Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:35]3[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=3)[O:14][C:13]3[C:15]4[C:20]([C:21]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)=[C:22]([C:23]([O:25][CH2:26][CH2:27][OH:28])=[O:24])[C:12]=3[CH:11]=[CH:10]2)=[CH:19][CH:18]=[CH:17][CH:16]=4)=[CH:5][CH:4]=1.[C:43](Cl)(=[O:46])[CH2:44][CH3:45]>ClCCl.C(N(CC)CC)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2([C:35]3[CH:36]=[CH:37][C:38]([O:41][CH3:42])=[CH:39][CH:40]=3)[O:14][C:13]3[C:15]4[C:20]([C:21]([C:29]5[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=5)=[C:22]([C:23]([O:25][CH2:26][CH2:27][O:28][C:43](=[O:46])[CH2:44][CH3:45])=[O:24])[C:12]=3[CH:11]=[CH:10]2)=[CH:19][CH:18]=[CH:17][CH:16]=4)=[CH:7][CH:8]=1
Reactant: COc1ccc(C2(c3ccc(OC)cc3)C=Cc3c(C(=O)OCCO)c(-c4ccccc4)c4ccccc4c3O2)cc1
Reactant: CCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(=O)OCCOC(=O)c1c2c(c3ccccc3c1-c1ccccc1)OC(c1ccc(OC)cc1)(c1ccc(OC)cc1)C=C2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
2,2-Bis(4-methoxyphenyl)-5-(2-hydroxyethoxycarbonyl)-6-phenyl-[2H]-naphtho[1,2-b]pyran (U.S. Pat. No. 6,113,814) (0.50 g, 0.90 mmol) was dissolved in dry dichloromethane (20 ml) together with triethylamine (0.25 ml), under nitrogen. To this solution was added propionyl chloride (0.083 g, 0.90 mmol) and the mixture stirred at RT for 15 minutes. The solvent was evaporated and the crude residue purified by column chromatography (silica gel, EtOAc/hexane, 2:3) giving a pink foamy solid on evaporation of the solvent in vacuo. Analysis of the purified product by 1H NMR gave a spectrum consistent with the structure of 2,2-Bis(4-methoxyphenyl)-5-(2-propionyloxy-ethoxycarbonyl)-6-phenyl-[2H]-naphtho[1,2-b]pyran.
Reaction SMILES: C[Si](I)(C)C.C[O:7][C:8]1[CH:30]=[CH:29][C:11]([CH2:12][NH:13][CH2:14][CH:15]2[C:21]3=[CH:22][NH:23][C:24]4[CH:25]=[CH:26][CH:27]=[C:19]([C:20]=43)[C:18](=[O:28])[NH:17][CH2:16]2)=[CH:10][CH:9]=1.N12CCN(CC1)CC2.Cl>CO.O>[OH:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:12][NH:13][CH2:14][CH:15]2[C:21]3=[CH:22][NH:23][C:24]4[CH:25]=[CH:26][CH:27]=[C:19]([C:20]=43)[C:18](=[O:28])[NH:17][CH2:16]2)=[CH:29][CH:30]=1
Reactant: COc1ccc(CNCC2CNC(=O)c3cccc4[nH]cc2c34)cc1
Agent: C1CN2CCN1CC2
Agent: C[Si](C)(C)I
Agent: Cl
Solvent: O
Solvent: CO
Product: O=C1NCC(CNCc2ccc(O)cc2)c2c[nH]c3cccc1c23
Temperature: 150 °C
Reaction time: 2 h
Yield: 41.7 %

Procedure:
2 ml of trimethylsilyl iodide were added to a mixture of 1.5 g of 3-[N-(4-methoxybenzyl)aminomethyl]-3,4,5,6-tetrahydro-6-oxo-1H-azepino[5,4,3-cd]indole (see Example 21 for preparation) and 2.5 g of 1,4-diazabicyclo[2.2.2]octane (=DABCO). The reaction mixture was heated at 150° C. under a nitrogen atmosphere for 24 hours. The reaction mixture was cooled to room temperature and then diluted with 25 ml of methanol and acidified with 20% strength aqueous hydrochloric acid. The mixture was then vigorously stirred at room temperature for 2 hours. To work up the reaction mixture it was diluted with 30 ml of water, the aqueous phase was separated and the organic phase was washed twice more with 20 ml portions of water. The combined aqueous phases were neutralized with dilute sodium hydroxide solution and subsequently evaporated under reduced pressure (water pump vacuum). The crude product which remained as an oily residue was purified by chromatography on silica gel under slightly elevated pressure (flash chromatography) using methanol/25% strength aqueous ammonia solution 98:2 as eluent. 0.6 g of 3-[N-(4-hydroxybenzyl)aminomethyl] 3,4,5,6-tetrahydro-6-oxo-1H-azepino(5,4,3-cd]indole was obtained as an oil.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[C:5]([CH:14]=[O:15])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Br:22][CH2:23][CH2:24]Br.O>CN(C=O)C>[Br:22][CH2:23][CH2:24][O:1][C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[C:5]([CH:14]=[O:15])=[CH:4][CH:3]=1
Reactant: BrCCBr
Reactant: COc1cccc2c(O)ccc(C=O)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cccc2c(OCCBr)ccc(C=O)c12
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.1 %

Procedure:
4-hydroxy-8-methoxynaphthalene-1-carbaldehyde (1 g, 5 mmol) was dissolved in DMF (15 mL). To this mixture potassium carbonate (3.4 g, 25 mmol) and 1,2-dibromoethane (4 mL, 50 mmol) were added and the resulting mixture was stirred at room temperature for 16 hours. Water. (150 mL) was added and the resulting mixture was extracted with ethyl acetate (3×90 mL). The combined organic extracts were washed with saturated sodium chloride (100 mL), dried (MgSO4) and evaporated in vacuo to afford 1.13 g (74%) of 4-(2-bromoethoxy)-8-methoxynaphthalene-1-carbaldehyde.
Reaction SMILES: C([Sn](CCCC)=O)CCC.[N:11]([Si](C)(C)C)=[N+:12]=[N-:13].[CH2:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][CH:19]1[NH:27][C:28]1[N:29]=[CH:30][C:31]2[CH2:36][N:35]([C:37](=[O:44])[CH2:38][CH2:39][CH2:40][CH2:41][C:42]#[N:43])[CH2:34][C:32]=2[N:33]=1>C1(C)C=CC=CC=1>[CH2:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][CH:19]1[NH:27][C:28]1[N:29]=[CH:30][C:31]2[CH2:36][N:35]([C:37](=[O:44])[CH2:38][CH2:39][CH2:40][CH2:41][C:42]3[NH:43][N:13]=[N:12][N:11]=3)[CH2:34][C:32]=2[N:33]=1
Reactant: N#CCCCCC(=O)N1Cc2cnc(NC3Cc4ccccc4C3)nc2C1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: O=C(CCCCc1nnn[nH]1)N1Cc2cnc(NC3Cc4ccccc4C3)nc2C1
Temperature: 105 °C
Yield: 30.8 %

Procedure:
Add dibutyloxostannane (0.071 g; 1.33 equiv; 0.29 mmoles) and azidotrimethylsilane (1.6 mL; 56 equiv; 12.01 mmoles) to a stirred solution of 6-[2-(indan-2-ylamino)-5,7-dihydropyrrolo[3,4-d]pyrimidin-6-yl]-6-oxo-hexanenitrile (0.077 g; 1.0 equiv; 0.213 mmoles) in toluene (6 mL). Heat the resulting solution to 105° C. for 16 hours. Cool the reaction mixture to ambient temperature and concentrate. Dissolve the residue in methanol (5 mL) and load the solution on an SCX column (eluting with methanol to 7N ammonia in methanol) to afford the crude product, which is purified by reverse phase chromatography to give 1-[2-(2,3-dihydro-1H-inden-2-ylamino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl]-5-(1H-tetrazol-5-yl)pentan-1-one (0.0265 g; 31%): MS (m/z): 405(M+1).
Reaction SMILES: N[C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[C:4]#[N:5].N([O-])=O.[Na+].[BrH:15]>O1CCOCC1.O.[Cu]Br>[Br:15][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[C:4]#[N:5]
Reactant: Br
Reactant: N#Cc1c(N)cccc1F
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: N#Cc1c(F)cccc1Br
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 70 %

Procedure:
2-Amino-6-fluorobenzonitrile (18.0 g, 132 mmol) was dissolved in hot 1,4-dioxane (20 mL), 48% hydrobromic acid (200 mL) was added and the mixture cooled to 0° C. before dropwise addition of sodium nitrite (10.5 g, 152 mmol) in water (20 mL) over 1.5 h. The resulting mixture was stirred at 0° C. for 1.5 h then poured onto a cooled (0° C.) solution of copper(I) bromide (56.8 g, 396 mmol) in 48% hydrobromic acid (50 mL). The solution was stirred at 0° C. for 15 min then heated at 50° C. for 20 min. The mixture was cooled to ambient temperature, diluted with water (1200 mL) and extracted with ethyl acetate (2×400 mL). The combined organics were washed with 10% aqueous ammonia solution (400 mL), water (400 mL) and brine (500 mL), dried over anhydrous magnesium sulfate, filtered and evaporated to give an orange oil. Purification by chromatography on silica gel eluting with isohexane on a gradient of ethyl acetate (2-4%) gave 2-bromo-6-fluorobenzonitrile (18.5 g, 70%) as a white solid: δH (400 MHz, CDCl3) 7.17-7.23 (1H, ddd, J 8, 8 and 1), 7.44-7.52 (2H, m).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[C:3]=1[NH2:16].[C:17](Cl)(Cl)=[O:18]>C1COCC1.C1(C)C=CC=CC=1>[NH2:8][C:6]1[N:5]=[C:4]2[C:3]([NH:16][C:17](=[O:18])[N:9]2[CH:10]2[CH2:11][CH2:12][O:13][CH2:14][CH2:15]2)=[C:2]([Cl:1])[N:7]=1
Reactant: O=C(Cl)Cl
Reactant: Nc1nc(Cl)c(N)c(NC2CCOCC2)n1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Nc1nc(Cl)c2[nH]c(=O)n(C3CCOCC3)c2n1
Temperature: 25 °C
Yield: 97 %

Procedure:
To a solution of 6-chloro-N4-(tetrahydro-2H-pyran-4-yl)pyrimidine-2,4,5-triamine (1 g, 4.1 mmol) in 900 mL of anhydrous THF at −78° C. under Ar was added dropwise, over 40 min, a solution of phosgene in THF (3.8 mL of a 20% solution of phosgene in toluene, 7 mmol, 1.7 equiv., diluted with 26 mL of anhydrous THF). The reaction mixture was left to gradually warm up to room temperature over 16 h. It was purged with air for 30 min, then the solvent was removed in vacuo to give 1.2 g (97% yield) of the desired product (HCl salt) as a white solid. 1H NMR (300 MHz, d6-DMSO) δ, ppm: 11.40 (s, 1H), 7.00 (br s, 2H), 4.50-4.37 (m, 1H), 4.12-4.04 (m, 2H), 3.50 (app t, 2H), 2.68-2.55 (m, 2H), 1.78-1.71 (m, 2H); MS (EI) m/z 270.3 (MH)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8](=[O:15])[CH2:9][CH:10]([OH:14])[CH2:11][CH:12]=[CH2:13])[CH:5]=[CH:6][CH:7]=1.N1C=CN=C1.[C:21]([Si:25]([CH3:28])([CH3:27])Cl)([CH3:24])([CH3:23])[CH3:22]>CN(C=O)C.ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([C:8](=[O:15])[CH2:9][CH:10]([O:14][Si:25]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:28])[CH3:27])[CH2:11][CH:12]=[CH2:13])[CH:5]=[CH:6][CH:7]=1
Reactant: C=CCC(O)CC(=O)c1cccc(Br)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C=CCC(CC(=O)c1cccc(Br)c1)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 1-(3-bromophenyl)-3-hydroxyhex-5-en-1-one (9.08 g, 33.7 mmol), 1H-imidazole (5.34 g, 77.6 mmol) and tert-butyldimethylchlorosilane (6.29 g, 40.5 mmol) in DMF (40 mL) is stirred at room temperature for 2 h. The mixture is diluted with dichloromethane and is washed sequentially with water and saturated ammonium chloride aqueous solution. The organic layer is dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product is purified by silica gel chromatography eluting with a linear gradient of 0% to 5% ethyl acetate in hexanes over 20 minutes to give the title compound as a racemic mixture (11.3 g, 88%). ES/MS m/e (79Br/81Br) 383, 385 (M+1).
Reaction SMILES: [OH:1][CH2:2][CH:3]([NH:10][C:11]([C:13]1[NH:14][CH:15]=[C:16]([C:18](=O)[C:19]([CH3:24])=[CH:20]N(C)C)[CH:17]=1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH:26]1([NH:29][C:30]([NH2:32])=[NH:31])[CH2:28][CH2:27]1.Cl.C(=O)([O-])[O-].[K+].[K+]>CN(C)C(=O)C.C(OCC)(=O)C>[OH:1][CH2:2][C@@H:3]([NH:10][C:11]([C:13]1[NH:14][CH:15]=[C:16]([C:18]2[C:19]([CH3:24])=[CH:20][N:32]=[C:30]([NH:29][CH:26]3[CH2:28][CH2:27]3)[N:31]=2)[CH:17]=1)=[O:12])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(=CN(C)C)C(=O)c1c[nH]c(C(=O)NC(CO)c2ccccc2)c1
Reactant: N=C(N)NC1CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: Cc1cnc(NC2CC2)nc1-c1c[nH]c(C(=O)N[C@H](CO)c2ccccc2)c1
Temperature: 100 °C
Reaction time: 24 h
Yield: 7.1 %

Procedure:
4-(3-Dimethylamino-2-methyl-acryloyl)-1H-pyrrole-2-carboxylic acid (2-hydroxy-1-phenyl-ethyl)-amide (100 mg, 0.29 mmol) was combined with cyclopropyl guanidine•HCl (80 mg) and potassium carbonate (121 mg) in N,N-dimethylacetamide (2 mL). The resulting suspension was heated and stirred at 100° C. for 24 hours. The crude material was diluted with ethyl acetate, washed with saturated NaHCO3 and brine, dried over MgSO4 then concentrated in vacuo. Purification by preparative TLC (silica, 1:1 EtOAc:Hexanes) afforded III-a-162 as a yellow solid (7.8 mg). HPLC Method B, Rt=4.29 minutes; LC/MS(m/z) 378.2 (M+1), 376.2 (M−1); 1H NMR consistent with structure.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([N+:15]([O-:17])=[O:16])=[C:5]([CH:12]=[CH:13][CH:14]=1)[C:6]([N:8]([O:10][CH3:11])[CH3:9])=[O:7].C(=O)([O-])[O-:19].[Ca+2].O>O1CCOCC1>[OH:19][CH2:2][C:3]1[C:4]([N+:15]([O-:17])=[O:16])=[C:5]([CH:12]=[CH:13][CH:14]=1)[C:6]([N:8]([O:10][CH3:11])[CH3:9])=[O:7]
Reactant: CON(C)C(=O)c1cccc(CBr)c1[N+](=O)[O-]
Reactant: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: C1COCCO1
Solvent: O
Product: CON(C)C(=O)c1cccc(CO)c1[N+](=O)[O-]
Temperature: 25 °C
Yield: 92 %

Procedure:
A mixture of Intermediate 37B (3.7 g, 4.88 mmol) and calcium carbonate (2.93 g, 29.3 mmol) in dioxane (25 mL)/water (25 mL) was stirred at reflux for 5 h. The mixture was then cooled to room temperature, the solid was removed by filtration and the filtrate was extracted with EtOAc. The combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated to dryness. The crude residue was purified by flash chromatography (SiO2, 80 g column, EtOAc/hexane=20-100%) to afford Intermediate 37C (1.079 g, 78%). HPLC: RT=0.75 min (CHROMOLITH® SpeedROD column 4 6×50 mm, 10-90% aqueous methanol over 4 minutes containing 0.1% TFA, 4 mL/min, monitoring at 220 nm), MS(ES): m/z=241.0 [M+H+].
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([Cl:14])=[CH:9][CH:10]=2)[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:4]=1.[Cl:21][C:22]1[CH:23]=[C:24]([CH:36]=[CH:37][CH:38]=1)[CH2:25][N:26]1[CH:31]=[CH:30][C:29]([C:32](O)=[O:33])=[CH:28][C:27]1=[O:35]>>[Cl:14][C:8]1[CH:7]=[C:6]2[C:11]([C:12](=[O:13])[C:3]([CH2:2][NH:1][C:32]([C:29]3[CH:30]=[CH:31][N:26]([CH2:25][C:24]4[CH:36]=[CH:37][CH:38]=[C:22]([Cl:21])[CH:23]=4)[C:27](=[O:35])[CH:28]=3)=[O:33])=[CH:4][N:5]2[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:10][CH:9]=1
Reactant: NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O
Reactant: O=C(O)c1ccn(Cc2cccc(Cl)c2)c(=O)c1
Product: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)c1ccn(Cc2cccc(Cl)c2)c(=O)c1

Procedure:
1-(3-Chloro-benzyl)-2-oxo-1,2-dihydro-pyridine-4-carboxylic acid (7-chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-amide was prepared starting from intermediate D and 1-(3-chloro-benzyl)-2-oxo-1,2-dihydro-pyridine-4-carboxylic acid. MS calcd. for C29H22Cl2N3O3 [(M+H)+] 530.1, obsd. 530.0.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13]CC)=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]([CH2:32][CH3:33])=[CH:28][N:27]=3)=[CH:19][CH:18]=2)[N:5]=1)[CH3:2].[OH-].[Na+].O1CCCC1.C(O)C>Cl>[CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]([CH2:32][CH3:33])=[CH:28][N:27]=3)=[CH:19][CH:18]=2)[N:5]=1)[CH3:2]
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCCc3ccc(CC)cn3)cc2)nc1OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOc1nn(Cc2ccc(OCCc3ccc(CC)cn3)cc2)cc1CCC(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 46.8 %

Procedure:
A mixture of ethyl 3-[3-ethoxy-1-[4-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl]-1H-pyrazol-4-yl]propionate (519 mg), 1 N aqueous sodium hydroxide solution (2.5 ml), tetrahydrofuran (5 ml), and ethanol (5 ml) was stirred at room temperature for 3 hours, diluted with 1 N hydrochloric acid (2.5 ml), and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The obtained colorless crystals were collected by filtration, and 3-[3-ethoxy-1-[4-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl]-1H-pyrazol-4-yl]propionic acid (228 mg, yield: 47%) was obtained. This was recrystallized from ethanol-hexane. Melting point: 89–90° C.
Reaction SMILES: C1N(CCS(O)(=O)=O)CC[O:3]C1.[NH:13]1[CH2:20][CH2:19][CH2:18][C@H:14]1[C:15]([OH:17])=[O:16].O=C(CCC([O-])=O)C([O-])=O.O=C1O[C@H]([C@H](CO)O)C(O)=C1O>>[OH:3][C@H:19]1[CH2:20][NH:13][C@H:14]([C:15]([OH:17])=[O:16])[CH2:18]1
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: O=S(=O)(O)CCN1CCOCC1
Agent: O=C([O-])CCC(=O)C(=O)[O-]
Agent: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Product: O=C(O)[C@@H]1C[C@@H](O)CN1
Reaction time: 0.5 h

Procedure:
The enzyme reaction with purified L-proline-4-hydroxylase obtained in Example 5 was carried out. The reaction mixture was composed of 200 mM MES buffer (pH 6.5), 20 mM L-proline, 20 mM 2-ketoglutarate, 5 mM L-ascorbic acid, 2 mM ferrous sulfates and 90 U of purified enzyme preparation in total volume of 50 μl. The reaction was carried out at 35° C. for 30 min. As a result of the reaction, 12.9 mM (1.7 g/l) of trans-4-hydroxyL-proline was produced in the reaction mixture.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9][CH2:10][C:11]1[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=1[C:13]([O:15][CH3:16])=[O:14].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][C:23]=1[C:32]([F:35])([F:34])[F:33]>N1C=CC=CC=1>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([S:9][CH2:10][C:11]2[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=2[C:13]([O:15][CH3:16])=[O:14])=[C:2]([NH:1][S:28]([C:25]2[CH:26]=[CH:27][C:22]([Cl:21])=[C:23]([C:32]([F:35])([F:33])[F:34])[CH:24]=2)(=[O:30])=[O:29])[CH:7]=1
Reactant: COC(=O)c1ccccc1CSc1ccc(Cl)cc1N
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(C(F)(F)F)c1
Solvent: c1ccncc1
Product: COC(=O)c1ccccc1CSc1ccc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Yield: 37.3 %

Procedure:
Following General Procedure B, the title compound (936 mg, 37%) was prepared from methyl 2-(((2-amino-4-chlorophenyl)thio)methyl)benzoate (1.41 g, 4.56 mmol) and 4-chloro-3-(trifluoromethyl)benzene-1-sulfonyl chloride (1.3 g, 4.56 mmol) in pyridine (10 ml).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([OH:18])[CH2:16][Br:17])=[CH:11][C:10]=1[N+:19]([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1COCC1>O=[Pt]=O.C1(C)C=CC=CC=1>[NH2:19][C:10]1[CH:11]=[C:12]([C@@H:15]([OH:18])[CH2:16][Br:17])[CH:13]=[CH:14][C:9]=1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cc([C@@H](O)CBr)ccc1OCc1ccccc1
Agent: O=[Pt]=O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Nc1cc([C@@H](O)CBr)ccc1OCc1ccccc1

Procedure:
(R)-1-[4-(Benzyloxy)-3-nitrophenyl]-2-bromoethanol (0.200 g, 0.569 mmol) in 1:1 THF:toluene (5 mL) was reacted with PtO2 (1% w/w) on a Parr shaker at 45 psi at rt overnight. The next morning the PtO2 was removed by filtration over celite. The product was concentrated to give the title compound. ES/MS calcd. for C15H17BrNO2+ 322.0. Found m/z=322 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([N+:9]([O-])=O)[C:3]=1[OH:12].NC1C=CC=C(Cl)C=1O>>[NH2:9][C:4]1[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[C:3]=1[OH:12]
Reactant: O=[N+]([O-])c1cc(Cl)cc(Cl)c1O
Agent: Nc1cccc(Cl)c1O
Product: Nc1cc(Cl)cc(Cl)c1O

Procedure:
2-amino-4,6-dichlorophenol was prepared from 2,4-dichloro-6-nitrophenol (0.625 g, 2.40 mmol) in a manner similar to that described for 2-amino-6-chlorophenol. The compound was formed as a black solid (0.044 g, 10%). RP-HPLC (25 to 100% CH3CN in 0.1 N aqueous ammonium acetate over 10 min at 1 mL/min using a Hypersil HS C18, 100 Å, 5 μm, 250×4.6 mm column) tr=9.033 min., 74%; m/z 177 (MH+).
Reaction SMILES: F[C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=[C:4]([F:11])[N:3]=1.Cl.[F:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][CH2:22][CH2:23][C:24]([NH2:26])=[NH:25])=[CH:16][CH:15]=1>>[F:11][C:4]1[CH:5]=[CH:6][C:7]2[C:8](=[O:10])[NH:26][C:24]([CH2:23][CH2:22][CH2:21][CH2:20][C:17]3[CH:16]=[CH:15][C:14]([F:13])=[CH:19][CH:18]=3)=[N:25][C:2]=2[N:3]=1
Reactant: O=C(O)c1ccc(F)nc1F
Reactant: N=C(N)CCCCc1ccc(F)cc1
Agent: Cl
Product: O=c1[nH]c(CCCCc2ccc(F)cc2)nc2nc(F)ccc12

Procedure:
The title compound was prepared in analogy to example 85 from 2,6-difluoropyridine-3-carboxylic acid and 5-(4-fluoro-phenyl)-pentanamidine hydrochloride. White solid. MS: m/e=316.1 [M+H+].
Reaction SMILES: O.[OH-].[Na+].[OH:4][C:5]1[CH:18]=[CH:17][C:8]2[O:9][C:10]3[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][C:11]=3[C:7]=2[CH:6]=1.[ClH:19].[N:20]1([CH2:26][CH2:27][CH2:28][Cl:29])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>C1(C)C=CC=CC=1>[ClH:29].[ClH:19].[N:20]1([CH2:26][CH2:27][CH2:28][O:16][C:13]2[CH:14]=[CH:15][C:10]3[O:9][C:8]4[CH:17]=[CH:18][C:5]([O:4][CH2:28][CH2:27][CH2:26][N:20]5[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]5)=[CH:6][C:7]=4[C:11]=3[CH:12]=2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: ClCCCN1CCCCC1
Reactant: Oc1ccc2oc3ccc(O)cc3c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: c1cc2oc3ccc(OCCCN4CCCCC4)cc3c2cc1OCCCN1CCCCC1
Reaction time: 24 h

Procedure:
To 200 ml of water containing 13.0 g (0.33 mole) of sodium hydroxide and 12.0 g (0.06 mole) of 2,8-dihydroxydibenzofuran are added 250 ml of toluene and 29.7 g (0.15 mole) of 3-piperidinopropyl chloride hydrochloride, and the heterogeneous reaction mixture is heated to reflux with stirring for 24 hours. When cool, the organic layer is washed with water, dried over magnesium sulfate then concentrated in vacuo. The remaining oily residue is dissolved in ether and treated with ethereal HCl to give the desired product which is recrystallized twice from methanol-ethyl acetate yielding 2,8-bis(3-piperidonopropoxy)dibenzofuran dihydrochloride, M.P. 245°-246.5°C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C@:12]1([CH3:18])[CH2:16][O:15][C:14](=[O:17])[NH:13]1)[CH:6]=[CH:5]2.[CH2:19]([CH:24]1[CH2:29][CH2:28][CH:27](O)[CH2:26][CH2:25]1)[CH2:20][CH2:21][CH2:22][CH3:23].O1CCCC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C(OCC)(=O)C>[CH3:18][C@@:12]1([C:7]2[CH:6]=[CH:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([O:1][CH:27]4[CH2:26][CH2:25][CH:24]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:29][CH2:28]4)[CH:3]=3)[CH:8]=2)[CH2:16][O:15][C:14](=[O:17])[NH:13]1
Reactant: C[C@@]1(c2ccc3cc(O)ccc3c2)COC(=O)N1
Reactant: CCCCCC1CCC(O)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCCC1CCC(Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2)CC1
Reaction time: 0.08 h
Yield: 68.4 %

Procedure:
(R)-4-(6-Hydroxnaphthalen-2-yl)-4-methyl-oxazolidin-2-one (Example 4, 0.3303 g, 0.001358 mol) was added to a capped 40 mL vial equipped with a magnetic stir bar. 4-Pentyl-cyclohexanol (0.277 g, 0.00163 mol) was added, followed by tetrahydrofuran (6.00 mL, 0.0740 mol). Triphenylphosphine polymer-bound (1.17 g, 0.00217 mol) was then added and the mixture was stirred for 5 minutes. Diisopropyl azodicarboxylate (0.428 mL, 0.00217 mol) was then added and the mixture was stirred for 48 hours at room temperature. The mixture was diluted in ethyl acetate, filtered through CELITE™, concentrated under vacuum and purified by flash chromatography (0-5% MeOH in dichloromethane) to give 0.3672 g of the title compound (68% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[Br:15][C:16]1[CH:17]=[C:18]([C:23](=[O:25])[CH3:24])[CH:19]=[CH:20][C:21]=1[CH3:22].C(N(CC)CC)C>CCCCCCC>[Br:15][C:16]1[CH:17]=[C:18]([C:23](=[O:25])[CH2:24][C:9]([C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=2)([OH:14])[C:10]([F:11])([F:12])[F:13])[CH:19]=[CH:20][C:21]=1[CH3:22]
Reactant: O=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Reactant: CC(=O)c1ccc(C)c(Br)c1
Solvent: CCCCCCC
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)CC(O)(c2cc(Cl)cc(Cl)c2)C(F)(F)F)cc1Br
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a solution of 3.42 g of 3′,5′-dichloro-2,2,2-trifluoroacetophenone and 3.00 g of 3′-bromo-4′-methylacetophenone in 5 mL of heptane, 0.71 g of triethylamine was added and the resultant reaction mixture was stirred at 60° C. for 8 hours. After the completion of the reaction, the reaction mixture was left to be cooled down to room temperature. A deposited solid was separated off and was washed with 3 mL of hexane to obtain 6.16 g of the objective substance as a white crystal.