Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH3:16])[CH2:3][C:4]([C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1)=[O:5].[Br-:17].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1>O1CCCC1>[Br:17][CH:3]([CH:2]([CH3:16])[CH3:1])[C:4]([C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1)=[O:5]
Reactant: [Br-]
Reactant: CC(C)CC(=O)c1cccc2ccccc12
Agent: C[N+](C)(C)c1ccccc1
Solvent: C1CCOC1
Product: CC(C)C(Br)C(=O)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-methyl-1-(naphth-1-yl)butan-1-one (20 g) in anhydrous tetrahydrofuran (150 ml) was added phenyltrimethylammonium tribromide (35.7 g). The resulting mixture was stirred overnight at ambient temperature then partitioned between petroleum ether and water. The organic layer was separated, washed with water, brine, dried with sodium sulphate, filtered and evaporated in vacuo to yield crude 2-bromo-3-methyl-1-(naphth-1-yl)butan-1-one. Sodium acetate (7.7 g) and anhydrous dimethylformamide (40 ml) were added and the resulting mixture was stirred at 100° C. for 6 hours. After cooling, the mixture was partitioned between ethyl acetate and water. The aqueous layer was back-extracted once with ethyl acetate. The combined organic layers were washed with water, brine, dried with sodium sulphate, filtered and evaporated in vacuo. The title compound (8.4 g) was obtained following silica gel column chromatography of the residue in 50% dichloromethane in petroleum ether.
Reaction SMILES: C([O:9][C:10]1[CH:11]=[C:12]([CH:28]=[CH:29][C:30]=1[Cl:31])[CH2:13][N:14]([C:20]1[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=1)[N:15]1[CH:19]=[N:18][N:17]=[CH:16]1)(=O)C1C=CC=CC=1.C[O-].[Na+]>CO.O>[Cl:31][C:30]1[CH:29]=[CH:28][C:12]([CH2:13][N:14]([C:20]2[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=2)[N:15]2[CH:16]=[N:17][N:18]=[CH:19]2)=[CH:11][C:10]=1[OH:9]
Reactant: N#Cc1ccc(N(Cc2ccc(Cl)c(OC(=O)c3ccccc3)c2)n2cnnc2)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: N#Cc1ccc(N(Cc2ccc(Cl)c(O)c2)n2cnnc2)cc1
Temperature: 25 °C
Yield: 48.1 %

Procedure:
A solution of 4-[(3-benzoyloxy-4-chlorobenzyl)(4-cyanophenyl)amino]-4H-[1,2,4]triazole (1.13 g, 2.63 mmol) and NaOMe (500 mg) in MeOH (20 mL) and water (5 mL) was heated to reflux for 30 minutes. After cooling to room temperature most of the solvent was removed in vacuo and concentrated sodium bicarbonate solution (20 mL) and EtOAc (50 mL) were added. The organic layer was separated, dried (Na2SO4) and the solvent was removed under reduced pressure. The resulting white powder was refluxed in EtOAc (10 mL, product did not dissolve completely). The product was filtered off and dried in vacuo to give STX483 as a white powder (0.412 g, 48%); δH (400 MHz, DMSO-d6) 4.97 (s, 2H), 6.71-6.75 (m, 3H, AA′BB′ and ArH), 6.84 (d, J=2.0, 1H), 7.25 (d, J=8.2, 1H), 7.75 (AA′BB′, 2H), 8.76 (s, 2H), 10.21 (s, 1H—exchanges with D2O); LRMS (FAB+) m/z (rel. intensity) 326.1 (100, [M+H]+).
Reaction SMILES: Cl[C:2]1[C:11]([Cl:12])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:13]([O-:15])=[O:14])[CH:8]=2)[N:3]=1.O.[NH2:17][NH2:18]>C(O)C>[Cl:12][C:11]1[C:2]([NH:17][NH2:18])=[N:3][C:4]2[C:9]([N:10]=1)=[CH:8][C:7]([N+:13]([O-:15])=[O:14])=[CH:6][CH:5]=2
Reactant: O=[N+]([O-])c1ccc2nc(Cl)c(Cl)nc2c1
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNc1nc2ccc([N+](=O)[O-])cc2nc1Cl
Temperature: 25 °C
Yield: 94.7 %

Procedure:
A mixture of 6.1 g (25 mmol) of 2,3-dichloro-6-nitroquinoxaline and 2.75 g (55 mmol) of hydrazine hydrate in 150 ml of ethanol was stirred at room temperature over night. The precipitate was isolated and washed with water, cold ethanol and ether to give 5.67 g (95%) of crude product.
Reaction SMILES: CC([N+]1(C)[C@@H]2[CH2:9][C@@H:10]([O:12][C:13]([CH:15](C3C=CC=CC=3)[CH2:16][OH:17])=[O:14])C[C@H]1CC2)C.[OH2:25].[Br-]>C(O)C>[CH2:10]([OH:12])[CH3:9].[OH:17][CH2:16][CH:15]([CH2:13][OH:14])[OH:25]
Reactant: CC(C)[N+]1(C)[C@@H]2CC[C@H]1C[C@@H](OC(=O)C(CO)c1ccccc1)C2
Reactant: O
Agent: [Br-]
Solvent: CCO
Product: OCC(O)CO

Procedure:
The solubility of ipratropium bromide in ethanol is 42.48 mg/g.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1)=[O:3].F[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1>>[C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)(=[O:3])[CH3:1]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CC(=O)c1ccc(O)cc1
Product: CC(=O)c1ccc(Oc2ccc([N+](=O)[O-])cc2)cc1

Procedure:
Entry 26: 4-Hydroxyacetophenone was reacted with 4-fluoronitrobenzene according to Method A13, Step 1 to give 4-(4-acetylphenoxy)nitrobenzene. The nitrobenzene was reduced according to Method A13, Step 4 to afford 4-(4-acetylphenoxy)aniline, which was converted to the 4-(4-(1-(N-methoxy)iminoethyl)phenoxyaniline HCl salt according to Method A16. 5-(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method B1. 5-(Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 4-(4-(1-(N-methoxy)iminoethyl)phenoxyaniline HCl salt to Method C1a to afford the urea.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH3:12])=[C:5]([CH3:13])[CH:4]=1.BrCCBr.[N:18]1[C:27]2[C:22](=[CH:23][C:24]([CH:28]=[O:29])=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:9]([C:6]1[CH:7]=[CH:8][C:3]([CH:28]([C:24]2[CH:23]=[C:22]3[C:27](=[CH:26][CH:25]=2)[N:18]=[CH:19][CH:20]=[CH:21]3)[OH:29])=[CH:4][C:5]=1[CH3:13])[CH2:10][CH2:11][CH3:12]
Reactant: O=Cc1ccc2ncccc2c1
Reactant: CCCCc1ccc(Br)cc1C
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: BrCCBr
Solvent: C1CCOC1
Product: CCCCc1ccc(C(O)c2ccc3ncccc3c2)cc1C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 15.7 %

Procedure:
Magnesium (83 mg, 3.40 mmol), 4-bromo-1-butyl-2-methylbenzene (722 mg, 3.18 mmol) and, as an initiator, catalytic amount of 1,2-dibromoethane were added to tetrahydrofuran (2.5 mL) under nitrogen atmosphere, and the mixture was stirred for 10 minutes under reflux. This mixture was cooled to 0° C., a solution of quinoline-6-carbaldehyde (100 mg, 6.36 mmol) in tetrahydrofuran (12 mL) was added thereto, followed by stirring for 1 hour at this temperature. An aqueous solution of saturated ammonium chloride was added to the reaction mixture, which was extracted with chloroform and dried over anhydrous magnesium sulfate. The solvent was evaporated, the residue was purified by silica gel column chromatography (hexane:ethyl acetate), and the title compound (152 mg, 78%) was obtained as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:20]2[S:24][C:23]3[CH:25]=[CH:26][C:27]([O:29][CH2:30][CH2:31][N:32]4[CH2:37][CH2:36][N:35](C(OC(C)(C)C)=O)[CH2:34][CH2:33]4)=[CH:28][C:22]=3[CH:21]=2)=[N:4][C:5]([NH:8][CH2:9][CH2:10][N:11]2[C:15]([CH3:17])([CH3:16])[C:14](=[O:18])[NH:13][C:12]2=[O:19])=[N:6][CH:7]=1.FC(F)(F)C(O)=O>ClCCl>[Br:1][C:2]1[C:3]([C:20]2[S:24][C:23]3[CH:25]=[CH:26][C:27]([O:29][CH2:30][CH2:31][N:32]4[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]4)=[CH:28][C:22]=3[CH:21]=2)=[N:4][C:5]([NH:8][CH2:9][CH2:10][N:11]2[C:15]([CH3:17])([CH3:16])[C:14](=[O:18])[NH:13][C:12]2=[O:19])=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCN(CCOc2ccc3sc(-c4nc(NCCN5C(=O)NC(=O)C5(C)C)ncc4Br)cc3c2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)C(=O)NC(=O)N1CCNc1ncc(Br)c(-c2cc3cc(OCCN4CCNCC4)ccc3s2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 7.4 %

Procedure:
tert-butyl 4-(2-(2-(5-bromo-2-(2-(5,5-dimethyl-2,4-dioxoimidazolidin-1-yl)ethylamino)-pyrimidin-4-yl)benzo[b]thiophen-5-yloxy)ethyl)piperazine-1-carboxylate (0.23 g, 3.3 mmol) dissolved in dichloromethane (3 mL) was treated with trifluoroacetic acid (3 mL) and the mixture stirred at room temperature overnight. The volatiles were removed in vacuo and the residue dissolved in dichloromethane. The organic solution was washed with water, saturated sodium bicarbonate and brine. The solution was dried with sodium sulfate and purified by column chromatography using a gradient of 8% to 20% methanol in dichloromethane to give an off-white solid (0.143 g). MS (M+H)+ 588/590.
Reaction SMILES: [CH2:1](/[C:3](/[C:7]1[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=1)=[CH:4]\[C:5]#[CH:6])[CH3:2].[H-].[Na+].[C:16]([O:24][CH2:25][C:26]1[CH:31]=[C:30]([CH2:32]Br)[CH:29]=[CH:28][C:27]=1[CH2:34][O:35][C:36](=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C=O)C>[C:16]([O:24][CH2:25][C:26]1[CH:31]=[C:30]([CH2:32][O:13][C:9]2[CH:10]=[CH:11][CH:12]=[C:7](/[C:3](/[CH2:1][CH3:2])=[CH:4]/[C:5]#[CH:6])[CH:8]=2)[CH:29]=[CH:28][C:27]=1[CH2:34][O:35][C:36](=[O:43])[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)(=[O:23])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C(OCc1ccc(CBr)cc1COC(=O)c1ccccc1)c1ccccc1
Reactant: C#C/C=C(\CC)c1cccc(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C#C/C=C(\CC)c1cccc(OCc2ccc(COC(=O)c3ccccc3)c(COC(=O)c3ccccc3)c2)c1
Temperature: 25 °C

Procedure:
610 mg (3.5 mmol) of 3-((E)-1-ethylbut-1-en-3-ynyl)phenol are dissolved in 80 ml of DMF. 150 mg (3.7 mmol) of sodium hydride are added, and the mixture is stirred at ambient temperature. 1.5 g (6.2 mmol) of 2-benzoyloxymethyl-5-bromomethylbenzyl benzoate are then added, and the medium is stirred for 2 hours. After the usual treatment and purification by chromatography on a silica gel column, a colorless oil is obtained (m=1.66 g; Y=88%).
Reaction SMILES: [CH2:1]1[CH:8]2[N:4]([C:5](=[O:9])[CH2:6][CH2:7]2)[C:3](=[O:10])[CH2:2]1.Cl.[CH3:12][OH:13]>>[CH3:12][O:13][C:5](=[O:9])[CH2:6][CH2:7][CH:8]1[CH2:1][CH2:2][C:3](=[O:10])[NH:4]1
Reactant: CO
Reactant: O=C1CCC2CCC(=O)N12
Agent: Cl
Product: COC(=O)CCC1CCC(=O)N1

Procedure:
Twenty-eight grams of dihydro 1H-pyrrolizine-3,5 (2H, 6H) dione is dissolved in 100 g of methyl alcohol and 0.2 ml of concentrated hydrochloric acid is added. The solution is heated at reflux for 104 hours. The mixture is cooled and excess methyl alcohol is distilled at reduced pressure. The residual oil is dissolved in 1 of anhydrous diethylether, 1 g of activated charcoal is added and the resulting suspension is filtered through filter aid. The filtrate is concentrated at reduced pressure and the resulting crystals are isolated by filtration. Recrystallization from methanol yields 5-oxo-2-pyrrolidinepropanoic acid methyl ester with a melting point of 52°-53° C.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([O:9][CH3:10])=[O:8].N1C=CC=CC=1.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>C(Cl)(Cl)Cl>[CH3:10][O:9][C:7]([C:3]1[S:4][CH:5]=[CH:6][C:2]=1[NH:1][S:25]([C:22]1[CH:21]=[CH:20][C:19]([O:18][CH3:17])=[CH:24][CH:23]=1)(=[O:27])=[O:26])=[O:8]
Reactant: COC(=O)c1sccc1N
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: COC(=O)c1sccc1NS(=O)(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 65.8 %

Procedure:
To a solution of 5.00 g (0.032 mol) of 3-amino-2-carbomethoxythiophene dissolved in 40 mL of chloroform was added 7.73 mL (0.032 mol) of pyridine followed by 6.57 g (0.032 mol) of p-methoxybenzenesulfonyl chloride. The reaction mixture was stirred at room temperature for 5 h and then washed with 3N HCl and water. The organics were then dried over Na2SO4, filtered and concentrated in vacuo. The resulting cream colored solid was washed with ether and dried in vacuo to provide 6.89 g (66%) of the desired sulfonamide. Electrospray Mass Spec 328.2 M+H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[C:6]([O:11][C:12]1[CH:13]=[CH:14][C:15]([F:33])=[C:16]([NH:18][C:19](=[O:32])[C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]4([C:29]#[N:30])[CH2:28][CH2:27]4)[C:21]=3[Cl:31])[CH:17]=1)[N:5]=2.[C:34](Cl)(=[O:37])[CH2:35][CH3:36].O>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[Cl:31][C:21]1[C:22]([C:26]2([C:29]#[N:30])[CH2:28][CH2:27]2)=[CH:23][CH:24]=[CH:25][C:20]=1[C:19]([NH:18][C:16]1[CH:17]=[C:12]([O:11][C:6]2[N:5]=[C:4]3[S:3][C:2]([NH:1][C:34](=[O:37])[CH2:35][CH3:36])=[N:10][C:9]3=[CH:8][CH:7]=2)[CH:13]=[CH:14][C:15]=1[F:33])=[O:32]
Reactant: N#CC1(c2cccc(C(=O)Nc3cc(Oc4ccc5nc(N)sc5n4)ccc3F)c2Cl)CC1
Reactant: CCC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: c1ccncc1
Product: CCC(=O)Nc1nc2ccc(Oc3ccc(F)c(NC(=O)c4cccc(C5(C#N)CC5)c4Cl)c3)nc2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 45.2 %

Procedure:
To a solution of N-{5-[(2-amino[1,3]thiazolo[5,4-b]pyridin-5-yl)oxy]-2-fluorophenyl}-2-chloro-3-(1-cyanocyclopropyl)benzamide (0.16 g, 0.33 mmol) and N,N-dimethylpyridine-4-amine (0.12 g, 1.00 mmol) in pyridine (2 mL) was added dropwise propionyl chloride (0.09 g, 1.00 mmol) under ice-cooling, and the mixture was stirred at room temperature for 2 hr. To the reaction mixture was added water (50 mL), and the mixture was extracted with ethyl acetate (50 mL×2). The ethyl acetate layers were combined, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in methanol (5 mL), 8N aqueous sodium hydroxide solution (1 mL) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into water (50 mL), and the mixture was extracted with ethyl acetate (50 mL×2). The ethyl acetate layers were combined, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane=0/100→100/0), and recrystallized from methanol to give the title compound (80 mg, 45%) as white crystals.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:11](=[N:12][C:13]=1[CH3:14])[N:10]=[CH:9][CH:8]=[C:7]2O)[CH3:2].P(Cl)(Cl)([Cl:18])=O>>[Cl:18][C:7]1[CH:8]=[CH:9][N:10]=[C:11]2[C:6]=1[CH:5]=[C:4]([O:3][CH2:1][CH3:2])[C:13]([CH3:14])=[N:12]2
Reactant: CCOc1cc2c(O)ccnc2nc1C
Reactant: O=P(Cl)(Cl)Cl
Product: CCOc1cc2c(Cl)ccnc2nc1C

Procedure:
In a similar manner to Example B1, 6-ethoxy-7-methyl-1,8-naphthyridin-4-ol (2.15 g) and phosphorus oxychloride (25 ml) were heated at 60° C. for 1 hour to give 5-chloro-3-ethoxy-2-methyl-1,8-naphthyridine, m.p. 164° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:10]([N:11]([CH2:20][CH:21]([F:23])[F:22])[S:12]([CH2:15][C:16]([O:18][CH3:19])=[O:17])(=[O:14])=[O:13])=[N:9][CH:8]=[CH:7][N:6]=1)=O.C[Si](C)(C)[N-][Si](C)(C)C.[Na+]>O1CCCC1>[CH3:19][O:18][C:16]([C:15]1[S:12](=[O:14])(=[O:13])[N:11]([CH2:20][CH:21]([F:23])[F:22])[C:10]2[C:5]([C:3]=1[OH:2])=[N:6][CH:7]=[CH:8][N:9]=2)=[O:17]
Reactant: COC(=O)CS(=O)(=O)N(CC(F)F)c1nccnc1C(=O)OC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C1=C(O)c2nccnc2N(CC(F)F)S1(=O)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 69.8 %

Procedure:
To a solution of 3-[(2,2-difluoro-ethyl)-methoxycarbonylmethanesulfonyl-amino]-pyrazine-2-carboxylic acid methyl ester (Example 9.2) (0.819 g) in tetrahydrofuran (40 ml) under nitrogen atmosphere was added in portions a solution of sodium hexamethyldisilazide (“NaHMDS”) (5.8 ml) (1M in THF) at ambient temperature. The reaction mixture was stirred for 3 hours at ambient temperature. The reaction was quenched by addition of glacial acetic acid and the mixture was concentrated. The residue was partitioned between ethyl acetate (30 ml) and aqueous hydrochloric acid (2M) (15 ml). The phases were separated and the organic layer was concentrated to give 1-(2,2-difluoro-ethyl)-4-hydroxy-2,2-dioxo-1,2-dihydro-2-λ-6-thia-1,5,8-triaza-naphthalene-3-carboxylic acid methyl ester (0.520 g). 1H-NMR (400 MHz, CDCl3): 8.65 (d, 1H), 8.59 (d, 1H), 6.02-6.32 (m, 1H), 4.60-4.67 (m, 2H), 4.13 (s, 3H) ppm.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:23]2[C:22]([CH3:25])([CH3:24])[N:10]3[CH2:11][CH2:12][C:13]4[C:18]([C:9]3=[CH:8][C:7]=2[CH:6]=[CH:5][C:4]=1[O:26][CH3:27])=[CH:17][C:16]1[O:19][CH2:20][O:21][C:15]=1[CH:14]=4.I[Cl:29]>ClCCl>[Cl:29][C:6]1[C:7]2[CH:8]=[C:9]3[C:18]4[C:13](=[CH:14][C:15]5[O:21][CH2:20][O:19][C:16]=5[CH:17]=4)[CH2:12][CH2:11][N:10]3[C:22]([CH3:24])([CH3:25])[C:23]=2[C:3]([O:2][CH3:1])=[C:4]([O:26][CH3:27])[CH:5]=1
Reactant: COc1ccc2c(c1OC)C(C)(C)N1CCc3cc4c(cc3C1=C2)OCO4
Reactant: ClI
Solvent: ClCCl
Product: COc1cc(Cl)c2c(c1OC)C(C)(C)N1CCc3cc4c(cc3C1=C2)OCO4
Temperature: 25 °C
Reaction time: 72 h
Yield: 4.8 %

Procedure:
To a solution of 9,10-dimethoxy-8,8-dimethyl-5,8-dihydro-6H-[1,3]dioxolo[4,5-g]isoquino[3,2-a]isoquinoline (182 mg, 0.5 mmol) in anhydrous dichloromethane (20 mL) at 25° C. was added Iodine monochloride (0.57 g, 3.5 mmol). After stirring in the dark at 25° C. for 72 h, the reaction was washed twice with aqueous 10% sodium thiosulfate solution (2×50 mL) to remove excessive iodine monochloride, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by Waters Automated Flash System (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 12-chloro-9,10-dimethoxy-8,8-dimethyl-5,8-dihydro-6H-[1,3]dioxolo[4,5-g]isoquino[3,2-a]isoquinoline (9.6 mg, 4%). LC/MS m/e calcd for C22H22ClNO4 (M+H)+: 400.88, observed: 400.1; 1H NMR (400 MHz, MeOD) δ ppm 2.05 (s, 6 H) 3.14 (m, 2 H) 3.93 (s, 3 H) 4.01 (s, 3 H) 4.23 (m, 2 H) 6.22 (s, 2 H) 7.04 (s, 1 H) 7.32 (s., 1 H) 7.63 (s, 1 H).
Reaction SMILES: [C:1]([NH2:11])(=[S:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Cl:12][CH2:13][C:14]([CH2:16]Cl)=O.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[Cl:12][CH2:13][C:14]1[N:11]=[C:1](/[CH:2]=[CH:3]/[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[S:10][CH:16]=1
Reactant: NC(=S)C=Cc1ccccc1
Reactant: O=C(CCl)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: ClCc1csc(/C=C/c2ccccc2)n1
Yield: 55.6 %

Procedure:
A mixture of thiocinnamamide (11.7 g), 1,3-dichloroacetone (9.10 g) and ethanol (145 ml) was heated for one hour under reflux. The reaction mixture was poured onto ice-water, neutralized with potassium carbonate, and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4), and concentrated under reduced pressure. The residue was subjected to a silica gel column chromatography. From the fraction eluted with diethyl ether-hexane (1:5, v/v), 4-chloromethyl-2-[(E)-2-phenylethenyl]thiazole (9.40 g, 66%) was obtained. Recrystallization from diethyl ether-hexane gave colorless plates, mp 88-89° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][C@H:18]([NH2:26])[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:27][O:28][C:29](=[O:40])[C:30](=[CH:35][CH:36]=[CH:37]OC)[C:31](OC)=[O:32].C[O-].[Na+]>CO.O>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][C@@H:18]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[N:26]2[CH:37]=[CH:36][CH:35]=[C:30]([C:29]([O:28][CH3:27])=[O:40])[C:31]2=[O:32])=[CH:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1cn(C(=O)OC(C)(C)C)c2ccccc12
Reactant: COC=CC=C(C(=O)OC)C(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)c1cccn([C@@H](Cc2cn(C(=O)OC(C)(C)C)c3ccccc23)C(=O)OC(C)(C)C)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.2 %

Procedure:
To a solution of (S)-3-(2-Amino-2-tert-butoxycarbonyl-ethyl)-indole-1-carboxylic acid tert-butyl ester (2.5 g, 7 mmol) in methanol (15 ml) was added 2-(3-methoxy-allylidene)-malonic acid dimethyl ester (1.5 g, 7 mmol) and stirred overnight at room temperature. Sodium methoxide (78 mg, 1.4 mmol) was added and stirred for three hours at room temperature. The reaction mixture was diluted with water (50 ml) and extracted with ethylacetate (60 ml). The organic layer was washed with brine, dried (MgSO4), filtered and evaporated to afford the crude product, which was perified by flash chromatography (30-70% ethylacetate/petroleum ether) to afford the title compound as a white solid (2.3 g, 57%); 1H NMR (400 MHz, CDCl3) δ 1.43 (9H, s), 1.72 (9H, s), 3.50 (2H, m), 3.91 (3H, m), 5.68 (1H, br s), 6.08 (1H, t), 7.2-7.5 (5H, m), 8.15 (2H, m); M+H 497.5, M−H 495.5.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:10]=1.N1C=CC=CC=1.[C:17](OC(=O)C)(=[O:19])[CH3:18]>C(Cl)Cl>[C:17]([NH:1][C:2]1[S:3][C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:10]=1)(=[O:19])[CH3:18]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1nc2cnccc2s1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Nc1nc2cnccc2s1
Yield: 46 %

Procedure:
To a suspension of 2-aminothiazolo[4,5-c]pyridine [prepared according to the procedure in T. Takahashi et al., Pharm. Bull. (Japan) 2, 34 (1954)] (151 mg, 1 mmole) in acetic anhydride (1 ml) was added pyridine (1 ml), and the mixture was heated at 100°-120° C. for an hour. After cooling, the mixture was diluted with CH2Cl2 (20 ml). The resulting precipitate was collected by filtration and recrystallized from methanol (20 ml) to give 90 mg of the title compound as fine needles (46%). Mp. >212° C. (sub.).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH:3]=1.[Li+].CC([N-]C(C)C)C.[CH:19]([N:32]1[CH2:35][C:34](=[O:36])[CH2:33]1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1COCC1>[CH:19]([N:32]1[CH2:35][C:34]([C:3]2[O:4][C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:2]=2[CH3:1])([OH:36])[CH2:33]1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: Cc1coc2ccccc12
Reactant: O=C1CN(C(c2ccccc2)c2ccccc2)C1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1c(C2(O)CN(C(c3ccccc3)c3ccccc3)C2)oc2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 30.7 %

Procedure:
A solution of 3-methylbenzofuran (550 mg, 4.16 mmol) in dry THF (17 mL) was cooled to −78° C. and LDA (1.8 M in THF/heptane/ethylbenzene) (2.8 mL, 5.04 mmol) was added dropwise under N2 over 5 min. After stirring for 30 min, 1-benzhydrylazetidin-3-one (1.61 g, 6.78 mmol) was added portionwise over 10 min. The reaction was stirred under N2 at −78° C. for 15 min, and was then allowed to warm to rt and stirred for 1.5 h. The reaction was quenched with 0.5N HCl and extracted with EtOAc. The organic layer was washed with water and brine, dried on Na2SO4 and concentrated. The residue was purified by flash chromatography (heptane/EtOAc, 5%->35%), yielding the product (472 mg, 31%) as a yellow oil.
Reaction SMILES: [C:1]([C:5]1[CH:30]=[CH:29][C:8]([O:9][C:10]2[CH:19]=[C:18]3[C:13]([CH:14]=[C:15]([C:26](O)=[O:27])[N:16]=[C:17]3[CH2:20][CH:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:12][CH:11]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.C[O:33][C:34](=[O:48])[C@@H:35]([NH2:47])[CH2:36][C:37]1[CH:42]=[CH:41][C:40]([C:43]([CH3:46])([CH3:45])[CH3:44])=[CH:39][CH:38]=1>>[C:1]([C:5]1[CH:30]=[CH:29][C:8]([O:9][C:10]2[CH:19]=[C:18]3[C:13]([CH:14]=[C:15]([C:26]([NH:47][C@@H:35]([CH2:36][C:37]4[CH:42]=[CH:41][C:40]([C:43]([CH3:46])([CH3:45])[CH3:44])=[CH:39][CH:38]=4)[C:34]([OH:33])=[O:48])=[O:27])[N:16]=[C:17]3[CH2:20][CH:21]3[CH2:22][CH2:23][CH2:24][CH2:25]3)=[CH:12][CH:11]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@@H](N)Cc1ccc(C(C)(C)C)cc1
Reactant: CC(C)(C)c1ccc(Oc2ccc3cc(C(=O)O)nc(CC4CCCC4)c3c2)cc1
Agent: Cl
Product: CC(C)(C)c1ccc(C[C@H](NC(=O)c2cc3ccc(Oc4ccc(C(C)(C)C)cc4)cc3c(CC3CCCC3)n2)C(=O)O)cc1
Yield: 98.1 %

Procedure:
50 mg (0.12 mmol) of 7-(4-tert-butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carboxylic acid (Example 419) was reacted with (2S)-amino-3-(4-tert-butyl-phenyl)-propionic acid methyl ester HCl (36.8 mg, 0.14 mmol) as described in general procedure A. The resulting ester was hydrolyzed as described in general procedure C to afford 71.4 mg of the title compound as a white solid.