Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:15]([C:16]([N:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)=[O:17])=[N:14][NH:13][C:12](=[O:23])[C:7]=3[N:8]([CH3:11])[C:9]=2[CH:10]=1.C(=O)([O-])[O-].[K+].[K+].Br[C:31]1[N:36]=[CH:35][CH:34]=[CH:33][N:32]=1>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:15]([C:16]([N:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)=[O:17])=[N:14][N:13]([C:31]4[N:36]=[CH:35][CH:34]=[CH:33][N:32]=4)[C:12](=[O:23])[C:7]=3[N:8]([CH3:11])[C:9]=2[CH:10]=1
Reactant: Cn1c2cc(F)ccc2c2c(C(=O)N3CCCC3)n[nH]c(=O)c21
Reactant: Brc1ncccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1c2cc(F)ccc2c2c(C(=O)N3CCCC3)nn(-c3ncccn3)c(=O)c21

Procedure:
A solution of 0.24 g (0.73 mmol) of 1-[[7-fluoro-5-methyl-4-oxo-3,5-dihydro-4H-pyridazino[4,5-b]indol-1-yl]carbonyl]pyrrolidine (obtained in stage 5.1.), 0.120 g (0.63 mmol) of cuprous iodide, 0.15 g (1.09 mmol) of potassium carbonate and of 0.30 g (1.89 mmol) of 2-bromopyrimidine in 40 ml of N,N-dimethylformamide is heated at 150° C. for 16 h. The reaction mixture is cooled and concentrated under reduced pressure. Dichloromethane, water and a concentrated sodium hydroxide solution are added. The organic phase is separated by settling, filtered through Celite®, washed with water, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified by chromatography on a column of silica gel (eluent: dichloromethane/ethyl acetate: 80/20 to 0/100; ethyl acetate/methanol: 100/0 to 90/10). The solid obtained is recrystallized from a dichloromethane/ethyl acetate mixture and washed with diethyl ether.
Reaction SMILES: O.[C:2]1([OH:10])[CH:9]=[C:7]([CH3:8])[CH:6]=[C:4]([OH:5])[CH:3]=1.[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[S:19](Cl)(=[O:21])=[O:20])#[N:12]>C([O-])(O)=O.[Na+].C(OCC)C.O>[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[S:19]([O:5][C:4]1[CH:3]=[C:2]([OH:10])[CH:9]=[C:7]([CH3:8])[CH:6]=1)(=[O:21])=[O:20])#[N:12]
Reactant: N#Cc1ccccc1S(=O)(=O)Cl
Reactant: Cc1cc(O)cc(O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: Cc1cc(O)cc(OS(=O)(=O)c2ccccc2C#N)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
Orcinol monohydrate (1.42 g, 10.0 mmol) and 2-cyanobenzenesulfonyl chloride (2.02 g, 10.0 mmol) were rnixed in saturated aqueous NaHCO3 (30 mL) and diethyl ether (30 mL). The biphasic mixture was stirred vigorously at room temperature overnight. The reaction mixture was diluted with water (50 mL) and extracted into ethyl acetate (3×50 mL). The organic phase was washed with brine (2×50 mL) and dried over Na2SO4. After removing the solvent in vacuo, the residue was purified by flash column chromatography (dichloromethane to 5% ethyl acetate in dichloromethane) to give the title compound as a white solid (1.65 g, 57%). 1H-NMR (300 MHz, CDCl3) δ 8.07 (m, 1H), 7.94 (m, 1H), 7.75-7.80 (m, 2H), 6.57 (s, 1H), 6.53 (s, 1H), 6.49 (s, 1H), 5.69 (br s, 1H), 2.22 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5]O)[CH3:2].[C:7]1([CH3:17])[CH:12]=[CH:11][C:10]([S:13](Cl)(=[O:15])=[O:14])=[CH:9][CH:8]=1.C(OCC)(=[O:20])C>N1C=CC=CC=1>[CH2:1]([O:3][CH2:4][CH2:5][C:8]1[CH:9]=[C:10]([S:13]([OH:20])(=[O:15])=[O:14])[CH:11]=[CH:12][C:7]=1[CH3:17])[CH3:2]
Reactant: CCOC(C)=O
Reactant: CCOCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: CCOCCc1cc(S(=O)(=O)O)ccc1C
Temperature: 25 °C
Yield: 56 %

Procedure:
2 g of 2-ethoxyethanol were dissolved in 40 ml of pyridine, to which 5.66 g of p-toluenesulfonyl chloride was added under ice-cooling conditions, followed by raising to room temperature. Ethyl acetate was added, followed by washing with water and a saturated sodium hydrogencarbonate aqueous solution and drying with anhydrous magnesium sulfate. This was filtered and, after removal of the solvent by distillation, the resultant residue was subjected to silica gel column chromatography (developing solvent: ethyl acetate:hexane=5.95) to obtain 3.69 g of the captioned compound (yield 56%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:15]=[C:16]([O:18][C@@H:19]([CH3:23])[CH2:20][O:21][CH3:22])[CH:17]=1)[C:5]([NH:7][C:8]1[CH:13]=[N:12][C:11]([CH3:14])=[CH:10][N:9]=1)=[O:6].F[C:25]1[CH:37]=[CH:36][C:28]2[S:29](=[O:35])(=[O:34])[CH2:30][CH2:31][CH2:32][O:33][C:27]=2[CH:26]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>C(#N)C.O>[O:35]=[S:29]1(=[O:34])[C:28]2[CH:36]=[CH:37][C:25]([O:1][C:2]3[CH:3]=[C:4]([CH:15]=[C:16]([O:18][C@@H:19]([CH3:23])[CH2:20][O:21][CH3:22])[CH:17]=3)[C:5]([NH:7][C:8]3[CH:13]=[N:12][C:11]([CH3:14])=[CH:10][N:9]=3)=[O:6])=[CH:26][C:27]=2[O:33][CH2:32][CH2:31][CH2:30]1
Reactant: O=S1(=O)CCCOc2cc(F)ccc21
Reactant: COC[C@H](C)Oc1cc(O)cc(C(=O)Nc2cnc(C)cn2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O
Product: COC[C@H](C)Oc1cc(Oc2ccc3c(c2)OCCCS3(=O)=O)cc(C(=O)Nc2cnc(C)cn2)c1
Temperature: 160 °C
Reaction time: 5 h
Yield: 34.8 %

Procedure:
A mixture of 3-hydroxy-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-N-(5-methylpyrazin-2-yl)benzamide (0.15 g, 0.47 mmol), 8-fluoro-3,4-dihydro-2H-1,5-benzoxathiepine 5,5-dioxide (103 mg, 0.47 mmol) and potassium carbonate (131 mg, 0.95 mmol) in acetonitrile (5 mL) was stirred in a microwave reactor at 160° C. for 5 hours. The mixture was reduced in vacuo and ethyl acetate (50 mL) and water (50 mL) were added. The aqueous layer was re-extracted into ethyl acetate (50 mL) and the combined organics washed with water (50 mL), brine (50 mL), dried (MgSO4), filtered and reduced in vacuo to give a golden oil. The oil was chromatographed on silica, eluting with 40-100% ethyl acetate in isohexane, to give the desired compound as a white foam (84 mg). 1H NMR δ (CDCl3): 1.34 (d, 3H), 2.39-2.47 (m, 2H), 2.56 (s, 3H), 3.34-3.37 (m, 2H), 3.41 (s, 3H), 3.49-3.61 (m, 2H), 4.24-4.27 (m, 2H), 4.58-4.65 (m, 1H), 6.76 (d, 1H), 6.85-6.88 (m, 2H), 7.16 (t, 1H), 7.35 (t, 1H), 7.94 (d, 1H), 8.14 (s, 1H), 8.30 (s, 1H), 9.53 (s, 1H); m/z 514 (M+H)+
Reaction SMILES: [N:1]([C@H:4]1[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@@H:6]([CH3:16])[CH2:5]1)=[N+]=[N-].[F:17][C:18]([F:33])([F:32])[C:19]1[CH:20]=[C:21]([CH:29]=[CH:30][CH:31]=1)[C:22]([NH:24][CH2:25][C:26](O)=[O:27])=[O:23].C(N(CC)CC)C.C(Cl)CCl>C(Cl)Cl>[CH3:16][C@H:6]1[CH2:5][C@@H:4]([NH:1][C:26](=[O:27])[CH2:25][NH:24][C:22](=[O:23])[C:21]2[CH:29]=[CH:30][CH:31]=[C:19]([C:18]([F:17])([F:33])[F:32])[CH:20]=2)[CH2:8][N:7]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10]
Reactant: O=C(O)CNC(=O)c1cccc(C(F)(F)F)c1
Reactant: C[C@H]1C[C@@H](N=[N+]=[N-])CN1C(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: ClCCCl
Product: C[C@H]1C[C@@H](NC(=O)CNC(=O)c2cccc(C(F)(F)F)c2)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the amine of step D (0.5 g, 2.5 mmol), the carboxylic acid obtained in step A, Example 114 and triethylamine (0.7 mL, 5.0 mmol) in methylene chloride (25 mL) cooled in an ice bath was added EDC (0.53 g, 2.75 mmol). After being stirred at room temperature overnight, the solution was concentrated. The residue was purified on silica gel eluting with a gradient of 0-4% MeOH(CH2Cl2 provided 0.6 g of the title compound. MS calculated (M+H)+ 430, found 430.1.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([OH:12])[CH:11]=1)[C:8](=[O:13])[CH2:7][CH2:6][C:5]2([CH3:15])[CH3:14].C(N(CC)CC)C.[CH3:23][Si:24]([C:27]#[CH:28])([CH3:26])[CH3:25].C(OCC)(=O)C>CCCCCC.[Cu]I.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>[OH:12][C:10]1[CH:11]=[C:2]([C:28]#[C:27][Si:24]([CH3:26])([CH3:25])[CH3:23])[CH:3]=[C:4]2[C:9]=1[C:8](=[O:13])[CH2:7][CH2:6][C:5]2([CH3:15])[CH3:14]
Reactant: CC1(C)CCC(=O)c2c(O)cc(Br)cc21
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC1(C)CCC(=O)c2c(O)cc(C#C[Si](C)(C)C)cc21
Yield: 100.5 %

Procedure:
Following General Procedure D and using 6-bromo-8-hydroxy-4,4-dimethyl-3,4-dihydro-2H-naphthalen-1-one (Intermediate 65, 1.56 g, 5.8 mmol), triethyl amine (20 mL), copper(I)iodide (0.088 g, 0.46 mmol), trimethylsilyl acetylene (3 mL, 21.22 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.325 g, 0.46 mmol) followed by flash column chromatography over silica gel (230-400 mesh) using hexane to 2-5% ethyl acetate in hexane as the eluent, the title compound (1.67 g, 100%) was obtained as an orange solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:10]([CH3:11])=[CH:9][C:8]([F:12])=[CH:7][N:6]=1)=[O:4].O.[OH-].[Li+]>CO.O>[F:12][C:8]1[CH:9]=[C:10]([CH3:11])[C:5]([C:3]([OH:4])=[O:2])=[N:6][CH:7]=1
Reactant: COC(=O)c1ncc(F)cc1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cc(F)cnc1C(=O)O
Reaction time: 16 h
Yield: 86.9 %

Procedure:
To a solution of 5-fluoro-3-methyl-pyridine-2-carboxylic acid methyl ester (1.28 g) in MeOH (6 ml) was added at 22° C. a solution of lithium hydroxide mono hydrate (636 mg) in water (3 ml) and stiring was continued for 16 h. The mixture was diluted with water, the MeOH was evaporated at reduced pressure and the pH was adjusted to 1 using 1 N aqueous HCl. The aqueous layer was extracted with AcOEt, the organic layer was dried, evaporated and the residue was crystallized from AcOEt/n-heptane to give the title compound (1.02 g) as a pale yellow solid. MS: m/z=153.7 [M−H]−.
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:3]=1[CH2:4][S:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1.ClC1C=CC=C(C(OO)=[O:25])C=1.[OH2:28]>C(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:3]=1[CH2:4][S:5]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)(=[O:25])=[O:28]
Reactant: Cc1ccc(C)c(CSc2ccccn2)c1
Reactant: O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: Cc1ccc(C)c(CS(=O)(=O)c2ccccn2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a well-stirred and cooled (−10° C.) solution of 6.9 g (0.03 mole) of 2-(2,5-dimethyl-benzylthio)pyridine in 75 ml of chloroform was added portion-wise a solution of 12 g (0.06 mole) of metachloroperbenzoic acid dissolved in 100 ml of chloroform. The mixture was kept at −10° C. for 10 minutes and then allowed to warm to room temperature over the next six hours. It was stirred at room temperature overnight. Water was then added and the phases separated. he chloroform phase was washed with aqueous sodium bicarbonate and then again with water. he chloroform phase was dried with anhydrous sodium sulfate, filtered, and the chloroform removed using a rotary evaporator to give 8 g of an oil. The oil was crystallized from a small amount of ethanol, with a melting point of 77-78° C., and a yield of 3 g (30%). IR spectrum showed the presence of SO2 at 1160, 1310 cm−1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:13]=[N:12][C:11]([SH:14])=[N:10]2)=[CH:5][CH:4]=1.[OH-].[Na+].CO.S(OC)(O[CH3:23])(=O)=O>O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH:13]=[N:12][C:11]([S:14][CH3:23])=[N:10]2)=[CH:7][CH:8]=1
Reactant: COS(=O)(=O)OC
Reactant: COc1ccc(-n2cnc(S)n2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc(-n2cnc(SC)n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65 %

Procedure:
A mixture of 8 parts of 1-(4-methoxyphenyl)-1H-1,2,4-triazole-3-thiol, 3.1 parts of sodium hydroxide and 40 parts of methanol is stirred for 30 minutes at room temperature. Then there are added 4.9 parts of dimethyl sulfate and stirring at room temperature is continued for 3 hours. Water is added to the reaction mixture and the product is extracted twice with 1,1'-oxybisethane. The combined extracts are dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using trichloromethane as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from 2,2'-oxybispropane, yielding 5.6 parts (65%) of 1-(4-methoxyphenyl)-3-(methylthio)-1H-1,2,4-triazole; mp. 54.9° C.
Reaction SMILES: [OH:1][C@@H:2]([C@@H:7]([OH:19])[CH:8]1[CH2:10][N@@:9]1[C@@H:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:12])[C:3]([O:5][CH3:6])=[O:4].[CH3:20]S(N)(=O)=O>CC(O)(C)C.O>[OH:1][C@H:2]([C@@H:7]([OH:19])[CH:8]1[CH2:10][N@@:9]1[C@@H:11]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH3:12])[C:3]([O:5][CH2:6][CH3:20])=[O:4]
Reactant: COC(=O)[C@@H](O)[C@@H](O)C1C[N@@]1[C@H](C)c1ccccc1
Reactant: CS(N)(=O)=O
Agent: CCOC(=O)[C@H](O)[C@@H](O)C1C[N@]1[C@H](C)c1ccccc1
Agent: COC(=O)[C@@H](O)[C@@H](O)C1C[N@]1[C@H](C)c1ccccc1
Solvent: O
Solvent: CC(C)(C)O
Product: CCOC(=O)[C@H](O)[C@@H](O)C1C[N@@]1[C@H](C)c1ccccc1
Reaction time: 24 h

Procedure:
To a solution of (2S,3S)-methyl 2,3-dihydroxy-3-((R)-1-((R)-1-phenylethyl)aziridin-2-yl)propanoate (3.3 g, 13.3 mmol) in t-BuOH/H2O (60 mL, 0.2 M/60 mL, 0.2 M) were added AD-mix α (33 g, 1000 w/w %) and methanesulfonamide (1.9 g, 19.9 mmol, 1.5 equiv) at 0° C. The reaction mixture was stirred for 24 hrs and quenched with water. The aqueous layer was extracted with ethyl acetate and the combined organic layer was washed with brine, dried over MgSO4, filtered through a pad of celite, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography with ethyl acetate/hexane (2/3) to afford the title product (diastereomeric mixture, ratio=7/1). Yield: 2.3 g (62%); yellow oil.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[C:5]1([CH2:15][NH2:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:5]1([CH2:15][N:16]=[C:1]=[O:2])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1
Reactant: NCc1cccc2ccccc12
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C=NCc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of phosgene (20% in toluene, 5 ml) was diluted with toluene (10 ml). A mixture of 1-naphthalenemethylamine (500 μl, 3.41 mmol), triethylamine (0.95 ml, 6.82 mmol) in toluene (5 ml) was added dropwise. The reaction mixture was heated at reflux overnight. The mixture was cooled to room temperature, and the solvent was removed. The residue was stirred with ether (50 ml) for 10 minutes and filtered. The filtrate was concentrated to give the crude product which was purified by flash chromatography (silica gel, methylene chloride) to give the desired product (518 mg) as a colorless oil. IR 2260 cm−1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]#[C:18][CH2:19][CH2:20][CH2:21]I)[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.C[CH:24]=[CH:25][CH2:26][NH2:27].[CH3:28]O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]#[C:18][CH2:19][CH2:20][CH2:21][N:27]([CH2:26][CH:25]=[CH2:24])[CH3:28])[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1
Reactant: CO
Reactant: O=C(Oc1ccc(Cl)cc1)N1CCC(C#CCCCI)CC1
Reactant: CC=CCN
Product: C=CCN(C)CCCC#CC1CCN(C(=O)Oc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44 %

Procedure:
300 mg (corresponds to 0.7 mmol) of crude 4-(5-Iodo-pent-1-ynyl)-piperidine-1-carboxylic acid 4-chloro-phenyl ester in 5 ml MeOH was treated with 0.7 ml (6.95 mmol) of N-methylallylamine (at 0° C.). The reaction was stirred overnight at room temperature and partitioned between aqueous 1N NaOH /ether (3×), the organic phases were dried (Na2SO4) and evaporated. Purification by flash-chromatography on silica gel (CH2Cl2/MeOH 19:1) gave 116 mg (44% over two steps) of 4-[5-(Allyl-methyl-amino)-pent-1-ynyl]-piperidine-1-carboxylic acid 4-chloro-phenyl ester, MS: 375 (MH+, 1Cl).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:11])[CH2:9][CH3:10])=[CH:4][CH:3]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13]>C1(C)C=CC=CC=1>[C:8]([C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:12](=[O:14])[CH3:13])=[CH:7][CH:6]=1)(=[O:11])[CH2:9][CH3:10]
Reactant: CC(=O)OC(C)=O
Reactant: CCC(=O)c1ccc(N)cc1
Solvent: Cc1ccccc1
Product: CCC(=O)c1ccc(NC(C)=O)cc1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To 400 ml of toluene are added 30 g of 1-(4-aminophenyl)propan-1-one and 38 ml (402 mM) of acetic anhydride. The reaction medium is heated at 60° C. with stirring for 1 hour. A solid precipitates out. After filtration and washing with toluene, 37.9 g of N-(4-propanoylphenyl)acetamide are obtained in the form of a white powder.
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH2:9])=[C:4]([NH2:8])[CH:5]=[CH:6][CH:7]=1.[Cl:10][CH2:11][C:12](O)=O.[OH-].[NH4+]>Cl>[Cl:10][CH2:11][C:12]1[NH:9][C:3]2[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][C:4]=2[N:8]=1
Reactant: Cc1cccc(N)c1N
Reactant: O=C(O)CCl
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Product: Cc1cccc2nc(CCl)[nH]c12
Temperature: 25 °C

Procedure:
A solution of 1.83 g (15 m mol) of 3-methyl-1,2-phenylenediamine in 20 ml of 4N aqueous hydrochloric acid was stored at room temperature overnight. To the solution was added 2.13 g (22.5 m mol) of monochloroacetic acid and refluxed for 3 hours. The reaction solution was cooled to room temperature, rendered alkaline by addition of ammonium hydroxide and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried on anhydrous sodium sulfate. The solvent was evaporated in vacuo and the residue was crystallized from ethyl ether to give 0.8 g (29.52%).
Reaction SMILES: [Al](Cl)([CH2:4][CH3:5])CC.[H][H].[CH3:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]C>>[CH2:9]=[CH:10][CH2:11][CH2:12][CH2:13][CH3:14].[CH2:9]=[CH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH:4]=[CH2:5]
Reactant: CCCCCCC
Reactant: CC[Al](Cl)CC
Reactant: [H][H]
Product: C=CCCCC
Product: C=CCCCCC=C
Reaction time: 20 h

Procedure:
A solution of 985.94 grams (11.715 mole) 1-hexene and 58.24 grams (0.4831 mole) 1,7-octadiene (molar charge ratio 96:4) in 450 grams of heptane was polymerized with Et2AlCl (13.5 millimoles) and AATiCl3 (6.97 millimoles) at 25° C. for 20 hours. During the course of the reaction, hydrogen was bubbled through the reaction mixture. The conversion of the polymer was 62 percent, inherent viscosity was 1.6 dl/gram. The composition of monomers in the copolymer was 97.8:2.2 mole ratio from NMR analysis.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[CH2:20][CH2:21][NH:22][C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[H-].[Na+].[F:27][C:28]1[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=1[CH2:30]Cl>>[F:27][C:28]1[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=1[CH2:30][N:22]1[CH2:21][CH2:20][N:16]2[C:17]3[CH:18]=[CH:19][C:11]([O:10][CH:7]4[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]4)=[CH:12][C:13]=3[CH:14]=[C:15]2[C:23]1=[O:24]
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3CCNC2=O)CC1
Reactant: Fc1ccccc1CCl
Agent: [H-]
Agent: [Na+]
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3CCN(Cc3ccccc3F)C2=O)CC1
Yield: 77 %

Procedure:
The title compound was synthesized in analogy to example 17, from 8-(1-isopropyl-piperidin-4-yloxy)-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (example 1), sodium hydride and 2-fluorobenzyl chloride, to give the desired product as a white solid (77%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[F:30])[CH2:5][NH:6][C:7]([C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([NH2:18])[CH:16]=2)[N:11]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:10]=1[CH3:26])=[O:8].[C:31](OC(=O)C)(=[O:33])[CH3:32]>N1C=CC=CC=1.CCOC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[F:30])[CH2:5][NH:6][C:7]([C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([NH:18][C:31](=[O:33])[CH3:32])[CH:16]=2)[N:11]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:10]=1[CH3:26])=[O:8]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1c(C(=O)NCc2ccc(F)c(F)c2)c2cc(N)ccc2n1Cc1ccccc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=O)Nc1ccc2c(c1)c(C(=O)NCc1ccc(F)c(F)c1)c(C)n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 68.9 %

Procedure:
To a solution of 5-amino-1-benzyl-2-methyl-1H-indole-3-carboxylic acid, 3,4-difluorobenzylamide (Compound 46, 50 mg, 0.12 mmol) in pyridine (3 ml) was added acetic anhydride (120 μl, 1.23 mmol). The reaction was stirred at room temperature for 72 h, diluted with EtOAc, washed successively with 1M HCl, H2O, brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was crystallized from CH2Cl2-Et2O to yield 5-acetamido-1-benzyl-2-methyl-1H-indole-3-carboxylic acid, 3,4-difluorobenzylamide (Compound 47) as a white solid (37 mg, 68%).
Reaction SMILES: BrC1C=CC=C2C=1C(C1C(O)=CC3OCOC=3C=1)[C:5](=[O:16])N2CCCCC.[CH2:27]([O:34][CH2:35][CH2:36][CH2:37][N:38]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH:40]([C:47]2[C:55]([OH:56])=[CH:54][C:50]3[O:51][CH2:52][O:53][C:49]=3[CH:48]=2)[C:39]1=[O:57])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:27]([O:34][CH2:35][CH2:36][CH2:37][N:38]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[C:40]([C:47]2[C:55]([OH:56])=[CH:54][C:50]3[O:51][CH2:52][O:53][C:49]=3[CH:48]=2)([CH2:5][OH:16])[C:39]1=[O:57])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: O=C1C(c2cc3c(cc2O)OCO3)c2ccccc2N1CCCOCc1ccccc1
Reactant: CCCCCN1C(=O)C(c2cc3c(cc2O)OCO3)c2c(Br)cccc21
Product: O=C1N(CCCOCc2ccccc2)c2ccccc2C1(CO)c1cc2c(cc1O)OCO2

Procedure:
Following the procedure as described in PREPARATION 1E, and making non-critical variations to replace 4-bromo-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-one with 1-[3-(benzyloxy)propyl]-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-one, the title compound was obtained (93%): MS (ES+) m/z 448.2 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([OH:12])[CH:3]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=[O:29].O.[O:45]1[CH2:49][CH2:48][CH2:47][CH2:46]1>C(OCC)(=O)C>[C:46]([O:45][CH2:49][CH2:48][O:12][C:4]1[CH:3]=[C:2]([F:1])[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7])(=[O:29])[CH3:47]
Reactant: C1CCOC1
Reactant: COC(=O)c1ccc(F)cc1O
Reactant: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: CCCCP(CCCC)CCCC
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1ccc(F)cc1OCCOC(C)=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 2 g of methyl 4-fluoro-2-hydroxybenzoate in 60 mL of tetrahydrofuran were added 1.83 g of hydroxyethyl 2-acetate and 3.56 g of tributylphosphine, and then 5.93 g of 1,1′-(azodicarbonyl)dipiperidine was slowly added thereto under ice-cooling, followed by stirring for 20 minutes. The mixture was warmed to room temperature and stirred for 6 hours. The reaction mixture was poured into a mixed liquid of water and ethyl acetate. The aqueous layer was separated, the organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (normal hexane/ethyl acetate) to obtain 2.4 g of methyl 2-(2-acetoxyethoxy)-4-fluorobenzoate.
Reaction SMILES: N#N.[NH2:3][CH2:4][CH2:5][CH2:6][Si:7]([O:12][CH3:13])([O:10][CH3:11])[O:8][CH3:9].C[O-].[Na+].[C:17](Cl)(=[O:20])[CH:18]=[CH2:19]>C1(C)C=CC=CC=1.CO>[C:17]([NH:3][CH2:4][CH2:5][CH2:6][Si:7]([O:12][CH3:13])([O:8][CH3:9])[O:10][CH3:11])(=[O:20])[CH:18]=[CH2:19]
Reactant: CO[Si](CCCN)(OC)OC
Reactant: C=CC(=O)Cl
Agent: C[O-]
Agent: N#N
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: C=CC(=O)NCCC[Si](OC)(OC)OC
Temperature: 0 °C

Procedure:
A one liter, three-necked flask equipped with a thermometer, stirring paddle, air tight stirring sleeve, N2 inlet and dropping funnel was charged with aminopropyltrimethoxysilane (100.0 g, 0.558 moles), toluene (160.1 g), sodium methoxide (33.16 g, 0.614 moles) and methanol (10.11 g). The mixture was stirred under N , atmosphere and cooled to 0° C using a dry ice/isopropanol bath. To this, 55.37 g (0.614 moles) of acrylyl chloride dissolved in 100 g of toluene was added gradually over a period of 30 minutes. The mixture was agitated for another 30 minutes. By-product sodium chloride was removed by filtration and the solvent was removed under reduced pressure to obtain acrylamidopropyltrimethoxysilane in essentially quantitative yield. Sodium nitrite (0.001 g) was added as an inhibitor.