Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC(=O)CC[S:6]([C:9]1[CH:14]=[CH:13][C:12]([CH:15]([NH:19][C:20]([C:22]2[CH:23]=[N:24][N:25]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)[C:26]=2[CH3:27])=[O:21])[CH2:16][CH2:17][CH3:18])=[CH:11][N:10]=1)(=[O:8])=[O:7].C[O-].[Na+].[Na].ClN1C(=[O:46])CCC1=O.[O:48]1[CH2:53][CH2:52][CH:51]([NH2:54])[CH2:50][CH2:49]1>C1COCC1.CO>[O:48]1[CH2:53][CH2:52][CH:51]([NH:54][S:6]([C:9]2[N:10]=[CH:11][C:12]([CH:15]([NH:19][C:20]([C:22]3[CH:23]=[N:24][N:25]([C:28]4[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=4)[C:26]=3[CH3:27])=[O:21])[CH2:16][CH2:17][CH3:18])=[CH:13][CH:14]=2)(=[O:7])=[O:8])[CH2:50][CH2:49]1.[Cl:34][C:31]1[CH:30]=[CH:29][C:28]([N:25]2[C:26]([CH3:27])=[C:22]([C:20]([NH:19][CH:15]([C:12]3[CH:13]=[CH:14][C:9]([S:6]([OH:7])(=[O:8])=[O:46])=[N:10][CH:11]=3)[CH2:16][CH2:17][CH3:18])=[O:21])[CH:23]=[N:24]2)=[CH:33][CH:32]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCCC(NC(=O)c1cnn(-c2ccc(Cl)cc2)c1C)c1ccc(S(=O)(=O)CCC(=O)OC)nc1
Reactant: NC1CCOCC1
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Solvent: C1CCOC1
Product: CCCC(NC(=O)c1cnn(-c2ccc(Cl)cc2)c1C)c1ccc(S(=O)(=O)NC2CCOCC2)nc1
Product: CCCC(NC(=O)c1cnn(-c2ccc(Cl)cc2)c1C)c1ccc(S(=O)(=O)O)nc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 9 %
Yield: 12 %

Procedure:
To a solution of 3-[5-(1-{[1-(4-chloro-phenyl)-5-methyl-1H-pyrazole-4-carbonyl]-amino}-butyl)-pyridine-2-sulfonyl]-propionic acid methyl ester (150 mg, 0.29 mmol) in anhydrous THF (15 mL) is added sodium methoxide in methanol (2.6 M solution freshly prepared by dissolving 120 mg of sodium in 2.0 mL of methanol, 0.12 mL, 0.32 mmol). After stiffing at room temperature for 15 min, the reaction mixture is concentrated in vacuo. Anhydrous THF (10 mL) is added and the concentration process is repeated. The resultant residue is dried under high vacuum for 5 min, dissolved in THF (15 mL) and treated with N-chlorosuccinimide (77 mg, 0.58 mmol). The reaction mixture is stirred at room temperature for 15 min and then tetrahydro-pyran-4-ylamine (130 mg, 1.3 mmol) is added in one portion. After 20 min the reaction mixture is concentrated in vacuo and purified directly by preparative reverse phase HPLC (eluted with 10 to 90% CH3CN/H2O and 0.1% TFA as additive) followed preparative TLC (eluted with 70% EtOAc/hexanes) to afford 1-(4-chloro-phenyl)-5-methyl-1H-pyrazole-4-carboxylic acid {1-[6-(tetrahydro-pyran-4-ylsulfamoyl)-pyridin-3-yl]-butyl}-amide (14 mg, 9%) and 5-(1-{[1-(4-chloro-phenyl)-5-methyl-1H-pyrazole-4-carbonyl]-amino}-butyl)-pyridine-2-sulfonic acid (15 mg, 12%).
Reaction SMILES: [CH:1](=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].Cl.[NH2:15][OH:16]>CO.C(OCC)(=O)C.[Pt].[Pt]=O>[CH2:1]([N:15]([CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1])[OH:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: NO
Reactant: CCCCCCCCCCCC=O
Agent: O=[Pt]
Agent: [Pt]
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCN(O)CCCCCCCCCCCC
Yield: 49.8 %

Procedure:
A solution of dodecanal (9.2 g, 50 mmol) and hydroxylamine hydrochloride (2.0 g, 29 mmol) in 70 ml of methanol and 10 ml of ethyl acetate is shaken under hydrogen at 40-45 psi (2.8-3.15 Kg/cm2) for 2.5 hours at room temperature in the presence of a catalytic amount of 5% platinum on carbon (400 mg) and platinum oxide (15 mg). The reaction mixture is then worked up as described in Example 4 to give, after recrystallization from methanol, 4.6 g (50% yield) of the title compound as a white solid identical to that prepared in Example 4.
Reaction SMILES: [CH2:1]([SH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[Na+].[Na].Cl[C:14]1[S:15][CH:16]=[C:17]([Cl:19])[N:18]=1>C(O)C>[Cl:19][C:17]1[N:18]=[C:14]([S:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[S:15][CH:16]=1
Reactant: SCc1ccccc1
Reactant: Clc1csc(Cl)n1
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: Clc1csc(SCc2ccccc2)n1
Reaction time: 0.25 h
Yield: 90.7 %

Procedure:
Benzylmercaptan (24.8 g) was added dropwise to a solution of 10.8 of sodium methoxide in 100 ml ethanol. After stirring 15 minutes, the ethanolic solution of sodium benzylmercaptide was added dropwise to a solution of 30.8 g 2,4-dichlorothiazole [prepared by the method of P. Reynaud et al., Bull. Soc. Chim. France, 1735 (1962)], resulting in a temperature increase of 28° to 48°. When the exotherm subsided, the suspension was refluxed 1 hour, then the solvent was evaporated. Cold water (300 ml) was added to the oily residue, and the aqueous mixture was extracted with methylene chloride. The organic solution was washed with water, followed by saturated brine, then dried over magnesium sulfate, filtered and the solvent evaporated to give 43.8 g of 4-chloro-2-phenylmethylthiothiazole as a brown oil.
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][N:7]=[CH:8]2.CS([Cl:17])(=O)=O.C(N(CC)CC)C>C(Cl)Cl>[Cl:17][CH2:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][N:7]=[CH:8]2
Reactant: OCc1cccc2cnccc12
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: ClCc1cccc2cnccc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 0.1212 g (0.76 mmol) 15 in 8 mL CH2Cl2 at 0° C. was added 64.8 μL (0.84 mmol) methanesulfonyl chloride and 84.7 μL (0.61 mmol) triethylamine. After 3 h at 0° C., the reaction mixture was warmed to room temperature and 32.0 μL (0.23 mmol) triethylamine added. The reaction was recooled to 0° C., and 14.7 μL (0.19 mmol) methanesulfonyl chloride and 26.5 μL (0.19 mmol) triethylamine were added. After 62 h at room temperature, the reaction mixture was diluted with 25 mL CH2Cl2 and washed with 10 mL saturated NaHCO3 solution. The aqueous layer was extracted with 10 mL CH2Cl2, and the combined organic layers were washed with 10 mL brine, dried over Na2SO4, filtered and concentrated in vacuo. The product was purified by flash chromatography (15×140 mm silica gel, 2% (10% NH40H:MeOH):CH2Cl2). Mixed fraction repurified by flash chromatography (12×75 mm silica gel, 1% (10% NH40H:MeOH):CH2Cl2) to give 16. 1H NMR (CDCl3, 400 MHz) δ 9.305 (s, 1H, ArH); 8.653 (d, 1H, J=5.85 Hz, ArH); 7.992 (d, 1H, J=8.23 Hz, ArH); 7.927 (d, 1H, J=5.94 Hz, ArH); 7.753 (d, 1H, J=7.04 Hz, ArH); 7.583 (dd, 1H, J=7.14, 8.14 Hz, ArH); 5.020 (s, 1H, ArCH2); MS (Electrospray): m/z 177.9, 179.9 (M+H, 35Cl, 37Cl).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C1(C)C=CC=CC=1.C(N(CC)CC)C.Cl[C:38](Cl)([O:40]C(=O)OC(Cl)(Cl)Cl)Cl.[CH3:49][CH:50]([CH3:59])[CH:51]([C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)[OH:52]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:38](=[O:40])[O:52][CH:51]([C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[CH:50]([CH3:59])[CH3:49])=[CH:18][CH:17]=1
Reactant: CC(C)C(O)c1ccccc1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc2nccc(Oc3ccc(NC(=O)OC(c4ccccc4)C(C)C)cc3)c2cc1OC
Temperature: 25 °C
Yield: 63.6 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (77 mg) was added to toluene/triethylamine=10/1 (8 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (118 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 2-methyl-1-phenyl-1-propanol (39 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (78 mg, yield 59%).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:10]=[C:11](Br)[CH:12]=[CH:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[CH:21](=[O:32])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].O>O1CCCC1>[C:1]1([CH2:7][O:8][C:9]2[CH:10]=[C:11]([CH:21]([OH:32])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH:12]=[CH:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Brc1cccc(OCc2ccccc2)c1
Reactant: CCCCCCCCCCC=O
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCCCCC(O)c1cccc(OCc2ccccc2)c1
Temperature: -70 °C
Yield: 89 %

Procedure:
Under a nitrogen atmosphere, a solution of 17.0 grams (0.065 mole) of 3-(phenylmethoxy)phenyl bromide in 125 mL of tetrahydrofuran was stirred and cooled to -70° C. To this was added dropwise 28.0 mL (0.071 mole) of 2.5M n-butyllithium (in hexanes) during a 15 minute period. The reaction mixture temperature was maintained below -60° C. during the addition. Upon completion of addition, a solution of 11.5 grams (0.068 mole) of undecanaldehyde in 15 mL of tetrahydrofuran was added dropwise during a 5 minute period. Upon completion of addition, the reaction mixture was allowed to warm to 0° C. during a one hour period. The reaction mixture was again cooled to -60° C., and 100 mL of water was added. The reaction mixture was allowed to warm to ambient temperature, and then it was extracted with 200 mL of diethyl ether. The ether extract was washed with 50 mL of water, and then it was concentrated under reduced pressure to a residue. The residue was subjected to column chromatography on silica gel. Elution was accomplished using 9:1 petroleum ether and diethyl ether, and 7:3 petroleum ether and diethyl ether. The product-containing fractions were combined and concentrated under reduced pressure, yielding 20.5 grams of 1-[3-(phenylmethoxy) phenyl]undecanol. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: CCN=C=NCCCN(C)C.[I:12][C:13]1[CH:14]=[C:15]([CH:19]=[C:20]([N+:22]([O-:24])=[O:23])[CH:21]=1)[C:16]([OH:18])=O.C1C=CC2N(O)N=NC=2C=1.[NH2:35][CH:36]([CH3:40])[CH2:37][O:38][CH3:39].CN1C(=O)CCC1>C(Cl)Cl.CN(C=O)C>[I:12][C:13]1[CH:14]=[C:15]([CH:19]=[C:20]([N+:22]([O-:24])=[O:23])[CH:21]=1)[C:16]([NH:35][CH:36]([CH3:40])[CH2:37][O:38][CH3:39])=[O:18]
Reactant: COCC(C)N
Reactant: O=C(O)c1cc(I)cc([N+](=O)[O-])c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCCC1=O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COCC(C)NC(=O)c1cc(I)cc([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 27.9 %

Procedure:
EDCI (7.07 g, 36.9 mmol) was added in one portion to a stirred solution of 3-Iodo-5-nitro-benzoic acid (2.31 g, 24.6 mmol), HOBt (4.985 g, 36.9 mmol), 2-Amino-1-methoxypropane (2.73 ml, 24.6 mmol) and NMP (4.06 ml 36.9 mmol) in CH2Cl2 (120 ml) and DMF (10 ml) at 0° C. The reaction was allowed to warm to room temperature and was stirred over night. The reaction mixture was then washed with 2N NaOH, water, brine, and dried over Na2SO4. Solvent was removed in vacuo to give 2.50 g of 3-Iodo-N-(2-methoxy-1-methyl-ethyl)-5-nitro-benzamide as a yellow solid, MS (M+H)=365. This material was used without further purification.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.O=[C:13]([CH2:19][CH3:20])[CH2:14][C:15]([O:17][CH3:18])=[O:16].C1(C)C=CC=CC=1>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:9]=[CH:8][C:6]([NH:7][C:13]([CH2:19][CH3:20])=[CH:14][C:15]([O:17][CH3:18])=[O:16])=[CH:5][CH:4]=1
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: CCC(=O)CC(=O)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCC(=CC(=O)OC)Nc1ccc(C(F)(F)F)cc1
Reaction time: 15 h
Yield: 75.8 %

Procedure:
In a 2L-flask were placed 4-trifluoromethylaniline (161 g, 1.00 mol), methyl 3-oxopentanoate (143 g, 1.10 mol) and toluene (640 ml). To this solution was added p-toluenesulfonic acid monohydrate (3.2 g, 0.017 mol), and the resulting mixture was heated in a bath kept at 100° C. under a reduced pressure of 27 kPa, while the water generated was taken out of the reaction system by using a Dean-Stark trap under reflux. After 15 hours, the heating was discontinued, nitrogen leaked in, and the reaction mixture cooled. The solvent was evaporated by means of a rotary-evaporator, and the residue was distilled under reduced pressure to give 207 g of the title compound. The yield was 75.8%.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([CH2:12][OH:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]>ClCCl.[O-2].[Mn+2]>[Cl:1][C:2]1[CH:11]=[C:10]([CH:12]=[O:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccc(CO)cc1Cl
Agent: [Mn+2]
Agent: [O-2]
Solvent: ClCCl
Product: COC(=O)c1ccc(C=O)cc1Cl
Temperature: 27 °C
Reaction time: 6 h
Yield: 62.2 %

Procedure:
A mixture of methyl 2-chloro-4-(hydroxymethyl)benzoate (350 mg, 1.7 mmol) in and manganese oxide (756 mg, 30.9 mmol) in dichloromethane (10 mL) was stirred at 27° C. for 6 hours. The mixture was filtered and evaporated in vacuo to give Intermediate 75 (210 mg, 61%).
Reaction SMILES: [OH:1]O.[C:3]1([C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[C:17]=2[CH2:16][CH:15]=[CH:14]3)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C(O)=O>[C:3]1([C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[C:17]=2[CH2:16][C:15](=[O:1])[CH2:14]3)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C1=Cc2cccc(-c3ccccc3)c2C1
Reactant: OO
Solvent: O=CO
Product: O=C1Cc2cccc(-c3ccccc3)c2C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A stirred solution of 53.2 ml of formic acid and 10.5 ml of 30% hydrogen peroxide was heated to 35° C., and 14.5 g (0.075 mole) of 7-phenyl-1H-indene was added dropwise causing the reaction mixture temperature to rise to 41° C. Upon complete addition the reaction mixture was allowed to cool to ambient temperature and was stirred for 16 hours. The reaction mixture was concentrated under reduced pressure to give a residual semi-solid which was subjected to steam distillation in the presence of aqueous dilute sulfuric acid. The steam distillates were filtered to give 1.84 of 4-phenyl-2-indanone; m.p. 133°-136° C. The nmr and the ir spectra were consistent with the proposed structure.
Reaction SMILES: C([O:3][C:4](=[O:19])[C@@H:5]([O:17][CH3:18])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15]Br)=[CH:9][CH:8]=1)C.[OH:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]([CH:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)=[O:29])=[CH:23][CH:22]=1.CO[C@@H](CC1C=CC(OCCCOC2C=CC=CC=2)=CC=1)C(O)=O>>[CH:30]1([C:28]([NH:27][C:24]2[CH:25]=[CH:26][C:21]([O:20][CH2:15][CH2:14][O:13][C:10]3[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:17][CH3:18])[C:4]([OH:3])=[O:19])=[CH:12][CH:11]=3)=[CH:22][CH:23]=2)=[O:29])[CH2:31][CH2:32][CH2:33][CH2:34]1
Reactant: O=C(Nc1ccc(O)cc1)C1CCCC1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCBr)cc1)OC
Agent: CO[C@@H](Cc1ccc(OCCCOc2ccccc2)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCCOc2ccc(NC(=O)C3CCCC3)cc2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(2-bromo-ethoxy)-phenyl]-2-methoxy-propionic acid ethyl ester (Example 283, Step 2) and cyclopentanecarboxylic acid (4-hydroxy-phenyl)-amide via the same procedure used for the preparation of (2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example 285, Step 1), to produce a white solid. MS (ES) for C24H29NO6 [M+H]+: 428.3.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4](=[O:6])N.N[C@H](C(O)=[O:16])C(C)C.[NH2:18][CH:19]([NH2:21])[CH3:20].[C:22]([C:26]1[C:27]([NH:29][C:30](=[O:32])[CH:31]=1)=[O:28])(=[O:25])[CH2:23][CH3:24].[NH:33](C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[C@H:34]([C:39]([OH:41])=[O:40])[CH2:35][CH2:36][S:37][CH3:38]>>[NH2:33][C@H:34]([C:39]([OH:41])=[O:40])[CH2:35][CH2:36][S:37][CH3:38].[NH2:1][C@@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4]([OH:16])=[O:6].[NH2:18][CH:19]([NH2:21])[CH3:20].[C:22]([C:26]1[C:27]([NH:29][C:30](=[O:32])[CH:31]=1)=[O:28])(=[O:25])[CH2:23][CH3:24]
Reactant: CC(C)[C@H](N)C(=O)O
Reactant: CSCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: NC(=O)C[C@H](N)C(=O)O
Agent: CC(N)N
Agent: CCC(=O)C1=CC(=O)NC1=O
Product: CSCC[C@H](N)C(=O)O
Product: N[C@H](CC(=O)O)C(=O)O
Reaction time: 0.18 h

Procedure:
AF-Methionine-(D)Aspartic Acid-diaminoethane-propionyl maleimide (7d) was prepared using the same method as 5c starting with 100 mg of Fmoc-(D)Asp(OtBu)-diaminoethane-trityl resin (3), and using Fmoc-Met as AA1. Yield: 19.4 mg (25%) of white solid. RP-HPLC analysis: >95% at 10.97 min; ESMS m/z=1185.195 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5].CCN(CC)CC.[I:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21]>C(Cl)Cl>[I:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]([NH:5][C:4]1[CH:6]=[CH:7][CH:8]=[CH:9][C:3]=1[O:2][CH3:1])=[O:21]
Reactant: O=C(Cl)c1ccccc1I
Reactant: COc1ccccc1N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccccc1NC(=O)c1ccccc1I
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 80.7 %

Procedure:
To a solution of 2-methoxyaniline 5 (2.46 g, 20 mmol) in dry CH2Cl2 (50 mL) was added Et3N (6.14 mL, 44 mmols) at 0° C. and under dry N2 atmosphere. A solution 2-iodobenzoyl chloride 2 (5.33 g, 20 mmol) in dry CH2Cl2 (25 mL) was slowly added to the reaction mixture keeping the temperature at 0° C. After 15 min the reaction mixture was allowed to warm to room temperature and stirred overnight. Reaction mixture was diluted with CH2Cl2 (100 mL), washed with H2O (40 mL) and saturated aqueous NaCl solution (40 mL), dried (Na2SO4) and evaporated to yield a light pink solid. Recrystallization from ethyl acetate-hexanes (1:3) provided 3 as white needles (5.7 g). The filtrate was concentrated and the residue was purified by flash chromatography on silica, eluting with 15% ethyl acetate (EtOAc) in hexanes, to provide additional pure product (1.25 g). Total yield: 6.95 g, 98%; 1H NMR (400 MHz, CDCl3) δ 8.54 (dd, J=8.0, 2.0 Hz, 1H), 8.10 (br s, 1H), 7.92 (dd, J=8.0, 1.2 Hz, 1H), 7.52 (dd, J=7.6, 1.2 Hz, 1H), 7.43 (ddd, J=8.8, 7.6, 1.2 Hz, 1H), 7.17-7.09 (m, 2H), 7.03 (t, J=8.0 Hz, 1H), 6.92 (d, J=8.0 Hz, 1H), 3.87 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 167.10, 148.29, 142.58, 140.30, 131.49, 128.52, 128.43, 127.58, 124.45, 121.33, 120.12, 110.25, 92.70, 55.92; MS (ESI): m/z 376.20 (M+Na)+.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][P:7](=[O:14])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])=[CH:4][CH:3]=1.[CH2:17]([CH:24]([C:30](OCC)=[O:31])[C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:12]([O:11][P:7]([CH2:6][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:30]([CH:24]([CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[O:31])=[CH:16][CH:15]=1)([O:8][CH2:9][CH3:10])=[O:14])[CH3:13]
Reactant: CCOC(=O)C(Cc1ccccc1)C(=O)OCC
Reactant: CCOP(=O)(Cc1ccc(N)cc1)OCC
Product: CCOC(=O)C(Cc1ccccc1)C(=O)Nc1ccc(CP(=O)(OCC)OCC)cc1
Temperature: 160 °C
Reaction time: 24 h
Yield: 45.1 %

Procedure:
A mixture of diethyl 4-aminobenzylphosphonate (10 g) and diethyl benzylmalonate (24 g) was stirred at 160° C. for 24 hours. After cooling, the reaction mixture was purified by column chromatography on silica gel. Elution with chloroform-methanol (100:1, v/v) gave ethyl 2-(p-diethoxyphosphorylmethylphenylaminocarbonyl)-3-phenylpropionate (8.3 g, 45%) as crystals. Recrystallization from ethyl acetate-hexane gave colorless crystals having melting point of 115 to 116° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH2:7])=[CH:5][C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[N:3]1.[Cl:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[C:17]([CH3:23])[CH:16]=1.[SH:24][CH2:25][C:26](=O)[CH3:27].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(#N)C>[Cl:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]2[S:24][CH2:25][C:26]([CH3:27])=[N:7][C:6]3[N:2]([CH3:1])[N:3]=[C:4]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=4)[C:5]2=3)=[C:17]([CH3:23])[CH:16]=1
Reactant: Cc1cc(Cl)ccc1C=O
Reactant: CC(=O)CS
Reactant: Cn1nc(-c2ccccn2)cc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC#N
Product: CC1=Nc2c(c(-c3ccccn3)nn2C)C(c2ccc(Cl)cc2C)SC1
Temperature: 150 °C
Yield: 76.4 %

Procedure:
A mixture of 1-methyl-3-(2-pyridyl)pyrazol-5-amine (0.215 g, 1.23 mmol), 4-chloro-2-methyl-benzaldehyde (0.1906 g, 1.23 mmol, Fluorochem), 1-sulfanylpropan-2-one (0.45 g, 4.93 mmol, Enamine), and p-toluenesulfonic acid (0.070 g, 0.37 mmol) in acetonitrile (3 mL) was heated, in a sealed microwave vessel, for about 30 min, at about 150° C., in a microwave. After cooling to rt the mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (70 mL) and methanol (10 mL), and washed with 5% aqueous sodium bicarbonate (20 mL). The aqueous layer was extracted with ethyl acetate (20 mL). The combined organic layers were washed with water (40 mL), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, ethyl acetate/hexanes 1:4) to afford 4-(4-chloro-2-methyl-phenyl)-1,7-dimethyl-3-(2-pyridyl)-4,6-dihydropyrazolo[3,4-e][1,4]thiazepine (0.36 g, 0.94 mmol, 76%), as a yellow oil: LC-MS (Table 1, Method a) Rt=5.41 min, m/z 383 (M+H)+; 1H-NMR (CDCl3, Bruker 400 MHz) δ 2.36 (3H, s) 2.60 (3H, s) 3.16 (1H, d, J=16.3 Hz) 3.29 (1H, dd, J=16.3, 1.5 Hz) 4.03 (3H, s) 6.50 (1H, d, J=8.2 Hz) 6.60 (1H, d, J=1.5 Hz) 6.88 (1H, dd, J=8.2, 2.1 Hz) 7.01 (1H, ddd, J=7.4, 4.9, 1.1 Hz) 7.16 (1H, d, J=2.1 Hz) 7.56 (1H, td, J=7.8, 1.7 Hz) 7.86 (1H, dt, J=8.1, 1.0 Hz) 8.35 (1H, ddd, J=4.8, 1.8, 0.8 Hz).
Reaction SMILES: C(N)C1C=CC=CC=1.[NH2:9][NH:10][C:11]([NH:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[NH:12].[Cl:21][C:22]1[C:29]([O:30][CH3:31])=[C:28]([O:32][CH3:33])[CH:27]=[CH:26][C:23]=1[CH:24]=O.CO>C(O)C>[Cl:21][C:22]1[C:29]([O:30][CH3:31])=[C:28]([O:32][CH3:33])[CH:27]=[CH:26][C:23]=1[CH:24]=[N:9][NH:10][C:11]([NH:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[NH:12]
Reactant: COc1ccc(C=O)c(Cl)c1OC
Reactant: N=C(NN)NCc1ccccc1
Solvent: CO
Solvent: NCc1ccccc1
Solvent: CCO
Product: COc1ccc(C=NNC(=N)NCc2ccccc2)c(Cl)c1OC
Temperature: 25 °C

Procedure:
536 mg (5 mmol) benzylamine and 1.17 g (5 mmol) S′-methylthiosemicarbazide hydroiodide was mixed in 10 ml of ethanol. The reaction mixture was refluxed for 5 minutes after which it was cooled down to room temperature and the residue filtered off. The crude product of N-amino-N′-benzylguanidine was reacted with 1.0 g (5 mmol) 2-chloro-3,4-dimethoxybenzaldehyde under reflux for 5 h, after which the solvent was removed under vacuum to give a white solid. The product was obtained by recrystallisation from methanol. Yield of title compound 1, was 1.65 g (77%). M.p. 0.223–225° C.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:5]=1[CH:6]([OH:8])[CH3:7].[F:14][C:15]1[CH:22]=[CH:21][CH:20]=[C:19](F)[C:16]=1[C:17]#[N:18]>CN(C=O)C>[F:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:5]=1[CH:6]([O:8][C:19]1[CH:20]=[CH:21][CH:22]=[C:15]([F:14])[C:16]=1[C:17]#[N:18])[CH3:7]
Reactant: CC(O)c1c(F)cccc1F
Reactant: N#Cc1c(F)cccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(Oc1cccc(F)c1C#N)c1c(F)cccc1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 69.3 %

Procedure:
To a cold (ice water) suspension of sodium hydride (409 mg; 10 mmol) in anhydrous DMF (4 mL) is added a solution of 2,6-difluoro-alpha-methylbenzyl alcohol (1.63 g; 10 mmol) in anhydrous DMF (5 mL) over 10 minutes. After allowing to room temperature over 1 hour, this solution is added to a cold (ice water) stirred solution of 2,6-difluorobenzonitrile (1.53 g; 11 mmol) in anhydrous DMF (6 mL), and allowed to room temperature over 2.5 hours. The reaction mixture is poured into ice water with vigorous stirring and the resulting solid is filtered, washed with water, and dried under vacuum at 40° C. overnight to give 1.92 grams of 2-[1-(2,6-difluorophenyl)-ethoxy]-6-fluorobenzonitrile.