Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH2:5][NH2:6])[CH3:2].[F:7][C:8]([F:15])([F:14])[C:9]([O:11]CC)=O.O>C(#N)C>[F:15][C:8]([F:7])([F:14])[C:9]([NH:6][CH2:5][CH2:4][NH:3][CH2:1][CH3:2])=[O:11]
Reactant: CCNCCN
Reactant: CCOC(=O)C(F)(F)F
Solvent: O
Solvent: CC#N
Product: CCNCCNC(=O)C(F)(F)F
Reaction time: 18 h

Procedure:
A solution of N-ethylethylenediamine (10.0 g, 113.4 mmol) and ethyl trifluoroacetate (32.0 mL, 261 mmol) in a mixture of acetonitrile (110 mL) and water (2.5 mL, 139 mmol) was refluxed with stirring overnight (˜18 hours (hr, h)). Solvents were evaporated in vacuo. Residue was re-evaporated with isopropanol (3×100 mL). Residue was dissolved in dichloromethane (500 mL) and left overnight at room temperature (rt). The formed crystals were filtered, washed with dichloromethane (100 mL) and dried in vacuo to provide compound QQ (24.6 g, 82.4 mmol) as a white solid powder.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][N:12]=2)=[N:8][O:9][CH:10]=1)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>C1COCC1>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C:7]2[C:6]([CH2:4][OH:3])=[CH:10][O:9][N:8]=2)=[N:12][CH:13]=1
Reactant: CCOC(=O)c1conc1-c1ccc(F)cn1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCc1conc1-c1ccc(F)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 30.3 %

Procedure:
To a solution of 3-(5-fluoro-pyridin-2-yl)-isoxazole-4-carboxylic acid ethyl ester (1.0 g, 4.23 mmol) in THF (52 mL) was added portionwise lithiumaluminiumhydride (89 mg, 2.33 mmol) at 0° C. and the reaction mixture was stirred at room temperature for 1 h. The mixture was then cooled to 0° C. and water (88 μL) added followed by sodium hydroxide (15% solution, 88 μL) and then again water (264 μL) and the mixture then stirred overnight at room temperature. The precipitate was then filtered off and washed with THF. The combined washings and filtrate were then evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 1:1) afforded the title compound (249 mg, 30%) which was obtained as a light yellow solid. MS: m/e=195.1 [M+H]+.
Reaction SMILES: [CH:1]([CH:4]1[NH:8][CH:7]([PH:9](=[O:11])[OH:10])[C:6]([CH3:13])([CH3:12])[S:5]1)(C)C.Cl.NO.Cl.[CH:18](Cl)(Cl)Cl>O.[OH-].[Na+]>[CH3:18][C:4]1([CH3:1])[NH:8][CH:7]([PH:9](=[O:11])[OH:10])[C:6]([CH3:12])([CH3:13])[S:5]1
Reactant: ClC(Cl)Cl
Reactant: CC(C)C1NC([PH](=O)O)C(C)(C)S1
Agent: Cl
Agent: NO
Agent: [Na+]
Solvent: O
Product: CC1(C)NC([PH](=O)O)C(C)(C)S1
Temperature: 25 °C

Procedure:
2.23 g of racemic (2-isopropyl-5,5-dimethyl-4-thiazolidinyl)phosphinic acid and 0.77 g of hydroxylamine hydrochloride were dissolved in 15 ml of de-oxygenated water containing 0.48 g of sodium hydroxide and 15 ml of chloroform were added. The mixture was heated under reflux for 1 hour, cooled to room temperature and 3 ml of concentrated hydrochloric acid were added. The chloroform layer was removed and the aqueous layer was extracted with two 15 ml portions of chloroform. The aqueous layer was filtered, evaporated to dryness (twice with ethanol) and the residue was suspended in 15 ml of ethanol and treated with 10 ml of acetone. The mixture was heated under reflux for 0.5 hour, cooled to room temperature and filtered. The filtrate was treated with 1.5 ml of propylene oxide. The mixture was cooled at 0°-5° C. for 2 hours. The resulting solid was collected, washed with isopropanol and dried, there being obtained 1.5 g of DL-(2,2,5,5-tetramethyl-4-thiazolidinyl)phosphinic acid of melting point 190° C. (decomposition).
Reaction SMILES: [C:1]([C:3]1[N:7]2[CH:8]=[C:9]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[CH:10]=[C:11]([CH3:12])[C:6]2=[N:5][CH:4]=1)#[CH:2].Br[C:24]1[S:28][C:27]([S:29]([NH2:32])(=[O:31])=[O:30])=[CH:26][CH:25]=1>>[CH3:12][C:11]1[C:6]2[N:7]([C:3]([C:1]#[C:2][C:24]3[S:28][C:27]([S:29]([NH2:32])(=[O:31])=[O:30])=[CH:26][CH:25]=3)=[CH:4][N:5]=2)[CH:8]=[C:9]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:22])[F:20])=[CH:15][CH:14]=2)[CH:10]=1
Reactant: NS(=O)(=O)c1ccc(Br)s1
Reactant: C#Cc1cnc2c(C)cc(-c3ccc(C(F)(F)F)cc3)cn12
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cn2c(C#Cc3ccc(S(N)(=O)=O)s3)cnc12

Procedure:
The title compound was prepared from 3-ethynyl-8-methyl-6-(4-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridine (example C.20) (300 mg, 1 mmol) and commercially available 5-bromothiophene-2-sulfonamide (230 mg, 1 mmol) according to general procedure II. Obtained as a light brown solid (200 mg, 50%). MS (ISP) 462 [(M+H)+]; mp 270° C.
Reaction SMILES: [S:1]1[C:10]2[CH2:9][C:8]3[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=3[NH:6][CH2:5][C:4]=2[CH:3]=[CH:2]1.[CH3:15][C:16]1[CH:33]=[CH:32][CH:31]=[CH:30][C:17]=1[C:18]([NH:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1)=[O:19].C(N(CC)CC)C>C(Cl)Cl>[S:1]1[C:10]2[CH2:9][C:8]3[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=3[N:6]([C:25]([C:24]3[CH:23]=[CH:22][C:21]([NH:20][C:18](=[O:19])[C:17]4[CH:30]=[CH:31][CH:32]=[CH:33][C:16]=4[CH3:15])=[CH:29][CH:28]=3)=[O:26])[CH2:5][C:4]=2[CH:3]=[CH:2]1
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)Cl)cc1
Reactant: c1ccc2c(c1)Cc1sccc1CN2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2Cc3ccsc3Cc3ccccc32)cc1
Yield: 62.3 %

Procedure:
A mixture of 400 mg of 4,10-dihydro-5H-thieno[3,2-c][1]benzazepine and 700 mg of 4-[(2-methylbenzoyl)amino]benzoyl chloride is stirred in 30 ml of methylene chloride in the presence of 3 ml of triethylamine for 8 hours. The volatiles are removed in vacuo to give a residue which is partitioned between chloroform and water. The organic layer is dried (Na2 SO4) and the filtrate evaporated in vacuo to give a residue which is purified by column chromatography on silica gel by elution with 30% ethyl acetate-hexane to give 543 mg of the desired product. M+1=439.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)[CH:6]=[CH:5][C:4]=1[NH:15][CH:16]=O.[H-].[Na+].[CH3:20][C:21]1[N:34]=[C:33]([NH:35][CH2:36][C:37]([CH3:40])([CH3:39])[CH3:38])[C:24]2[N:25]=C(S(C)(=O)=O)[N:27]=[CH:28][C:23]=2[CH:22]=1>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)[CH:6]=[CH:5][C:4]=1[NH:15][C:16]1[N:27]=[CH:28][C:23]2[CH:22]=[C:21]([CH3:20])[N:34]=[C:33]([NH:35][CH2:36][C:37]([CH3:40])([CH3:39])[CH3:38])[C:24]=2[N:25]=1
Reactant: COc1cc(-c2cnn(C)c2)ccc1NC=O
Reactant: Cc1cc2cnc(S(C)(=O)=O)nc2c(NCC(C)(C)C)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(-c2cnn(C)c2)ccc1Nc1ncc2cc(C)nc(NCC(C)(C)C)c2n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 31.3 %

Procedure:
To a cooled (0° C.) suspension of N-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)formamide (Preparation 56, 8.5 mg, 0.037 mmol) in THF (1 mL) was added NaH (60% dispersion in oil, 2.4 mg, 0.059 mmol). The reaction mixture was stirred at room temperature for 10 minutes. The reaction mixture was cooled to 0° C. and 6-methyl-2-(methysulfonyl)-N-neopentylpyrido[3,4-d]pyrimidin-8-amine (Preparation 54, 12.5 mg, 0.040 mmol) in THF (1 mL) was added. The reaction mixture was stirred for 5 hours, whilst slowly warming to room temperature. The reaction mixture was concentrated in vacuo. The residue was partitioned between EtOAc (30 mL) and water (30 mL). The aqueous layer was re-extracted with EtOAc and DCM (25 mL). The combined organic layers were washed with water (25 mL) and brine (25 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 50-100% EtOAc in cyclohexane. The residue was purified by passage through a SCX-2 cartridge eluting with 100% MeOH-1M NH3 in MeOH to give the title compound (5.0 mg, 32%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([OH:7])[CH:2]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:15][C:16]#[N:17]>CC#N>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][CH2:15][C:16]#[N:17])[CH:2]=1
Reactant: N#CCBr
Reactant: Oc1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#CCOc1cccnc1
Temperature: 25 °C
Reaction time: 40 h
Yield: 16 %

Procedure:
To a mixture of pyridin-3-ol (4.0 g, 42.1 mmol) and K2CO3 (6.96 g, 50.4 mmol) in CH3CN (6 mL) was added dropwise 2-bromoacetonitrile (2.52 g, 21.0 mmol) at rt and the mixture was stirred at rt for 40 h. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=2:1) to give the title compound as a yellow solid (0.45 g, 16%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([N:11]2[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]2)[C:5]([Br:24])=[CH:4][N:3]=1.C(O)(C(F)(F)F)=O.N1C=CC=CC=1.[C:38]1([S:44](Cl)(=[O:46])=[O:45])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C(Cl)Cl>[Br:24][C:5]1[C:6]([N:11]2[CH2:12][CH2:13][N:14]([S:44]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)(=[O:46])=[O:45])[CH2:15][CH2:16]2)=[C:7]([N+:8]([O-:10])=[O:9])[C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2c(Br)cnc(N)c2[N+](=O)[O-])CC1
Solvent: c1ccncc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ncc(Br)c(N2CCN(S(=O)(=O)c3ccccc3)CC2)c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
A solution of tert-butyl 4-(2-amino-5-bromo-3-nitropyridin-4-yl)piperazine-1-carboxylate (250 mg, 0.62 mmol) in CH2Cl2 (2.5 mL) at 0° C. was treated with TFA (2.5 mL) and stirred at 0° C. for 1.5 h. After this time, the solvents were evaporated in vacuo and the excess TFA removed by azeotroping with toluene (3×10 mL). The residue was suspended in CHCl3 (3 mL) and pyridine (3 mL) and treated with benzenesulfonyl chloride (1.1 eq, 0.68 mmol, 0.09 mL), warmed to room temperature and stirred for 12 h. The solvents were removed in vacuo and the residue partition between water (5 mL) and EtOAc (5 mL). The aqueous layer was extracted with EtOAc (2×5 mL) and the combined organic extracts were dried (MgSO4) and concentrated in vacuo. Column chromatography (hexane-EtOAc, 1:1) gave the product (107 mg, 39% for two steps) as a yellow solid; 1H-NMR (500 MHz, DMSO-d6) 3.09 (br s, 8H, 2× piperazine N(CH2)2), 7.08 (br s, 2H, NH2), 7.67-7.70 (m, 2H, phenyl H-3 & H-5), 7.74-7.78 (m, 3H, phenyl H-2, H-4 & H-6), 8.16 (s, 1H, pyridine H-6);
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]=[C:14]([NH2:16])[N:13]=[CH:12][N:11]=1.[CH:17]1([CH:20]=O)[CH2:19][CH2:18]1.OOS([O-])=O.[K+].C(=O)(O)[O-].[Na+]>CN(C=O)C>[Br:8][C:5]1[CH:6]=[CH:7][C:2]2[N:1]=[C:20]([CH:17]3[CH2:19][CH2:18]3)[N:9]([C:10]3[N:11]=[CH:12][N:13]=[C:14]([NH2:16])[N:15]=3)[C:3]=2[CH:4]=1
Reactant: Nc1ncnc(Nc2cc(Br)ccc2N)n1
Reactant: O=CC1CC1
Agent: O=C([O-])O
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1ncnc(-n2c(C3CC3)nc3ccc(Br)cc32)n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 2-N-(2-amino-5-bromophenyl)-1,3,5-triazine-2,4-diamine (6 g, 21.34 mmol) in DMF (60 mL) was added cyclopropanecarbaldehyde (2.07 ml, 27.75 mmol) followed by oxone (7.83 g, 12.81 mmol). The reaction mixture was stirred at RT for 24 hr. The reaction mixture was then cooled to 0° C. and saturated aqueous sodium bicarbonate introduced. A brown precipitate was removed by vacuum filtration. The solid was washed with DCM (100 ml). The organic phase of the filtrate was separated and the aqueous phase extracted with DCM (2×100 mL extractions). The combined organics were washed with brine and then dried (Na2SO4), filtered and concentrated in vacuo to furnish the crude title compound as a brown solid: 1H NMR (500 MHz, DMSO) delta 1.32-1.02 (4H, m), 7.41 (1H, dd, J=8.5, 1.9 Hz), 7.50 (1H, d, J=8.5), 8.05 (1H, s), 8.11 (1H, s), 8.49 (1H, d, J=1.8 Hz), 8.66 (1H, s); LC-MS: m/z=+330.90 (M+H)+. This compound of 85% purity LC-MS (UV) was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.Cl.[NH2:11][CH2:12][CH2:13][SH:14]>CCO.O>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]2[NH:11][CH2:12][CH2:13][S:14]2)=[CH:4][CH:3]=1
Reactant: NCCS
Reactant: O=Cc1ccc(Br)cc1
Agent: Cl
Solvent: O
Solvent: CCO
Product: Brc1ccc(C2NCCS2)cc1
Yield: 68 %

Procedure:
To a solution of 4-bromobenzaldehyde (2.5 g, 13.5 mmol) in EtOH (15 ml) was added a solution of cysteamine HCl (0.5 g, 4.4 mmol) in water (5 ml) dropwise with stirring. The solution was then stirred at RT for 18 h before the bulk of the EtOH was removed by rotary evaporator. The residue was diluted with water (15 ml) and extracted with ether (3×20 ml) to remove excess aldehyde. The acidic aqueous layer was then basified with the slow addition of solid sodium carbonate (0.3 g) to give a heavy white precipitate, which was filtered and washed carefully with water (3×10 ml). The solid was dried in a vacuum desiccator to give 2-(4-bromophenyl)-1,3-thiazolane (4) as a white crystalline solid (0.73 g, 68%), mp 107° (lit. mp, 105-107°). 1H nmr (d6-dmso, 300 MHz) 2.4, br s, NH; 3.05-3.2, m, H4,4,5; 3.5-3.6, m, H5; 5.55, s, H2; 7.38, d (8.4 Hz), ArH; 7.47, d (8.4), ArH. ESI (+ve) MS m/z 287/285 (M+MeCN+H, 30%), 246/244 (M+H, 100).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[CH:7]2)([O-:3])=[O:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:20][CH:21]([O:24][CH3:25])[O:22][CH3:23]>CN(C=O)C>[CH3:23][O:22][CH:21]([O:24][CH3:25])[CH2:20][N:9]1[C:10]2[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=2)[CH:7]=[N:8]1
Reactant: O=[N+]([O-])c1ccc2[nH]ncc2c1
Reactant: COC(CBr)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(Cn1ncc2cc([N+](=O)[O-])ccc21)OC
Temperature: 55 °C
Yield: 23.4 %

Procedure:
To a stirred mixture of 3.00 g (18.4 mmol) of 5-nitroindazole and 5.08 g (36.9 mmol) of K2CO3 in 61 mL of DMF was slowly added 3.42 g (20.2 mmol) of 2-bromo-1,1-dimethoxy-ethane and the mixture heated to 55° C. for 12 hours. The mixture was cooled to room temperature, filtered through a bed of celite. The filtrate was evaporated to dryness and the residue purified via column chromatography (30–80% ethyl acetate/hexanes) to provide 1.08 g of the title compound. 1H NMR (300 MHz, DMSO-D6) δ ppm 3.25 (m, 6 H), 4.61 (d, J=5.43 Hz, 2 H), 4.78 (t, J=5.43 Hz, 1 H), 7.91 (m, 1 H), 8.23 (m, 1 H), 8.43 (s, 1 H), 8.82 (m, 1 H); MS (DCI/NH3) m/z 252 [M+H]+.
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][N:7]=[C:6]2[N:15]1[CH2:20][CH2:19][N:18]([C:21](SC)=[CH:22][N+:23]([O-:25])=[O:24])[CH2:17][CH2:16]1.[NH2:28][CH2:29][C:30]1[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=1>N1C=CC=CC=1>[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][N:7]=[C:6]2[N:15]1[CH2:20][CH2:19][N:18]([C:21]([NH:28][CH2:29][C:30]2[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=2)=[CH:22][N+:23]([O-:25])=[O:24])[CH2:17][CH2:16]1
Reactant: NCc1ccncc1
Reactant: COc1cc2ncnc(N3CCN(C(=C[N+](=O)[O-])SC)CC3)c2cc1OC
Solvent: c1ccncc1
Product: COc1cc2ncnc(N3CCN(C(=C[N+](=O)[O-])NCc4ccncc4)CC3)c2cc1OC
Temperature: 80 °C
Yield: 15.5 %

Procedure:
To a pyridine solution (10 mL) of Compound 58 produced in Example 58 (730 mg, 1.87 mmol), 4-aminomethylpyridine (0.57 mL, 5.61 mmol) was added, followed by stirring in argon atmosphere under heating at 80° C. for 5 hours. After the reaction solution was allowed to stand for cooling, the solvent was evaporated, and the resulting residue was purified by silica gel column chromatography to give the target compound (130 mg, 0.29 mmol).
Reaction SMILES: C([O:3][C:4](=[O:27])[CH2:5][O:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[C:14](=[S:26])[NH:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=1)C.[OH-].[Na+]>C(O)C>[F:13][C:11]1[CH:10]=[CH:9][C:8]([C:14](=[S:26])[NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=2)=[C:7]([CH:12]=1)[O:6][CH2:5][C:4]([OH:27])=[O:3]
Reactant: CCOC(=O)COc1cc(F)ccc1C(=S)NCc1cccc([N+](=O)[O-])c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)COc1cc(F)ccc1C(=S)NCc1cccc([N+](=O)[O-])c1
Reaction time: 4 h
Yield: 98 %

Procedure:
A suspension of [5-Fluoro-2-(3-nitro-benzylthiocarbamoyl)-phenoxy]-acetic acid ethyl ester (4.39 g, 11.2 mmol) in ethanol (40 mL) was treated with aq 2 N NaOH (11 mL, 22.4 mmol). After stirring for 4 h, the solution was concentrated in vacuo until most of the ethanol was removed, and the mixture was acidified to pH of 1 with 2 N HCl. After extracting with ethyl acetate, the organic layer was washed with saturated aq NaCl, dried over MgSO4 and concentrated to give [5-fluoro-2-(3-nitro-benzylthiocarbamoyl)-phenoxy]-acetic acid (4.0 g, 98%) as an off-white solid: mp 147-150° C.; Rf 0.27 (20% methanol in dichloromethane); 1H NMR (DMSO-d6 300 MHz) δ 13.23 (s, 1H), 10.79 (t, J=5.7 Hz, 1H), 8.23 (t, J=1.8 Hz, 1H), 8.11 (ddd, J1=8.3 Hz, J2=2.7 Hz, J3=1.2 Hz, 1 H), 7.85 (br d, J=7.5 Hz, 1H), 7.73 (dd, J1=8.9 Hz, J2=7.1 Hz, 1H), 7.63 (t, J=8.1 Hz, 1H), 7.03 (dd, J1=11.4 Hz, J2=2.4 Hz, 1H), 6.86 (dt, J1=8.4 Hz, J2=2.4 Hz, 1H), 5.07 (d, J=5.7 Hz, 2H), 4.83 (s, 2H). ESI-LC/MS m/z calcd for C16H13FN2O5S: 364.4. Found 363.0 (M−1). Anal. calcd for C16H13FN2O5S: C, 52.74: H, 3.60; N, 7.69. Found C, 52.65; H, 3.62; N, 7.58.
Reaction SMILES: [C:1]1([N:7]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:8](=[O:24])[O:9][CH2:10][CH2:11][CH:12]2[C:21]3[C:16](=[C:17]([O:22]C)[CH:18]=[CH:19][CH:20]=3)[CH2:15][CH2:14][CH2:13]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.NC(C(O)=O)CCSC>CS(O)(=O)=O>[C:25]1([N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8](=[O:24])[O:9][CH2:10][CH2:11][CH:12]2[C:21]3[C:16](=[C:17]([OH:22])[CH:18]=[CH:19][CH:20]=3)[CH2:15][CH2:14][CH2:13]2)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: COc1cccc2c1CCCC2CCOC(=O)N(c1ccccc1)c1ccccc1
Agent: CS(=O)(=O)O
Agent: CSCCC(N)C(=O)O
Product: O=C(OCCC1CCCc2c(O)cccc21)N(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.8 %

Procedure:
A suspension of 2-(5-methoxy-1,2,3,4-tetrahydro-1-naphthyl)ethyl N,N-diphenylcarbamate (0.93 g) and DL-methionine (3.50 g) in methanesulfonic acid (15 ml) was stirred at room temperature for 16 hours, then poured into ice water. The resulting mixture was extracted with ethyl acetate. The extract was washed successively with 5% hydrochloric acid and brine, dried over sodium sulfate, and evaporated in vacuo to afford crude 2-(5-hydroxy-1,2,3,4-tetrahydro-1-naphthyl)ethyl N,N-diphenylcarbamate (0.77 g).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH2:8])=[CH:4][CH:3]=1.Cl[CH2:10][CH:11]=O>C(O)CCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:10]=[CH:11][N:8]=2)[N:7]=1
Reactant: O=CCCl
Reactant: Nc1ccc(Cl)nn1
Solvent: CCCCO
Product: Clc1ccc2nccn2n1
Temperature: 25 °C
Yield: 52.1 %

Procedure:
A mixture of 6-chloro-pyridazinamine (5.00 g, 38 mmol) in 1-butanol (5 mL) was treated with chloroacetaldehyde (50% in water, 5.0 mL, 38 mmol) and the tan suspension was refluxed two hours and to give a dark solution. The reaction mixture was cooled to room temperature and the solid was collected by filtration and washed with methanol to afford a brown solid (3.04 g); evaporation of the filtrate gave additional product (4.60 g). The solids were combined (7.64 g) and used in the next reaction without further purification: MS [M+H]+ 154.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[O:10][C:11]1[CH:19]=[C:18]2[C:14]([CH:15]=[C:16]([CH:20]=O)[NH:17]2)=[CH:13][CH:12]=1.[NH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[N:22]1([CH2:20][C:16]2[NH:17][C:18]3[C:14]([CH:15]=2)=[CH:13][CH:12]=[C:11]([O:10][C:2]2[S:1][C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[N:3]=2)[CH:19]=3)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: C1CCNCC1
Reactant: O=Cc1cc2ccc(Oc3nc4ccccc4s3)cc2[nH]1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: c1ccc2sc(Oc3ccc4cc(CN5CCCCC5)[nH]c4c3)nc2c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 31 %

Procedure:
To a suspension of 6-(benzothiazol-2-yloxy)-1H-indole-2-carbaldehyde (47 mg, 0.16 mmol) in DCM (3 mL) was added piperidine (0.14 mL, 0.12 g, 0.48 mmol), Na(OAc)3BH (51 mg, 0.24 mmol) and the reaction mixture was stirred (rt, 12 h). The reaction mixture was partitioned between saturated NaHCO3 (10 ml) and DCM (20 mL). The organic layer was separated and the aqueous layer was extracted with DCM (2×25 mL). The organic layer was dried, filtered and concentrated in vacuo. The resulting residue was purified by silica gel flash chromatography using MeOH (0.2 M):DCM (0-8%) to provide the title compound as a yellow solid (18 mg, 31%). MS (ESI): mass calcd. for C21H21N3OS, 363.1; m/z found, 364.1 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.80 (s, 1H), 7.76-7.71 (m, 1H), 7.62 (dd, J=7.9, 0.7, 1H), 7.54 (d, J=8.5, 1H), 7.41-7.33 (m, 1H), 7.30 (d, J=2.0, 1H), 7.25-7.20 (m, 1H), 7.04 (dd, J=8.5, 2.2, 1H), 6.34 (d, J=1.0, 1H), 3.61 (s, J=5.4, 2H), 2.62-2.26 (m, 4H), 1.72-1.53 (m, J=10.9, 5.6, 4H), 1.54-1.30 (m, J=5.1, 2H).
Reaction SMILES: O=C1CCC(=O)N1[O:8][C:9](=[O:59])[C@@H:10]([NH:20][C:21](=[O:58])[CH2:22][CH2:23][C@@H:24]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[NH:25][C:26](=[O:50])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:11]CC(OC(C)(C)C)=O.[NH2:60][C@H:61]([C:67]([O:69][C:70]([CH3:73])([CH3:72])[CH3:71])=[O:68])[CH2:62][CH2:63][C:64](=[O:66])[OH:65].Cl>C(#N)C.C([O-])([O-])=O.[Na+].[Na+]>[C:70]([O:69][C:67](=[O:68])[C@@H:61]([NH:60][C:9](=[O:8])[CH2:10][CH2:11][C@@H:10]([C:9]([O:8][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:59])[NH:20][C:21](=[O:58])[CH2:22][CH2:23][C@@H:24]([C:51]([O:53][C:54]([CH3:57])([CH3:55])[CH3:56])=[O:52])[NH:25][C:26](=[O:50])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:62][CH2:63][C:64]([OH:65])=[O:66])([CH3:73])([CH3:72])[CH3:71]
Reactant: CC(C)(C)OC(=O)[C@@H](N)CCC(=O)O
Reactant: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCCC(=O)N[C@@H](CCC(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)ON1C(=O)CCC1=O)C(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCCC(=O)N[C@@H](CCC(=O)N[C@@H](CCC(=O)N[C@@H](CCC(=O)O)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 126.8 %

Procedure:
(S)-2-[(S)-4-tert-Butoxycarbonyl-4-(17-tert-butoxycarbonylheptadecanoylamino)butyrylamino]-pentanedioic acid 5-tert-butyl ester 1-(2,5-dioxopyrrolidin-1-yl)ester (4 g, 4.77 mmol) was dissolved in acetonitrile (30 mL) and added to a solution of H-Glu-OtBu (1.07 g, 5.25 mmol) in Na2CO3 (0.1 M, 20 mL). The mixture was stirred at RT for 1 h, then neutralised with HCl (2M) to pH 7 and evaporated in vacuo. The residual oil was subsequently partitioned between ethyl acetate and HCl (0.1 M). The organic layer was dried (MgSO4), filtered and evaporated to dryness in vacuo. The residue (4 g) was dissolved in acetonitrile and treated with active carbon. After filteration and evaporation to dryness followed by drying overnight in vacuo, 2.8 g of (S)-2-{(S)-4-tert-Butoxycarbonyl-4-[(S)-4-tert-butoxycarbonyl-4-(17-tert-butoxycarbonylheptadecanoylamino)butyrylamino]butyrylamino}pentanedioic acid 1-tert-butyl ester was obtained as a crystalline solid. LC-MS (electrospray): m/z=927 (M+1).