THF were added to the clear yellow solution. This solution was hydrogenated under 20 bar of hydrogen at 30° C. The reaction was complete after 20 min. N-Acetyl-(S)-phenylalanine was isolated after workup in 97% yield and an optical purity of 99.6% ee.
Reaction SMILES: O1[CH:13]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][OH:22])[CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11].[OH:23]C(C(O)CCCCCCCCO)CCCCCCCC(O)=O.OCCCCCCCCCCCCCCCCCCCCCC(O)=O.OCCCCCCCCC=CCCCCCCCC(O)=O.C(O)(=O)CCCCCCCCCCCCCCCCCCCCC(O)=O>>[C:10]([OH:12])(=[O:11])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=[CH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:22])=[O:23]
Reactant: O=C(O)CCCCCCCC(O)C(O)CCCCCCCCO
Reactant: O=C(O)CCCCCCCC1OC1CCCCCCCCO
Agent: O=C(O)CCCCCCCC=CCCCCCCCCO
Agent: O=C(O)CCCCCCCCCCCCCCCCCCCCC(=O)O
Agent: O=C(O)CCCCCCCCCCCCCCCCCCCCCO
Product: O=C(O)CCCCCCCC=CCCCCCCCC(=O)O

Procedure:
The process of claim 1 wherein the hydrolysis is carried out at a pH of about 6.5 to about 7.5 and a mixture of9,16-dihydroxyhexadecanoic acid; 9,10-epoxy-18-hydroxyoctadecanoic acid; 9,10,18-trihydroxyoctadecanoic acid (phloionolic acid); 20-hydroxyeicasanoic acid; 22-hydroxydocosanoic acid; 18-hydroxyoctadec-9-enoic acid; docosandioic acid; and octadec-9-enedioic acid is obtained in a ratio of about 1.0-3.0:0-1.0:45.0-75.0:1.0-6.0:10.0-18.0:1.0-5.0:4.0-16.0:1.0-6.0.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:6]=1[NH2:12])#[C:2][CH2:3][CH3:4].O>CN1CCCC1=O>[CH2:3]([C:2]1[NH:12][C:6]2[C:5]([CH:1]=1)=[CH:10][C:9]([F:11])=[CH:8][CH:7]=2)[CH3:4]
Reactant: CCC#Cc1cc(F)ccc1N
Solvent: O
Solvent: CN1CCCC1=O
Product: CCc1cc2cc(F)ccc2[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.2 %

Procedure:
Under argon 4.9 g potassium-tert-butoxide are suspended in 25 ml N-methyl-2-pyrrolidinone and a suspension of 3.4 g 2-but-1-ynyl-4-fluorophenylamine in 25 ml N-methyl-2-pyrrolidinone is added dropwise thereto. The reaction mixture is stirred for 3 hours at ambient temperature and mixed with water. The product is extracted with diethyl ether and purified by chromatography (silica gel, cyclohexane/ethyl acetate 100/0-90/10). 2.83 g product are obtained in the form of a solid. 1H NMR (400 MHz, DMSO): 2.72 (2H, q); 1.27 (3H, t).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][CH:3]=1.[Mg].Cl[C:11]1[CH:16]=[CH:15][C:14]([Mg]Br)=[CH:13]C=1.C1(=O)CCCC1.Cl>CCOCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:13]2[CH2:14][CH2:15][CH2:16][CH:11]=2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(Br)cc1
Reactant: Clc1ccc([Mg]Br)cc1
Agent: Cl
Agent: [Mg]
Solvent: O=C1CCCC1
Solvent: CCOCC
Product: Clc1ccc(C2=CCCC2)cc1
Reaction time: 8 h

Procedure:
From 575 g of p-chlorophenyl bromide and 78 g of magnesium turnings in 2.6 liters of anhydrous ether is prepared p-chlorophenyl magnesium bromide to which is added dropwise a solution of 252 g of cyclopentanone in in 1 liter of ether. The mixture is stirred overnight and is decomposed by careful addition of dilute hydrochloric acid. The organic phase is separated, washed and dried, and the solvent is evaporated. The resulting solid is recrystallized from ethanol to give 316 g of 1-(p-chlorophenyl)cyclopentene, M.P. 71°-73° C, which was dissolved in 2.9 liters of acetic acid containing 6 ml of concentrated sulfuric acid. To this solution 133 g of 50% hydrogen peroxide is added dropwise during which time the reaction temperature is maintained at 30° to 33° C. The reaction temperature is maintained at 30° to 35° C. The reaction mixture is stirred overnight after which water is added and the product is extracted into ether. The extract is washed, dried and the solvent evaporated leaving crude 2-(p-chlorophenyl)cyclopentanone which distilled, B.P. 135°-154° C (0.1 mm) yielding 140 g. The oxime, M.P. 154°-155° C prepared by reaction with hydroxylamine hydrochloric acid is reduced using Raney nickel in alcoholic ammonia to give 1-(p-chlorophenyl)cyclopentylamine which is subsequently converted to the hydrochloride salt, M.P. 226°-228° C. Following the procedure of Example 23, only substituting for cis-2-phenylcyclopentylamine hydrochloride, an appropriate amount of 2-(p-chlorophenyl)-cyclopentylamine hydrochloride, the desired product is obtained, M.P. 253°-255° C.
Reaction SMILES: BrC1C=CC2OCC3(C4SC(C(OCC)=O)=[N:15]C=4C=2C=1)OCCO3.C([C@]1(O)CCN(C)C1=O)#C.[OH:35][C@@:36]1([C:43]#[C:44][C:45]2[CH:67]=[CH:66][C:48]3[O:49][CH2:50][C:51]4([C:56]5[S:60][C:59]([C:61]([O:63]CC)=O)=[N:58][C:57]=5[C:47]=3[CH:46]=2)[O:55][CH2:54][CH2:53][O:52]4)[CH2:40][CH2:39][N:38]([CH3:41])[C:37]1=[O:42]>>[OH:35][C@@:36]1([C:43]#[C:44][C:45]2[CH:67]=[CH:66][C:48]3[O:49][CH2:50][C:51]4([C:56]5[S:60][C:59]([C:61]([NH2:15])=[O:63])=[N:58][C:57]=5[C:47]=3[CH:46]=2)[O:55][CH2:54][CH2:53][O:52]4)[CH2:40][CH2:39][N:38]([CH3:41])[C:37]1=[O:42]
Reactant: CCOC(=O)c1nc2c(s1)C1(COc3ccc(Br)cc3-2)OCCO1
Reactant: CCOC(=O)c1nc2c(s1)C1(COc3ccc(C#C[C@]4(O)CCN(C)C4=O)cc3-2)OCCO1
Agent: C#C[C@]1(O)CCN(C)C1=O
Product: CN1CC[C@@](O)(C#Cc2ccc3c(c2)-c2nc(C(N)=O)sc2C2(CO3)OCCO2)C1=O

Procedure:
Similar to as described in General Procedure G, ethyl 9-bromo-5H-spiro[benzo[2,3]oxepino[4,5-d]thiazole-4,2′-[1,3]dioxolane]-2-carboxylate was reacted with (R)-3-ethynyl-3-hydroxy-1-methylpyrrolidin-2-one to give a diasteromeric mixture of (R)-ethyl 9-((3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl)-5H-spiro[benzo[2,3]oxepino[4,5-d]thiazole-4,2′-[1,3]dioxolane]-2-carboxylate. Following aminolysis of the ethyl ester (similar to as described in General Procedure M) the titled compound was obtained after purification by prep HPLC
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:20][CH3:21])[CH:16]=3)[CH2:11]2)=[C:7]([NH2:9])[CH:8]=1.N1C=CC=[CH:24][CH:23]=1.C(OC(=O)C)(=O)C.Cl>O1CCCC1>[CH2:23]([NH:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=1[CH:10]1[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:20][CH3:21])[CH:16]=2)[CH2:11]1)[CH3:24]
Reactant: c1ccncc1
Reactant: COc1ccc(C2CCc3cc(OC)ccc3C2)c(N)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: CC(=O)OC(C)=O
Product: CCNc1cc(OC)ccc1C1CCc2cc(OC)ccc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenylamine (9.3 g) in tetrahydrofuran (100 ml) were sequentially added pyridine (8.0 ml) and acetic anhydride (6.2 ml), and the solution was stirred overnight at room temperature. To the reaction solution was added 1N hydrochloric acid, the solution was extracted with ethyl acetate, then sequentially washed with a saturated aqueous solution of sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. To a solution of the resulting N-[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]acetamide (9.1 g) in tetrahydrofuran (100 ml) was added lithium aluminum hydride (2.7 g), and the solution was refluxed for 2 hours. Ammonia solution (1 ml) and anhydrous magnesium sulfate were added on an ice bath, the solution was filtered, and then the solvent was evaporated in vacuo to provide ethyl[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]amine (8.8 g). To a solution of 4-benzyloxybenzoic acid (9.1 g) in dichloromethane (80 ml) were sequentially added oxalyl chloride (5.1 ml) and N,N-dimethylformamide (0.05 ml), the solution was stirred overnight at room temperature, then the solvent was evaporated in vacuo. To the total amount of the resulting 4-benzyloxybenzoyl chloride were sequentially added 1,4-dioxane (100 ml), N,N-diisopropylethylamine (15 ml) and ethyl[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]amine (8.3 g), and the solution was refluxed for 30 minutes. To the reaction solution was added 1N hydrochloric acid, the solution was extracted with ethyl acetate, then sequentially washed with a saturated aqueous solution of sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, then the solvent was evaporated in vacuo. Synthesized from the total amount of the resulting 4-benzyloxy-N-ethyl-N-[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]benzamide (crude product) according to an analogous synthetic method to Example 22, the title compound (13 g) was obtained.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][C:9]([C:11]2[CH:12]=[C:13]3[C:18]4=[C:19]([CH2:21][CH2:22][N:17]4[C:16](=[O:23])[CH2:15][CH2:14]3)[CH:20]=2)=[O:10])[CH2:3][CH2:2]1.C(#N)C.C(=O)([O-])[O-].[K+].[K+].[F:33][C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][CH:41]=1)[CH2:37]Cl>O>[F:33][C:34]1[CH:35]=[C:36]([CH2:37][N:1]2[CH2:2][CH2:3][CH:4]([CH2:7][CH2:8][C:9]([C:11]3[CH:12]=[C:13]4[C:18]5=[C:19]([CH2:21][CH2:22][N:17]5[C:16](=[O:23])[CH2:15][CH2:14]4)[CH:20]=3)=[O:10])[CH2:5][CH2:6]2)[CH:39]=[CH:40][CH:41]=1
Reactant: Fc1cccc(CCl)c1
Reactant: O=C(CCC1CCNCC1)c1cc2c3c(c1)CCN3C(=O)CC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: O=C(CCC1CCN(Cc2cccc(F)c2)CC1)c1cc2c3c(c1)CCN3C(=O)CC2
Temperature: 55 °C
Reaction time: 3 h
Yield: 87.9 %

Procedure:
A mixture of 600 g of 8-[3-(4-piperidinyl)-1-oxopropyl]-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinoline-4-one, 6 L of acetonitrile, 0.3 L of water, 345 g (1.3 equivalent) of potassium carbonate and 278 g (1 equivalent) of 3-fluorobenzyl chloride was stirred at about 55° C. and 12 L of water was added dropwise thereto over about 20 minutes while maintaining about 45° C. The mixture was stirred at about 55° C. for 1.5 hours, and at about 20° C. for 3 hours. Precipitated crystals were separated, and washed with 15 L of water. The wet crystals were suspended in 8.0 L of 10% hydrous methanol-denatured ethanol. The material was dissolved at about 70° C., and passed through a dust-removing filter. The filtrate was stirred at about 20° C. for 1.5 hours, 6.9 L of water was added thereto, and the mixture was stirred at about 20° C. for 3 hours. Crystals were separated, washed with 1.8 L of 50% hydrous methanol-denatured ethanol twice and dried to obtain 0.71 kg (yield 88%) of the desired compound as crystals.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:21]([N+:22]([O-])=O)=[CH:20][C:19]([Br:25])=[CH:18][N:17]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.O.[Sn](Cl)Cl.C(=O)(O)[O-].[Na+]>C(O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:21]([NH2:22])=[CH:20][C:19]([Br:25])=[CH:18][N:17]=2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1cc(Br)cnc1Nc1ccc(OCc2ccccc2)cc1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Nc1cc(Br)cnc1Nc1ccc(OCc2ccccc2)cc1
Temperature: 70 °C

Procedure:
N-[4-(benzyloxy)phenyl]-5-bromo-3-nitropyridin-2-amine (28.5 g, 0.071 mmol) and tin (II) chloride dihydrate (160.67 g, 0.712 mmol) were dissolved in 500 mL ethanol under N2 and the reaction mixture heated at reflux (70° C.) for 30 min. Sodium bicarbonate was then added to the cooled mixture until the pH was greater than 9.5, and then the mixture was filtered through celite which was washed with methanol. The combined organic phases were concentrated in vacuo before being re-constituted in CH2Cl2, drying over Na2SO4, and concentration in vacuo to yield N2-[4-(benzyloxy)phenyl]-5-bromopyridine-2,3-diamine. 1H NMR (400 MHz, CDCl3) δ 3.44 (bs, 2H), 5.07 (s, 2H), 6.02 (bs, 1H), 6.97 (dt, 2H, J=5.6, 3.6 Hz), 7.12 (d, 1H, J=2.0 Hz), 7.32 (dt, 2H, J=4.8, 0.4 Hz), 7.34-7.48 (m, 5H), 7.84 (d, 1H, J=2 Hz); MS (ES+): m/z 371[MH+], 372 (35) [MH2+]
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=1>CN(C)C=O.C(OCC)(=O)C.[OH-].[Pd+2].[OH-].[C]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[CH:18][C:19]([NH2:22])=[CH:20][CH:21]=1
Reactant: COc1cc2nccc(Oc3ccc([N+](=O)[O-])cc3)c2cc1OC
Agent: [Pd+2]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 17 h
Yield: 88 %

Procedure:
6,7-Dimethoxy-4-(4-nitrophenoxy)quinoline (1.00 g) was dissolved in N,N-dimethylformamide/ethyl acetate (30 ml/15 ml), 10% palladium hydroxide-carbon (69 mg) was added, and the admixture was stirred at room temperature under hydrogen for 17 hours. The reaction mixture was filtered using Celite. The filtrate was washed with brine and then dried with anhydrous sodium sulfate. The solvent was removed by reduced-pressure distillation to obtain 799 mg of the title compound (yield: 88%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[CH:3]=[CH:2]1.[C:10](Cl)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.COC1C=C(C=CC=1)C(Cl)=O>>[C:10]([C:3]1[C:4]2[C:9](=[N:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: c1cnc2[nH]ccc2c1
Reactant: O=C(Cl)c1ccccc1
Agent: COc1cccc(C(=O)Cl)c1
Product: O=C(c1ccccc1)c1c[nH]c2ncccc12

Procedure:
Compound 41 was prepared from 7-azaindole 2 using aluminum chloride as described previously for the synthesis of Compound 25, with benzoyl chloride substituted for m-methoxy-benzoyl chloride.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:22]#[N:23])=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[N:5]([CH2:11][O:12][CH2:13][CH3:14])[C:6]=1[C:7]([F:10])([F:9])[F:8].[OH-:24].[Na+].OO>CO.O>[Br:1][C:2]1[C:3]([C:22]([NH2:23])=[O:24])=[C:4]([C:15]2[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=2)[N:5]([CH2:11][O:12][CH2:13][CH3:14])[C:6]=1[C:7]([F:8])([F:10])[F:9]
Reactant: [OH-]
Reactant: CCOCn1c(-c2ccc(Cl)cc2)c(C#N)c(Br)c1C(F)(F)F
Agent: OO
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCOCn1c(-c2ccc(Cl)cc2)c(C(N)=O)c(Br)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 7 h
Yield: 86.9 %

Procedure:
A mixture of 4-bromo-2-(p-chlorophenyl)-1-(ethoxymethyl)-5-(trifluoromethyl)pyrrole-3-carbonitrile (4.07 g, 10 mmol), sodium hydroxide (0.8 g, 20 mmol) and 30 wt/wt % hydrogen peroxide solution (7.2 mL, 70 mmol) in methanol is stirred at room temperature for 7 hours, treated with sodium hydroxide solution (0.8 g NaOH in 5 mL of H2O) and 30 wt/wt % hydrogen peroxide solution (7 mL), stirred at room temperature overnight, heated at 40° C. for 8 hours and diluted with water. The aqueous mixture is filtered and the filter cake is washed with water and heptane and dried to give the title product as a white solid (3.7 g) which is identified by 1H and 13C NMR spectral analyses.
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([O:6][C:7]2[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][N:8]=2)[CH2:3]1.Cl[C:15]([O:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)=[O:16]>>[N+:24]([C:21]1[CH:20]=[CH:19][C:18]([O:17][C:15]([N:2]2[CH2:3][CH:4]([O:6][C:7]3[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][N:8]=3)[CH2:5]2)=[O:16])=[CH:23][CH:22]=1)([O-:26])=[O:25]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: Brc1ccc(OC2CNC2)nc1
Agent: Cl
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CC(Oc2ccc(Br)cn2)C1
Yield: 37 %

Procedure:
This compound was prepared by the method outlined for example 5 step 3. Thus 2-(Azetidin-3-yloxy)-5-bromo-pyridine hydrochloride (2.0 g, 7.53 mmol) was reacted with 4-nitrophenyl chloroformate to afford the title compound (1.11 g, 37%) as a pale-yellow solid.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH2:5][C:6]3[C:12]([C:13]4[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=4)=[N:11][N:10]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:7]=3[C:8]=2[CH:9]=1.CC1(C)C(C)(C)OB([C:37]2[CH:38]=[C:39]([NH2:43])[CH:40]=[N:41][CH:42]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.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>[CH3:20][O:19][C:16]1[CH:15]=[CH:14][C:13]([C:12]2[C:6]3[CH2:5][C:4]4[S:3][C:2]([C:37]5[CH:38]=[C:39]([NH2:43])[CH:40]=[N:41][CH:42]=5)=[CH:9][C:8]=4[C:7]=3[N:10]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:26])([CH3:27])[CH3:28])[N:11]=2)=[CH:18][CH:17]=1
Reactant: COc1ccc(-c2nn(COCC[Si](C)(C)C)c3c2Cc2sc(Br)cc2-3)cc1
Reactant: CC1(C)OB(c2cncc(N)c2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1ccc(-c2nn(COCC[Si](C)(C)C)c3c2Cc2sc(-c4cncc(N)c4)cc2-3)cc1
Temperature: 100 °C
Yield: 68 %

Procedure:
A mixture of the corresponding 2-Bromo-6-(4-methoxy-phenyl)-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (1.1 g, 2.3 mmol), 5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-ylamine (0.75 g, 3.4 mmol), Na2CO3 (2 M, 5.4 mL), and Pd(PPh3)2Cl2 (260 mg, 0.23 mmol) in toluene/ethanol (1:1, 15 mL) was heated at 100° C. for 8 hr. The solution was cooled to room temperature and extracted with ethyl acetate. The target product was purified by gravity column chromatography (30% EtOAc in hexane) to give 5-[6-(4-Methoxy-phenyl)-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen-2-yl]-pyridin-3-ylamine as brown solid in 68% yield.
Reaction SMILES: [F:1][C:2]1[C:10]2[O:9][CH:8]=[CH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Li]CCCC.[O:16]=[C:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1>C1COCC1>[F:1][C:2]1[C:10]2[O:9][C:8]([C:17]3([OH:16])[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24])[CH2:21][CH2:22]3)=[CH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Fc1cccc2ccoc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(c2cc3cccc(F)c3o2)CC1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 87.5 %

Procedure:
To a solution of 7-fluorobenzofuran (0.3 g, 1.807 mmol) in dry THF (4.8 mL) at −78° C. under an argon atmosphere was slowly added BuLi (1.3 mL, 2.078 mmol). Upon completion of addition, the mixture was stirred at −78° C. for 20 min. After this time, a solution of tert-butyl 4-oxopiperidine-1-carboxylate (0.36 g, 1.807 mmol) in THF (2.4 mL) was slowly added. The reaction mixture was warmed to −40° C., where it stirred for 2 hrs. At the conclusion of this period, the reaction mixture was quenched with aqueous NH4Cl (saturated, 5 mL) and then extracted with EtOAc (3×5 mL). The combined organic layers were washed with H2O (2×4 mL), brine (5 mL), dried (Na2SO4), filtered, and concentrated to yield a residue. The residue was purified by column chromatography (silica gel, hexanes/EtOAc gradient 0 to 60% EtOAc) to afford Compound 1D as a white solid (530 mg, 94.7% purity, 83% yield).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([C:7]1[S:16][C:15]2[CH2:14][CH2:13][CH2:12][NH:11][C:10](=[O:17])[C:9]=2[CH:8]=1)=[O:6].Cl.[F:19][C:20]1[CH:34]=[CH:33][C:23]2[C:24]([CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[N:25][O:26][C:22]=2[CH:21]=1>>[F:19][C:20]1[CH:34]=[CH:33][C:23]2[C:24]([CH:27]3[CH2:28][CH2:29][N:30]([CH2:2][CH2:3][CH2:4][C:5]([C:7]4[S:16][C:15]5[CH2:14][CH2:13][CH2:12][NH:11][C:10](=[O:17])[C:9]=5[CH:8]=4)=[O:6])[CH2:31][CH2:32]3)=[N:25][O:26][C:22]=2[CH:21]=1
Reactant: O=C(CCCCl)c1cc2c(s1)CCCNC2=O
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: Cl
Product: O=C(CCCN1CCC(c2noc3cc(F)ccc23)CC1)c1cc2c(s1)CCCNC2=O
Yield: 11.8 %

Procedure:
The reaction and procedure were conducted in a similar manner as in Example 24 using 1.1 g of 2-(4-chlorobutyryl)-5,6,7,8-tetrahydro-4H-thieno[3,2-c]azepin-4-one and 1.0 g of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine hydrochloride to give 0.21 g of 2-(4-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)butyryl)-5,6,7,8-tetrahydro-4H-thieno[3,2-c]azepin-4-one, m.p. 142°-143° C.