Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:8](Cl)(=[O:10])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:12][O:13][C:14](=[O:49])[CH:15]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([NH:31][C:32]([NH:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])=[N:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH:26]=1)[O:16][P:17]([C@@H:20]([NH2:24])[CH:21]([CH3:23])[CH3:22])([OH:19])=[O:18].C(N(CC)CC)C>C(Cl)Cl>[CH3:12][O:13][C:14](=[O:49])[CH:15]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([NH:31][C:32]([NH:41][C:42]([O:44][C:45]([CH3:46])([CH3:48])[CH3:47])=[O:43])=[N:33][C:34]([O:36][C:37]([CH3:39])([CH3:40])[CH3:38])=[O:35])[CH:26]=1)[O:16][P:17]([C@@H:20]([NH:24][S:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:10])=[O:9])[CH:21]([CH3:23])[CH3:22])([OH:19])=[O:18]
Reactant: COC(=O)C(OP(=O)(O)[C@@H](N)C(C)C)c1cccc(NC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C(OP(=O)(O)[C@@H](NS(=O)(=O)Cc1ccccc1)C(C)C)c1cccc(NC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Alternatively, to a solution of benzylsulfonyl chloride (101.4 mg, 0.53 mmol) and 2-(3-(N′,N″-di(t-butoxycarbonyl)guanidino)phenyl)-2-((1R)-(1-amino-2-methylpropyl)(hydroxy)-phosphinoyloxy)ethanoic acid methyl ester (301.4 mg, 0.54 mmol) in 4 mL of methylene chloride was added triethylamine (0.13 mL, 0.93 mmol). After stirring at ambient temperature for 1.5 hours, the reaction mixture was concentrated in vacuo to give a yellow oil, 2-(3-(N′,N″-di(t-butoxy-carbonyl)guanidino)phenyl)-2-((1R)-(1-(benzylsulfonyl)amino-2-methylpropyl)-(hydroxy)phosphinoyloxy)ethanoic acid methyl ester, which was used without further purification in the following step.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1>[Pd].CCO.CO>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[CH2:6][CH2:7]1
Reactant: CN1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Agent: [Pd]
Solvent: CO
Solvent: CCO
Product: CN1CCN(c2ccc(N)cc2)CC1
Reaction time: 8 h

Procedure:
4-Methyl-1-(4-nitrophenyl)piperazine (2.0 g, 9 mmol, Step A) and 10% Pd/C (200 mg) were added to EtOH/MeOH (1:1) (50 ml) at RT. The reaction stirred under a H2 atmosphere (via balloon) overnight. The mixture was filtered through a plug of Celite® and the filtrate was concentrated under reduced pressure to leave the desired material as a light yellow oil. The material was used in subsequent reaction without purification. MS: (ES+) 192 (M+1)+; (ES−): 190 (M−1)−. Calc'd for C11H17N3: 191.14.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[C:8]1[N:9]=[N:10][C:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:12]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=12.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.C(N(CC)CC)C.[O:52]1[CH2:57][CH2:56][CH:55]([C:58](O)=[O:59])[CH2:54][CH2:53]1.C([O-])(O)=O.[Na+]>ClCCl.C(OCC)(=O)C>[CH3:1][C@H:2]1[N:3]([C:8]2[C:13]3[CH:14]=[N:15][CH:16]=[CH:17][C:12]=3[C:11]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[N:10][N:9]=2)[CH2:4][CH2:5][N:6]([C:58]([CH:55]2[CH2:56][CH2:57][O:52][CH2:53][CH2:54]2)=[O:59])[CH2:7]1
Reactant: C[C@@H]1CNCCN1c1nnc(-c2ccccc2)c2ccncc12
Reactant: O=C(O)C1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C[C@@H]1CN(C(=O)C2CCOCC2)CCN1c1nnc(-c2ccccc2)c2ccncc12
Reaction time: 1 h

Procedure:
To a solution of (R)-4-(2-methylpiperazin-1-yl)-1-phenylpyrido[4,3-d]pyridazine 16 (125 mg, 409 μmol) in dichloromethane (5 mL) was added HOBT (3.1 mg, 20 μmol), EDCI (86 mg, 450 μmol), triethylamine (114 μl, 819 μmol), and tetrahydro-2H-pyran-4-carboxylic acid (64 mg, 491 μmol). After 1 hour, 10 mL of sat NaHCO3 and 100 mL of ethyl acetate were added. The layers were separated and the organic layer was washed with 1×10 mL of brine, dried over MgSO4, filtered, and concentrated. Purified by column chromatography (hexanes:acetone) to isolate (R)-(3-methyl-4-(1-phenylpyrido[4,3-d]pyridazin-4-yl)piperazin-1-yl)(tetrahydro-2H-pyran-4-yl)methanone 30. MS: 417.2 (calc'd) 418.1 (M+H, found).
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][C:7](=O)[CH2:6][CH2:5]1)[CH2:2][CH3:3].[CH3:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([NH2:19])[CH:14]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:11][O:12][C:13]1[CH:14]=[C:15]([NH:19][CH:7]2[CH2:8][CH2:9][N:4]([CH2:1][CH2:2][CH3:3])[CH2:5][CH2:6]2)[CH:16]=[CH:17][CH:18]=1
Reactant: COc1cccc(N)c1
Reactant: CCCN1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCCN1CCC(Nc2cccc(OC)c2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 47 %

Procedure:
A solution of 4.5 mL (30 mmol) of N-propyl-4-piperidone, 3.4 mL (30 mmol) of m-anisidine, and 1.7 mL (30 mmol) of glacial acetic acid was stirred in 120 mL of 1,2-dichloroethane (DCE) and 9.49 g (45 mmol) of sodium triacetoxyborohydride was added. The solution was stirred at 25° C. for 3 h. The solution was washed with NaHCO3 solution and brine. It was dried and the solvent was evaporated. The m-anisidine excess was distilled off in a Kugelrohr at 100° C./0.05 Torr. There was obtained 3.5 g (47% yield) of N-(3-methoxyphenyl)-1-propyl-4-piperidinamine as a solid. MS m/z=249 (M++H). 300 MHz 1H NMR (CDCl3) δ7.1 (t, 1H); 6.15-6.35 (m, 3H); 3.75 (s, 3H ); 3.25 (m, 1H); 2.9 (m, 2H); 2.3 (m, 2H); 2.15 (m, 4H); 1.5 (m, 4H); 0.9 (t, 3H). Anal calcd. for C15H24N2O; C, 72.54; H, 9.74; N, 11.28. Found: C, 72.55; H, 9.51; N, 11.21.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][CH2:9]Cl.CC(C)=O.[OH:15][C:16]1[CH:43]=[CH:42][C:41]([CH3:44])=[CH:40][C:17]=1[C:18]([NH:20][C:21]1[CH:33]=[C:32]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:31]=[CH:30][C:22]=1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:19]>C(OCC)(=O)C.O>[CH3:7][O:8][CH2:9][O:15][C:16]1[CH:43]=[CH:42][C:41]([CH3:44])=[CH:40][C:17]=1[C:18]([NH:20][C:21]1[CH:33]=[C:32]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:31]=[CH:30][C:22]=1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:19]
Reactant: COCCl
Reactant: Cc1ccc(O)c(C(=O)Nc2cc(-c3ccccc3)ccc2C(=O)OC(C)(C)C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Solvent: O
Product: COCOc1ccc(C)cc1C(=O)Nc1cc(-c2ccccc2)ccc1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Potassium carbonate (0.51 g) and methoxymethyl chloride (0.23 mL) were sequentially added to an acetone (9.0 mL) suspension of tert-butyl 2-(2-hydroxy-5-methylbenzamido)-4-phenylbenzoate (0.60 g), followed by stirring at room temperature for 1 hour and 30 minutes. Potassium carbonate (0.21 g) and methoxymethyl chloride (0.11 mL) were sequentially added to the reaction mixture, followed by stirring at room temperature for 2 hours. Potassium carbonate (0.51 g) and methoxymethyl chloride (0.23 mL) were sequentially added to the reaction mixture, followed by stirring at room temperature for 2 hours and then heating to reflux for 20 minutes. The reaction mixture was cooled to room temperature, and then water and ethyl acetate were added thereto. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 100-80% hexane/ethyl acetate] to obtain 0.64 g of tert-butyl 2-(2-(methoxymethoxy)-5-methylbenzamido)-4-phenylbenzoate.
Reaction SMILES: ClC1C(F)=C(C=CC=1F)C(Cl)=O.C(OCC)(=O)CC(OCC)=O.[Cl:24][C:25]1[C:26]([F:45])=[C:27]([CH:41]=[CH:42][C:43]=1[F:44])[C:28]([CH:30]([C:36]([O:38][CH2:39][CH3:40])=O)[C:31]([O:33][CH2:34][CH3:35])=[O:32])=[O:29].ClC1C(F)=C(C=CC=1F)C(CC(OCC)=O)=O.C([O-])([O-])OCC.C(OC(=O)C)(=O)C>>[Cl:24][C:25]1[C:26]([F:45])=[C:27]([CH:41]=[CH:42][C:43]=1[F:44])[C:28]([C:30](=[CH:36][O:38][CH2:39][CH3:40])[C:31]([O:33][CH2:34][CH3:35])=[O:32])=[O:29]
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)c1ccc(F)c(Cl)c1F
Agent: CCOC(=O)CC(=O)c1ccc(F)c(Cl)c1F
Agent: CCOC([O-])[O-]
Agent: O=C(Cl)c1ccc(F)c(Cl)c1F
Solvent: CC(=O)OC(C)=O
Solvent: CCOC(=O)CC(=O)OCC
Product: CCOC=C(C(=O)OCC)C(=O)c1ccc(F)c(Cl)c1F

Procedure:
Reaction of 3-chloro-2,4-difluoro-benzoyl chloride with diethyl malonate gives diethyl (3-chloro-2,4-difluoro-benzoyl)-malonate, and partial hydrolysis and decarboxylation lead to ethyl (3-chloro-2,4-difluoro-benzoyl)-acetate, which is reacted with ethyl orthoformate/acetic anhydride to give ethyl 2-(3-chloro-2,4-difluorobenzoyl)-3-ethoxy-acrylate; further reaction with cyclopropylamine leads to ethyl 2-(3-chloro-2,4-difluoro-benzoyl)-3-cyclopropylaminoacrylate, which is cyclized with potassium carbonate/dimethylformamide to give ethyl 8-chloro-1-cyclopropyl-7-fluoro-1,4-dihydro-4-oxo-3 -quinolinecarboxylate; hydrolysis then finally leads to the corresponding carboxylic acid. The reaction sequence described can be represented by the following equation: ##STR4##
Reaction SMILES: C([NH:8][CH:9]([CH:11]=[CH:12][CH:13]1[C:17]([CH3:19])([CH3:18])[CH2:16][CH2:15][C:14]1([CH3:21])[CH3:20])[CH3:10])(OC(C)(C)C)=O.O.[OH-].[K+].F[C:26](F)(F)C(O)=O>>[NH2:8][C:9]([CH3:10])([CH:11]=[CH:12][CH:13]1[C:14]([CH3:20])([CH3:21])[CH2:15][CH2:16][C:17]1([CH3:18])[CH3:19])[CH3:26]
Reactant: CC(C=CC1C(C)(C)CCC1(C)C)NC(=O)OC(C)(C)C
Reactant: O=C(O)C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CC(C)(N)C=CC1C(C)(C)CCC1(C)C
Reaction time: 8 h

Procedure:
N-Boc-2-amino-4-(2,2,5,5-tetramethyl-1-cyclopentyl)-3-butene is dissolved in trifluoroacetic acid and the solution is stirred overnight. Water is added and the mixture is made basic with 20% KOH. The mixture is extracted with ether and the organic layer is dried over Na2SO4 and evaporated to yield 2-amino-2-methyl-4-(2,2,5,5-tetramethyl-1-cyclopentyl)butene.
Reaction SMILES: [H-].C([O:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][N:8]=1)=O)C>C(Cl)Cl>[N+:13]([C:10]1[CH:11]=[CH:12][C:7]([CH:5]=[O:4])=[N:8][CH:9]=1)([O-:15])=[O:14]
Reactant: CCOC(=O)c1ccc([N+](=O)[O-])cn1
Agent: [H-]
Solvent: ClCCl
Product: O=Cc1ccc([N+](=O)[O-])cn1
Temperature: 5 °C
Reaction time: 16 h
Yield: 49.8 %

Procedure:
Diisobutylaluminiumo hydride (1 M in DCM, 44 mL, 44 mmol, 1.3 equiv) was added dropwise to a cold (−78° C.) solution of 5-nitro-pyridine-2-carboxylic acid ethyl ester (step 39.4) (6.56 g, 33.5 mmol) in DCM (130 mL), under an argon atmosphere. The reaction mixture was allowed to warm to 5° C., quenched by addition of an aqueous solution of potassium sodium tartrate, diluted with DCM and H2O, stirred for 16 h at rt, and filtered through a pad of celite. The filtrate was extracted several times with DCM. The organic phase was washed with H2O and brine, dried (Na2SO4), filtered and concentrated. The residue was purified by by silica gel column chromatography (EtOAc/Hex, 1:1) to provide 2.54 g of the title compound as a beige solid: ESI-MS: 151.1 [M−H]−.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([CH:11]=[O:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C([Cl:16])=O>CN(C=O)C.CO>[F:1][C:2]1[CH:10]=[C:9]([CH:11]=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([Cl:16])=[O:5]
Reactant: O=Cc1ccc(C(=O)O)c(F)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CO
Solvent: CN(C)C=O
Product: O=Cc1ccc(C(=O)Cl)c(F)c1
Reaction time: 2 h

Procedure:
To a slurry of 2-fluoro-4-formylbenzoic acid (0.531 g, 3.16 mmol) 10 mL DCM was added oxalyl chloride (0.168 mL, 1.89 mmol) and catalytic DMF (2 drops). The reaction was allowed to stir under a positive pressure of argon with a needle outlet to air. After 2 h, a quenched aliquot of the reaction (MeOH) was determined to contain no acid. The reaction was concentrated in vacuo and dried on a hood pump for 10 min to give a yellow solid, which was used without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[CH:11][N:12]=2)=[CH:4][CH:3]=1.[CH2:13]([CH:15]1[O:17][CH2:16]1)Cl.C(=O)([O-])[O-].[K+].[K+]>>[O:17]1[CH2:16][CH:15]1[CH2:13][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][CH:10]=[CH:11][N:12]=2)=[CH:6][CH:7]=1
Reactant: Oc1ccc(-c2nccs2)cc1
Reactant: ClCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: c1csc(-c2ccc(OCC3CO3)cc2)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
0.5 g of 2-(4-hydroxyphenyl)-thiazole is added in one portion to a mixture, heated under reflux, of 5 ml of epichlorohydrin and 0.79 g of potassium carbonate and the reaction mixture is then heated under reflux for a further 20 minutes. After cooling, the mixture is filtered, the filtrate is concentrated by evaporation in a rotary evaporator and the residue is dissolved in 6 ml of dichloromethane; 100 mg of tetrabutylammonium hydrogen sulphate and 6 ml of 2N sodium hydroxide solution are added to the solution and the whole is stirred for 3 hours at room temperature. The organic phase is separated off, washed with water and dried over sodium sulphate and the solvent is then removed in a rotary evaporator. The residue is recrystallised from a mixture of ether/hexane, yielding 2-[4-(2,3-epoxypropoxy)-phenyl]-thiazole having a melting point of 82°-93°.
Reaction SMILES: [F:1][CH:2]1[CH:7](OC)[NH:6][C:5](=[O:10])[NH:4][C:3]1=[O:11].Cl>>[F:1][C:2]1[C:3](=[O:11])[NH:4][C:5](=[O:10])[NH:6][CH:7]=1
Reactant: COC1NC(=O)NC(=O)C1F
Agent: Cl
Product: O=c1[nH]cc(F)c(=O)[nH]1
Yield: 49.9 %

Procedure:
0.25 g of 5-fluoro-6-methoxy-5,6-dihydrouracil obtained in Example 1B above was placed in a reflux flask and then 1 ml of concentrated HCl was added to the flask. The flask contents were brought to refluxing temperature, and the precipitation of a solid soon occurred, producing 0.1 g of 5-fluorouracil.
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH:6]=[CH:5]2.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23](OS(C)(=O)=O)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].C([O-])([O-])=O.[K+].[K+].C(=O)([O-])O.[Na+]>CN(C)C=O.C(OCC)(=O)C.CCCCCCC>[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([S:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[C:8](=[O:12])[NH:7][CH:6]=[CH:5]3)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Reactant: O=c1[nH]ccc2cc(S)ccc12
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCCCCCC
Product: CC(C)(C)OC(=O)N1CCC(Sc2ccc3c(=O)[nH]ccc3c2)CC1
Temperature: 50 °C
Reaction time: 8 h
Yield: 14.9 %

Procedure:
A mixture of 6-mercapto-2H-isoquinolin-1-one (50 mg, 0.28 mmol), 4-methane-sulphonyloxy-piperidine-1-carboxylic acid tert-butyl ester (117 mg, 0.42 mmol) and K2CO3 (64 mg, 0.46 mmol) in N, N-dimethylformamide (1.5 ml) was heated at 50° C. then left at ambient temperature overnight. Saturated aqueous sodium hydrogen carbonate was added to the mixture which was extracted with ethyl acetate (x 3). The combined organics were dried (Na2SO4) and concentrated in vacuo to give a residue. Flash chromatography of the residue using ethyl acetate:heptane (1:9 to 99:1) gave 4-(1-Oxo-1,2-dihydroisoquinolin-6-ylsulfanyl)piperidine-1-carboxylic acid tert-butyl ester (15 mg). A dichloromethane:trifluoroacetic acetic acid solution (7:3, 5 ml) was added to the 4-(1-Oxo-1,2-dihydroisoquinolin-6-ylsulfanyl)piperidine-1-carboxylic acid tert-butyl ester and the mixture stirred for 2 h, then concentrated in vacuo to give a residue. The residue was loaded onto a pre-acidified SCX column using methanol and eluted with 2M ammonia in methanol to afford crude 6-(piperidin-4-ylsulfanyl)-2H-isoquinolin-1-one, which was purified by prep-HPLC (2 mg), El-MS: m/z=261.1 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][NH:10][CH2:11][CH2:12][O:13][CH2:14][CH3:15].C(N(CC)CC)C.Cl[C:24]([O:26][CH3:27])=[O:25].[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[CH3:27][O:26][C:24](=[O:25])[N:10]([CH2:9][CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Br:1])[CH2:11][CH2:12][O:13][CH2:14][CH3:15]
Reactant: CCOCCNCCc1ccccc1Br
Reactant: COC(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOCCN(CCc1ccccc1Br)C(=O)OC
Reaction time: 20 h

Procedure:
2.45 g of 2-(2-bromophenyl)-N-(2-ethoxyethyl)ethanamine and 1.4 cm3 of triethylamine in solution in 22 cm3 of anhydrous tetrahydrofuran are stirred under an inert atmosphere at 0° C. 1.3 cm3 of methyl chloroformate in solution in 4 cm3 of tetrahydrofuran are poured into the reaction mixture. This mixture is then stirred for 20 h at a temperature close to 20° C. 50 cm3 of a saturated aqueous solution of ammonium chloride and 50 cm3 of ethyl acetate are added. After decanting, the organic phase is washed twice with 20 cm3 of water then 20 cm3 of a saturated aqueous solution of sodium chloride, it is dried over magnesium sulfate and filtered through a bed of silica of 30 g. The latter is washed twice with 75 cm3 of ethyl acetate. The filtrate is concentrated using a rotary evaporator under reduced pressure (5 kPa). 2.97 g of methyl[2-(2-bromophenyl)ethyl](2-ethoxyethyl)carbamate are obtained in the form of a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:33]=[CH:32][C:15]([C:16]([NH:18][C@H:19]([C:27]([O:29]CC)=[O:28])[CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:17])=[CH:14][CH:13]=1)[CH:6]=[CH:5]2.[F:34][C:35]([F:48])([F:47])[O:36][C:37]1[CH:42]=[CH:41][C:40]([S:43](Cl)(=[O:45])=[O:44])=[CH:39][CH:38]=1>>[F:48][C:35]([F:34])([F:47])[O:36][C:37]1[CH:42]=[CH:41][C:40]([S:43]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[N:7]([CH2:11][C:12]2[CH:33]=[CH:32][C:15]([C:16]([NH:18][C@H:19]([C:27]([OH:29])=[O:28])[CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[O:17])=[CH:14][CH:13]=2)[CH:6]=[CH:5]3)(=[O:45])=[O:44])=[CH:39][CH:38]=1
Reactant: CCOC(=O)[C@H](Cc1ccccc1)NC(=O)c1ccc(Cn2ccc3cc(N)ccc32)cc1
Reactant: O=S(=O)(Cl)c1ccc(OC(F)(F)F)cc1
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)O)c1ccc(Cn2ccc3cc(NS(=O)(=O)c4ccc(OC(F)(F)F)cc4)ccc32)cc1

Procedure:
The title compound was prepared from ethyl N-{4-[(5-amino-1H-indol-1-yl)methyl]benzoyl}phenylalaninate and 4-trifluoromethoxyphenyl sulfonyl chloride following the procedure of Example 10: MS (ESI) m/z 638; MS (ESI) m/z 636.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[C:4]([CH3:9])[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].FC(F)(F)S(O[CH2:22][C:23]([F:26])([F:25])[F:24])(=O)=O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH3:9])[C:5]([O:8][CH2:22][C:23]([F:26])([F:25])[F:24])=[CH:6][N:7]=1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: Cc1cc(Cl)ncc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1cc(Cl)ncc1OCC(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.7 %

Procedure:
To a mixture of 6-chloro-4-methylpyridin-3-ol (2.00 g, 13.9 mmol) and cesium carbonate (6.81 g, 20.9 mmol) in DMF (40 mL) is added dropwise 2,2,2-trifluoroethyl trifluoromethanesulfonate (3.56 g, 15.3 mmol) at 0° C. After stirring at rt for 1 hour, the mixture is poured onto water (300 mL). The aqueous layer is extracted with EtOAc (300 mL). The separated organic layer is washed with water (200 mL), dried over sodium sulfate, and concentrated in vacuo. The residue is purified by column chromatography on silica gel eluting with n-hexane/EtOAc (9:1) to give 3.00 g (95% yield) of the title compound as white solid.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(N1C2C(=CC=CC=2)C=C1)([C:20]1C=CC(C)=CC=1)(=O)=O.C(C1C2C(=CC=CC=2)NC=1)(=O)CCCCC.C(C1C2C(=CC=CC=2)NC=1)CCCCC.C(C1C2C(=CC=CC=2)N(S(C2C=CC(C)=CC=2)(=O)=O)C=1)(=O)CCCCCCCCCCC.C(C1C2C(=CC=CC=2)NC=1)(=O)CCCCCCCCCCC.C(C1C2C(=CC=CC=2)NC=1)CCCCCCCCCCC>>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)[CH2:2][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH3:20]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3ccccc32)cc1
Reactant: c1ccc(Cn2ccc3ccccc32)cc1
Agent: CCCCCC(=O)c1c[nH]c2ccccc12
Agent: CCCCCCCCCCCC(=O)c1c[nH]c2ccccc12
Agent: CCCCCCCCCCCC(=O)c1cn(S(=O)(=O)c2ccc(C)cc2)c2ccccc12
Product: CCCCCCCCn1ccc2ccccc21

Procedure:
1-benzylindole; 1-tosylindole; 1-tosylindole; 3-hexanoxyl-1-tosylindole; 3-hexanoylindole; 3-hexylindole; 3-dodecanoyl-1-tosylindole; 3-dodecanoylindole and 3-dodecylindole.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]([C:13]2[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][C:16]([NH2:23])=[CH:15][C:14]=2[NH2:24])[C:8](=O)[O:9]CC)=[CH:4][CH:3]=1.[H-].[Na+].C(=O)(O)[O-].[Na+]>C(O)C>[NH2:23][C:16]1[CH:17]=[C:18]([C:19]([F:22])([F:20])[F:21])[C:13]2[N:7]([CH2:6][C:5]3[CH:25]=[CH:26][C:2]([Cl:1])=[CH:3][CH:4]=3)[C:8](=[O:9])[NH:24][C:14]=2[CH:15]=1
Reactant: CCOC(=O)N(Cc1ccc(Cl)cc1)c1c(N)cc(N)cc1C(F)(F)F
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: Nc1cc(C(F)(F)F)c2c(c1)[nH]c(=O)n2Cc1ccc(Cl)cc1
Yield: 35.8 %

Procedure:
Ethyl 4-chlorobenzyl[2,4-diamino-6-(trifluoromethyl)phenyl]carbamate (248.7 mg) was dissolved in ethanol (15 ml), and to the solution was added sodium hydride (51.3 mg). The reaction mixture was heated at reflux for 15 hours. After allowing to cool, to the reaction mixture was added saturated aqueous sodium bicarbonate solution, and the mixture was extracted 3 times with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The resultant residue was purified by preparative TLC (2 mm, 20×20 cm, CHCl3-methanol=10:1) to give the title compound (78.4 mg).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:3]=1[CH:4]=[O:5].Cl.[P:12](Cl)([O:17][CH2:18][CH3:19])([O:14][CH2:15][CH3:16])=[O:13]>ClCCl.C(N(CC)CC)C>[P:12]([O:1][C:2]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:3]=1[CH:4]=[O:5])([O:17][CH2:18][CH3:19])([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOP(=O)(Cl)OCC
Reactant: Cc1ccc(O)c(C=O)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOP(=O)(OCC)Oc1ccc(C)cc1C=O
Reaction time: 8 h
Yield: 81 %

Procedure:
To a solution of 2-hydroxy-5-methyl benzaldehyde (4A) (1000 mg) in dry dichloromethane (20 mL) and triethylamine (2 mL), diethyl chlorophosphate (1.17 mL) was added in a dropwise manner. The mixture was stirred for overnight and the reaction mixture was acidified using 5% HCl and extracted with ethyl acetate and the extracts were combined, washed with sodium bicarbonate and then concentrated. Flash column chromatography furnished the pure product as colorless oil (1620 mg, 81%): 1H-NMR (500 MHz, CDCl3) δ 10.34 (s, 1H), 7.7 (s, 1H), 7.3-7.4(d, J=8.4 Hz, 1H)7.3 (d, J=8.4 MHz), 4.2-4.3 (m, 4H) 2.3 (s, 3H), 1.3(t, J=6 Hz, 6H) (FIG. 7). 13C-NMR (CDCl3, 50.3 MHz) δ 188.5, 136.1, 135.1, 128.7, 120.8, 664.8, 20.4, 15.9. 31P-NMR (CDCl3, 81 MHz) δ −6.18 (FIG. 8). MS calcd for C12H17O5P 272.23, found 272.
Reaction SMILES: [CH3:1][CH:2]([CH3:4])[O-:3].[Na+].[Cl:6][C:7]1[CH:12]=[C:11](Cl)[N:10]=[CH:9][N:8]=1>C(O)(C)C>[Cl:6][C:7]1[CH:12]=[C:11]([O:3][CH:2]([CH3:4])[CH3:1])[N:10]=[CH:9][N:8]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: CC(C)[O-]
Agent: [Na+]
Solvent: CC(C)O
Product: CC(C)Oc1cc(Cl)ncn1
Yield: 271.7 %

Procedure:
A solution of sodium isopropoxide (prepared from 0.77 g sodium) in isopropanol (230 ml) was added dropwise over 8 hours to a stirred solution of 4,6-dichloropyrimidine (5.0 g) in isopropanol (60 ml) at room temperature. The solvent was evaporated in vacuo, the residue taken up in water and extracted three times with diethylether (3×70 ml). The combined ether extracts were dried (Na2SO4) and evaporated in vacuo to give 4-chloro-6-isopropoxy pyrimidine (4.4 g) as an oil, characterized spectroscopically, and used directly.