Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:18][C@@H:19]([C:24]([OH:26])=O)[CH2:20][CH2:21][S:22][CH3:23])([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2].N1C=CC=CC=1.N1C(F)=NC(F)=NC=1[F:35]>ClCCl>[C:1]([NH:18][C@@H:19]([C:24]([F:35])=[O:26])[CH2:20][CH2:21][S:22][CH3:23])([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2]
Reactant: Fc1nc(F)nc(F)n1
Reactant: CSCC[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CSCC[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)F
Temperature: 0 °C
Reaction time: 4 h

Procedure:
FMOC-D-Methionine (5.00 g, 13.46 mmol) (Bachem) was dissolved in dichloromethane (70 mL). Pyridine (1.09 mL, 13.46 mmol) (Aldrich) and cyanuric fluoride (1.82 g, 13.46 mmol) (Aldrich) were successively added at room temperature and the mixture was stirred for 4 hours. Ice cold water (100 mL) was added and the resulting slurry was filtered. The filtrate was poured into a separatory funnel and the layers were separated. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford FMOC-D-methionyl fluoride as a white powder. (Yield 3.7 g., 74%).
Reaction SMILES: [Cl:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[O:8].[Na].[CH3:10][SH:11].O>C(O)C>[CH3:10][S:11][C:2]1([Cl:1])[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[O:8]
Reactant: CS
Reactant: O=C1CCCCC1Cl
Agent: [Na]
Solvent: O
Solvent: CCO
Product: CSC1(Cl)CCCCC1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 78 %

Procedure:
In a 300-ml egg-plant type flask 7.07 g (0.053 mol) of 2-chlorocyclohexanone was dissolved in 50 ml of ethanol, and 25 ml of 15% aqueous solution of sodium salt of methylmercaptan was added dropwise with a dropping funnel, and the mixture was stirred at room temperature for 3 h. The reaction mixture was poured into 300 ml of water, and an organic layer was extracted with methylene chloride, dried with magnesium sulfate and distilled to remove methylene chloride. After that reduced pressure distillation was performed to obtain 6.0 g of methylmercapto-2-chlorocyclohexanone (78% yield; b.p. 48.5°-47.5° C./0.3 mmHg).
Reaction SMILES: [CH2:1]([OH:11])[C:2]#[C:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].N1C=CC=CC=1.[CH:18]1([C:21](Cl)=[O:22])[CH2:20][CH2:19]1>CCOCC>[CH:18]1([C:21]([O:11][CH2:1][C:2]#[C:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])=[O:22])[CH2:20][CH2:19]1
Reactant: O=C(Cl)C1CC1
Reactant: CCCCCCCC#CCO
Solvent: c1ccncc1
Solvent: CCOCC
Product: CCCCCCCC#CCOC(=O)C1CC1
Reaction time: 8 h

Procedure:
To a solution of 3.85 g. of 2-decyn-1-ol and 3.95 g. of pyridine in 100 ml. ether is added 3.0 g. of cyclopropanecarboxylic acid chloride. The mixture is stirred overnight under nitrogen. The reaction mixture is poured into distilled water, washed with dilute hydrochloric acid and then with sodium bicarbonate and solvent removed to yield 2-decynyl cyclopropanecarboxylate, b.p. 96°-97° (bath) at 0.1 mm.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:27])([CH3:26])[CH2:10][C:11]([NH:13][C@H:14]1[C:20](=[O:21])[NH:19][C:18]2[CH:22]=[CH:23][CH:24]=[CH:25][C:17]=2[S:16][CH2:15]1)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].I([O-])(=O)(=O)=[O:29].[Na+]>CO.O>[C:1]([O:5][C:6]([NH:8][C:9]([CH3:27])([CH3:26])[CH2:10][C:11]([NH:13][C@H:14]1[C:20](=[O:21])[NH:19][C:18]2[CH:22]=[CH:23][CH:24]=[CH:25][C:17]=2[S:16](=[O:29])[CH2:15]1)=[O:12])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(CC(=O)N[C@@H]1CSc2ccccc2NC1=O)NC(=O)OC(C)(C)C
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)(CC(=O)N[C@@H]1CS(=O)c2ccccc2NC1=O)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of 179 mg (0.46 mmol) of 3-t-butoxycarbonylamino-3-methyl-N-[3,4-dihydro-4-oxo-1,5-benzothiazepin-3(S)-yl]-butanamide (Example 46, Step A) in 4.5 mL of methanol/water (5:1) was treated with 102 mg (0.48 mmol, 1.05 eq) of sodium periodate and stirred at room temperature for 48 hours. The reaction mixture was filtered and the filtrate concentrated under vacuum. The residue was redissolved in chloroform, dried over potassium carbonate, filtered and concentrated under vacuum. Purification by flash chromatography on silica, eluting with ethyl acetate, afforded 47 mg (0.12 mmol, 25%) of the less polar, minor diastereomer A in addition to 105 mg (0.26 mmol, 56%) of the more polar, major diastereomer B.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][OH:5].C(N(CC)CC)C.[N:13]1([C:18](Cl)=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14]1>ClC(Cl)Cl>[OH:5][CH2:4][CH2:3][N:2]([CH3:1])[C:18]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:19]
Reactant: O=C(Cl)N1CCCC1
Reactant: CNCCO
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CN(CCO)C(=O)N1CCCC1
Reaction time: 6 h
Yield: 40.1 %

Procedure:
To a stirred solution of 7.5 parts of 2-(methylamino)ethanol in 75 parts of trichloromethane were added 9.8 parts of N,N-diethylethanamine while cooling in an ice bath. A solution of 13.4 parts of 1pyrrolidinecarbonyl chloride in 52.5 parts of trichloromethane was added dropwise (exothermic reaction, the temperature rose from -10° C. to ~0° C.). Upon complete addition, stirring was continued for 6 hours at room temperature. Another portion of 1.5 parts of 2-(methylamino)ethanol was added and stirring was continued over weekend at room temperature. The separated organic layer was washed with a hydrochloric acid solution 5% and water, dried, filtered and evaporated, yielding 7 parts (40.1%) of N-(2-hydroxyethyl)-N-methyl-1-pyrrolidinecarboxamide as a residue (int. 30).
Reaction SMILES: ClC(Cl)(Cl)CO[C:5](=[O:50])[NH:6][C:7]1[N:8]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([O:40][CH2:41][CH2:42][O:43][CH:44]3[CH2:49][CH2:48][CH2:47][CH2:46][O:45]3)[CH:35]=2)[N:9]=[C:10]([C:12]([CH3:33])([CH3:32])[CH2:13][O:14][Si:15]([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:11]=1.[CH3:53][C@H:54]1[CH2:59][CH2:58][CH2:57][CH2:56][N:55]1[C:60]1[N:64]2[CH:65]=[C:66]([O:69][C@H:70]3[C:79]4[C:74](=[CH:75][CH:76]=[CH:77][CH:78]=4)[C@@H:73]([NH2:80])[CH2:72][CH2:71]3)[CH:67]=[CH:68][C:63]2=[N:62][N:61]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[Si:15]([O:14][CH2:13][C:12]([C:10]1[CH:11]=[C:7]([NH:6][C:5]([NH:80][C@@H:73]2[C:74]3[C:79](=[CH:78][CH:77]=[CH:76][CH:75]=3)[C@H:70]([O:69][C:66]3[CH:67]=[CH:68][C:63]4[N:64]([C:60]([N:55]5[CH2:56][CH2:57][CH2:58][CH2:59][C@@H:54]5[CH3:53])=[N:61][N:62]=4)[CH:65]=3)[CH2:71][CH2:72]2)=[O:50])[N:8]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([O:40][CH2:41][CH2:42][O:43][CH:44]3[CH2:49][CH2:48][CH2:47][CH2:46][O:45]3)[CH:35]=2)[N:9]=1)([CH3:33])[CH3:32])([C:28]([CH3:29])([CH3:31])[CH3:30])([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC(C)(CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2cccc(OCCOC3CCCCO3)c2)n1
Reactant: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)CO[Si](c5ccccc5)(c5ccccc5)C(C)(C)C)nn4-c4cccc(OCCOC5CCCCO5)c4)c4ccccc43)cn12
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 73.2 %

Procedure:
A solution of Intermediate 153f (377 mg, 0.48 mmol) in 1,4-dioxane (4.8 mL) was treated with Intermediate 81d (164 mg, 0.43 mmol) and DIPEA (0.095 mL, 0.54 mmol) and the mixture was stirred at 70° C. for 30 mins then at 50° C. for 64 h then at 70° C. for 22 h. The cooled solution was concentrated in vacuo, and the residue was partitioned between DCM and water. The phases were separated and the aqueous layer was extracted with DCM (×2). The combined organic phase was washed with brine, dried (Na2SO4) and concentrated in vacuo to a brown gum. The gum was purified by FCC, using 0-7% MeOH in DCM to give the title compound as a brown glass (320 mg, 72%). LCMS (Method 3): Rt 5.66 min, m/z 1017.7 [MH+].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]([NH:20][CH2:21][CH2:22]F)=[O:19])[CH:5]=[CH:6][C:7]=1[B:8]1[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH3:16])([CH3:15])[O:9]1.C(CN)[OH:25]>>[F:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]([NH:20][CH2:21][CH2:22][OH:25])=[O:19])[CH:5]=[CH:6][C:7]=1[B:8]1[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH3:16])([CH3:15])[O:9]1
Reactant: CC1(C)OB(c2ccc(NC(=O)NCCF)cc2F)OC1(C)C
Reactant: NCCO
Product: CC1(C)OB(c2ccc(NC(=O)NCCO)cc2F)OC1(C)C

Procedure:
Method as described for 1-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-(2-fluoroethyl)urea (intermediate 31) using ethanolamine as starting material.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([C:20]3[S:21][CH:22]=[CH:23][CH:24]=3)[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[N:11]1([C:14]2[CH:19]=[C:18]([C:20]3[S:21][CH:22]=[CH:23][CH:24]=3)[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(-c3cccs3)ncn2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1csc(-c2cc(N3CCNCC3)ncn2)c1

Procedure:
A solution of 4-(6-thiophen-2-yl-pyrimidin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester (30 mg, 0.08 mmol) in 1:1 TFA/CH2Cl2 (3 mL) was stirred for 2 h, and then was concentrated to yield the title compound, as its corresponding TFA salt.
Reaction SMILES: I.[NH2:2][CH2:3][CH2:4][NH:5][C:6]1[C:7]([C:11]2[N:15]([C:16]3[CH:17]=[CH:18][C:19]([F:24])=[C:20]([CH:23]=3)[C:21]#[N:22])C(=O)[O:13][N:12]=2)=[N:8][O:9][N:10]=1.[S:26](N)([NH2:29])(=[O:28])=[O:27].[OH-].[Na+].O>N1C=CC=CC=1>[NH2:29][S:26]([NH:2][CH2:3][CH2:4][NH:5][C:6]1[C:7]([C:11](=[N:12][OH:13])[NH:15][C:16]2[CH:17]=[CH:18][C:19]([F:24])=[C:20]([C:21]#[N:22])[CH:23]=2)=[N:8][O:9][N:10]=1)(=[O:28])=[O:27]
Reactant: NS(N)(=O)=O
Reactant: N#Cc1cc(-n2c(-c3nonc3NCCN)noc2=O)ccc1F
Agent: I
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: c1ccncc1
Product: N#Cc1cc(NC(=NO)c2nonc2NCCNS(N)(=O)=O)ccc1F
Temperature: 120 °C
Reaction time: 8 h
Yield: 29 %

Procedure:
In a microwave vial, 5-[3-{4-[(2-aminoethyl)amino]-1,2,5-oxadiazol-3-yl}-5-oxo-1,2,4-oxadiazol-4(5H)-yl]-2-fluorobenzonitrile hydroiodide (20.0 mg, 0.044 mmol) and sulfamide (25 mg, 0.26 mmol) were suspended in pyridine (0.5 mL). The reaction was heated to 120° C. for 10 minutes in a microwave reactor. The solvent was removed and the residue dissolved in methanol (0.17 mL). A solution of 2.0 N NaOH in water (0.22 mL, 0.44 mmol) was added in one portion. The reaction was stirred at room temperature overnight. After neutralization with acetic acid (50 μL), the product was purified using preparative LCMS to give the title compound (4.9 mg, 29%). LCMS for C12H14FN8O4S (M+H)+: m/z=385.0. 1H NMR (400 MHz, DMSO-d6): δ 11.65 (s, 1H), 9.08 (s, 1H), 7.34 (t, J=9.1 Hz, 1H), 7.22 (dd, J=5.4, 2.8 Hz, 1H), 7.13 (m, 1H), 6.70 (t, J=5.9 Hz, 1H), 6.59 (s, 2H), 6.20 (t, J=6.1 Hz, 1H), 3.34 (m, 2H), 3.09 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1.[Cl:9][S:10](O)(=[O:12])=[O:11]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[S:10]([Cl:9])(=[O:12])=[O:11]
Reactant: O=S(=O)(O)Cl
Reactant: Brc1ccc(Br)cc1
Product: O=S(=O)(Cl)c1cc(Br)ccc1Br
Temperature: 90 °C
Yield: 79 %

Procedure:
A modification of the published procedures of Moroni et al. in Macromolecules 1994, 27, 562 was used. A 300 mL round-bottom flask equipped with a reflux condenser, stirring bar, and gas inlet was charged with 1,4-dibromobenzene (50 g, 0.21 moles) and chlorosulfonic acid (100 mL). The mixture was heated to 90° C. for 2 hours under nitrogen to give a clear solution. The solution was cooled to room temperature and carefully poured onto ice (1 kg) to give a precipitate. The solids were collected by vacuum filtration, washed well with water, and air dried on the filter then dried under vacuum at 50° C. to give 68.36 g. The product was recrystallized from cyclohexane after treating with decolorizing carbon, collected by vacuum filtration, and dried at 50° C. under vacuum to give 55.37 g (79% yield) of 2,5-dibromobenzenesulfonyl chloride. 1H NMR (CDCl3): 7.66 (dd, 8.4, 2.3 Hz, 1H), 7.72 (d, 8.4 Hz, 1H), 8.30 (d, 2.3 Hz, 1H).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([Cl:11])[N:5]=[CH:4][N:3]=1.[CH3:12][NH:13][CH3:14].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:12][N:13]([CH3:14])[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([Cl:11])[N:5]=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1c(Cl)ncnc1Cl
Reactant: CNC
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(C)c1ncnc(Cl)c1[N+](=O)[O-]
Temperature: -70 °C

Procedure:
Dissolve 50 g (0.26 mol) of 4,6-dichloro-5-nitropyrimidine in 500 mL of CH2Cl2 and cool to -70° C. Add a solution of 24 mL (0.28 mol) dimethylamine, 70 mL (0.40 mol) of diisopropylethylamine, and 100 mL of CH2Cl2 over 30 minutes. Warm to room temperature and wash the reaction mixture with 500 mL of 20% K2CO3. Dry the CH2Cl2 portion over MgSO4, treat with charcoal filter, and remove the filtrate under vacuum. Crystallize the residue with ether to provide 4-dimethylamino-6-chloro-5-nitropyrimidine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:34])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16]=[C:17]3[C:27]4[C:22](=[N:23][CH:24]=[CH:25][CH:26]=4)[O:21][C:20]4[CH:28]=[CH:29][CH:30]=[C:31]([CH2:32][OH:33])[C:19]=4[CH2:18]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1>C(Cl)Cl.C(OCC)(=O)C.[O-2].[Mn+4].[O-2]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:34])[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][CH:16]=[C:17]3[C:27]4[C:22](=[N:23][CH:24]=[CH:25][CH:26]=4)[O:21][C:20]4[CH:28]=[CH:29][CH:30]=[C:31]([CH:32]=[O:33])[C:19]=4[CH2:18]3)[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: OCc1cccc2c1CC(=CCCN1CCC(O)(c3ccc(Cl)cc3)CC1)c1cccnc1O2
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=Cc1cccc2c1CC(=CCCN1CCC(O)(c3ccc(Cl)cc3)CC1)c1cccnc1O2
Temperature: 25 °C
Reaction time: 12 h
Yield: 93.4 %

Procedure:
To a solution of the product of example 274(1.0 g) in methylene chloride (200 ml) was added manganese(IV)oxide (3.0 g), and the suspension was stirred at ambient temperature for 12 hours. The reaction mixture was diluted with ethyl acetate and filtered through Celite. The solvent was evaporated under reduced pressure to give the titled compound (930 mg).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11]([F:14])[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=O)=[CH:5]2)[CH2:3][CH2:2]1.C([N:22](CC)CC)C.ClC(OCC)=O.N>CN(C)C=O.C(OCC)(=O)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11]([F:14])[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([NH2:22])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: O=C(O)c1cn(C2CC2)c2cc(F)c(F)cc2c1=O
Reactant: CCN(CC)CC
Agent: CCOC(=O)Cl
Agent: N
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: NC(=O)c1cn(C2CC2)c2cc(F)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 123.5 %

Procedure:
1-Cyclopropyl-6,7-difluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid (1.00 g, 3.77 mmol) was dissolved in dimethylformamide (15 ml), added with triethylamine (0.788 ml, 5.66 mmol) and ethyl chloroformate (0.538 ml, 5.66 mmol) under ice cooling, and stirred for 1 hour. The reaction mixture was warmed to room temperature, stirred for 30 minutes, and further stirred at 0° C. for 1 hour. The reaction mixture was added with concentrated aqueous ammonia (0.75 ml) and stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate and washed successively with aqueous citric acid, saturated aqueous sodium hydrogencarbonate and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated to obtain the title compound (1.23 g, quantitative) as white solid.
Reaction SMILES: [OH-].[K+].[CH3:3]N(N=O)S(C1C=CC(C)=CC=1)(=O)=O.[N+](=C)=[N-].[C:20]([OH:28])(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CS(C)=O.CN(C=O)C>[C:20]([O:28][CH3:3])(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(O)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)N(C)N=O)cc1
Agent: C=[N+]=[N-]
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccccc1

Procedure:
In a 1.5 l double-walled glass reactor 531 g of aqueous 30% KOH solution are submitted and are heated, respectively, to 40° C., 55° C. and 70° C. By controlled dropwise addition of 405.8 g of 26.4% N-methyl-N-nitroso-p-toluenesulfonamide (MNTSA) solution in DMSO into this KOH solution, diazomethane (DAM) is generated and is aspirated in gaseous form into a glass reactor via a frit by means of vacuum at 500 mbar. The metered addition is effected in such a way that the diazomethane concentration in the gas phase does not exceed a partial pressure of 120 mbar. With a view to determining the DAM quantity and yield, this glass reactor is charged with an acid, for example with a solution of benzoic acid in DMF, so that the DAM aspirated via the frit reacts to completion immediately to form methyl benzoate, and the content thereof is determined analytically and can be utilized as an equivalent for DAM. The following table reproduces the results:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-])=O)[C:3]=1[OH:11].S(S([O-])=O)([O-])=O.[Na+].[Na+].NC1C(O)=C(Br)C=C(Br)C=1>C(O)C.O.O>[NH2:8][C:4]1[C:3]([OH:11])=[C:2]([Br:1])[CH:7]=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1cccc(Br)c1O
Agent: Nc1cc(Br)cc(Br)c1O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Nc1cccc(Br)c1O
Reaction time: 2 h

Procedure:
2-Bromo-6-nitrophenol (1.506 g, 0.0057 mol, containing 2,4-di-bromo-6-nitrophenol, 18% w/w) and sodium hydrosulfite (3.05 g, 85%, 0.015 mol) were heated at reflux in ethanol/water (50 ml of a 5:1 v/v mixture). After 2 hours, the reaction mixture was diluted with water (150 ml) and extracted with dichloromethane (3×50 ml), and ethyl acetate (100 ml). The organic extracts were combined, dried over calcium sulfate, evaporated in vacuo, and purified by flash chromatography (SiO2, petrol/ether 1:1 v/v) to furnish a mixture of the title compound and 6-amino-2,4-di-bromophenol (0.600 g, of a 76:24 w/w mixture as judged by 1 H-NMR). Yield 6-amino-2-bromophenol, 43%.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][CH:15]=1)[O:6][C@H:7]([CH3:12])[C:8]([O:10][CH3:11])=[O:9].[NH:16]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].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>C1(C)C=CC=CC=1>[C:27]([O:26][C:24]([N:16]([CH2:2][C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][CH:15]=1)[O:6][C@H:7]([CH3:12])[C:8]([O:10][CH3:11])=[O:9])[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:25])([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)OC(=O)NC(=O)OC(C)(C)C
Reactant: COC(=O)[C@@H](C)Oc1cccc(CO)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COC(=O)[C@@H](C)Oc1cccc(CN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
300 mg of methyl (2R)-2-[3-(hydroxymethyl)phenoxy]propionate, 465 mg of di-tert-butyl iminodicarboxylate, and 543 mg of triphenylphosphine were dissolved in 3.00 mL of toluene, and 445 mg of diisopropyl azodicarboxylate was added thereto under ice-cooling, followed by stirring at room temperature overnight. The reaction liquid was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=95:5 to 0:100) to obtain 584 mg of methyl (2R)-2-(3-{[bis(tert-butoxycarbonyl)amino]methyl}phenoxy)propionate.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([CH3:9])[C:6]([NH2:10])=[CH:5][CH:4]=1.[C:11](Cl)(Cl)=[S:12]>O1CCCC1.C(=O)([O-])O.[Na+]>[N:10]([C:6]1[C:7]([CH3:9])=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[C:11]=[S:12]
Reactant: COc1ccc(N)c(C)n1
Reactant: S=C(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(N=C=S)c(C)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 41 %

Procedure:
A mixture of 6-methoxy-2-methylpyridin-3-amine (10.0 g, 0.0724 mol) in tetrahydrofuran (50 mL) and aqueous saturated sodium hydrogen carbonate (50 mL) was added thiophosgene (6.62 mL, 0.0868 mol) at 0° C. The reaction mixture was stirred at room temperature for 1 hr. The mixture was extracted with ethyl acetate (×3). The combined organic layer was washed with brine (×1), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. To the residue was added n-hexane and the precipitate was removed by filtration and the filtrate was concentrated in vacuo. The residue was washed with cold-n-hexane to give the title compound as a pale yellow solid (5.35 g, 0.0297 mol, 41%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[C:5]([O:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Br:29])[CH:24]=1)([CH3:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13]CC2C=CC=CC=2)=[CH:9][CH:8]=1)[CH3:2].C(OC(=O)C(C)(OC1C=CC=CC=1)CC1C=CC(O)=CC=1)C>C(O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:30])[C:5]([O:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Br:29])[CH:24]=1)([CH3:21])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([OH:13])=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCOC(=O)C(C)(Cc1ccc(OCc2ccccc2)cc1)Oc1cccc(Br)c1
Agent: [Pd]
Agent: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccccc1
Solvent: CCO
Product: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1cccc(Br)c1
Reaction time: 2 h

Procedure:
3-(4-Benzyloxy-phenyl)-2-(3-bromo-phenoxy)-2-methyl-propionic acid ethyl ester (3.7 g, 7.8 mmol) was dissolved in ethanol (140 mL), treated with 5% palladium on carbon (0.37 g), and stirred under an atmosphere of hydrogen for 2 h. The suspension was filtered through celite and concentrated in vacuo. The residue was purified by flash column chromatography (25% ethyl acetate in hexanes) to provide a mixture of the title compound and 3-(4-Hydroxyphenyl)-2-methyl-2-phenoxy-propionic acid ethyl ester as a light yellow oil (2.8 g, 94%). 1H NMR (400 MHz, CDCl3): δ 7.24-6.94 (m, 4H), 6.83-6.80 (m, 1H), 6.75-6.71 (m, 3H), 5.12 (s, 1H), 4.19 (q, 2H, J=7.04 Hz), 3.24 (d, 1H, J=13.69 Hz), 3.06 (d, 1H, J=13.69 Hz), 1.40 (s, 3H), 1.26-1.17 (m, 3H). MS [EI−] 377 (M−H)+. Rf=0.24 in 25% ethyl acetate in hexanes.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[Li].N>C(O)C>[CH3:1][NH:2][CH2:3][CH2:4][CH:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH2:10]1
Reactant: CNCCc1ccccc1
Agent: N
Agent: [Li]
Solvent: CCO
Product: CNCCC1C=CC=CC1

Procedure:
46 g. (0.34 moles) of N-methylphenethylamine are reduced by treatment with 16 g. of lithium (2.3 g. atom) in 1.5 l. of ammonia and 250 ml. ethanol according to the procedure of Example 1(a) to yield crude N-methyldihydrophenethylamine.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8](Br)=[C:7]([O:12][CH2:13][O:14][CH3:15])[CH:6]=1.CN(C)CCN(C)C.[Li]CCCC.C[O:30][C:31]1[CH2:35][CH2:34][C:33](=O)[CH:32]=1.Cl>C1COCC1>[CH3:15][O:14][CH2:13][O:12][C:7]1[CH:6]=[C:5]([O:4][CH2:3][O:2][CH3:1])[CH:10]=[CH:9][C:8]=1[C:33]1[CH2:34][CH2:35][C:31](=[O:30])[CH:32]=1
Reactant: COC1=CC(=O)CC1
Reactant: COCOc1ccc(Br)c(OCOC)c1
Agent: CN(C)CCN(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCOc1ccc(C2=CC(=O)CC2)c(OCOC)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 12.7 %

Procedure:
1,3-Bis(methoxymethoxy)-4-bromobenzene (1.0 g) was dissolved in THF (20 ml) and cooled to −78° C. under argon. N,N,N′,N′-Tetramethylethylene diamine was added followed by dropwise addition of n-BuLi (3.4 ml of a 2.2M solution in hexanes) over 10 mins. After stirring at −78° C. for 1 hr, a solution of 3-methoxy-2-cyclopentene-1-one (605 mg) in THF (5 ml) was added slowly. The reaction mixture was stirred at −78° C. for 1 hr before warming to 0° C. 1 M HCl (20 ml) was added, and after 10 min the mixture was extracted with ethyl acetate (2×50 ml). The combined organic phases were washed with brine (30 ml), dried over magnesium sulfate, and concentrated in vacuo. The crude residue was purified by flash column chromatography (SiO2, ethyl acetate/petrol, 1:1 v/v) to furnish the title compound as yellow oil (128 mg, 13%); m/z (ES+) 279 (M+1)+.