Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]([N:9]([CH2:13][CH2:14]Cl)[CH2:10][CH2:11]Cl)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[NH2:16][CH:17]1[CH2:20][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:18]1.C(=O)(O)[O-].[Na+]>C(O)C>[CH2:2]([N:9]1[CH2:13][CH2:14][N:16]([CH:17]2[CH2:18][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20]2)[CH2:11][CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: ClCCN(CCCl)Cc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC(N)C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC(N2CCN(Cc3ccccc3)CC2)C1

Procedure:
6.33 g (29.0 mmol) of benzylbis(2-chloroethyl)amine hydrochloride were dissolved in ethanol (100 ml) and, while stirring, 5.00 g (29.0 mmol) of tert-butyl 3-aminoazetidine-1-carboxylate and 9.76 g (116 mmol) of sodium bicarbonate were added. The resulting reaction solution was heated under reflux for 4 h. The cooled reaction mixture was concentrated in vacuo, 100 ml of water were added and the aqueous phase was extracted with ethyl acetate (4×60 ml). The combined organic phases were washed with saturated aqueous NaHCO3 solution, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by chromatography on silica gel (mobile phase gradient 2.5-5% methanol in dichloromethane). Yield: 6.27 g (65%) of yellow oil
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:14])[CH:7]=[CH:8][C:9]=1[NH:10][CH2:11][CH2:12][OH:13])([O-:3])=[O:2].Cl[CH2:16][CH:17]([OH:20])[CH2:18][OH:19]>C(=O)([O-])[O-].[Na+].[Na+]>[OH:20][CH:17]([CH2:18][OH:19])[CH2:16][O:14][C:6]1[CH:7]=[CH:8][C:9]([NH:10][CH2:11][CH2:12][OH:13])=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: O=[N+]([O-])c1cc(O)ccc1NCCO
Reactant: OCC(O)CCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: O=[N+]([O-])c1cc(OCC(O)CO)ccc1NCCO
Temperature: 90 °C

Procedure:
0.2 mol (39.6 g) of 3-nitro-4-[N-(β-hydroxyethyl)-amino]-phenol is dissolved in 125 ml of 2N sodium carbonate solution. 0.25 mol (27.5 g) of 1-chloropropane-2,3-diol is added to this solution, heated beforehand to about 90° C. Heating is maintained for a further 2 hours. After cooling, the reaction medium is extracted with ethyl acetate. After the solvent has been evaporated off to dryness, 29 g of the desired product are obtained in the form of orange crystals.
Reaction SMILES: C([Li])CCC.Br[C:7]1[S:20][C:10]2[C:11]3[CH:19]=[N:18][CH:17]=[CH:16][C:12]=3[O:13][CH2:14][CH2:15][C:9]=2[CH:8]=1.[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]=[C:29]=[O:30].Cl.C([O-])(O)=O.[Na+]>CCCCCC.O1CCCC1>[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[NH:28][C:29]([C:7]1[S:20][C:10]2[C:11]3[CH:19]=[N:18][CH:17]=[CH:16][C:12]=3[O:13][CH2:14][CH2:15][C:9]=2[CH:8]=1)=[O:30]
Reactant: O=C=Nc1ccccc1Cl
Reactant: Brc1cc2c(s1)-c1cnccc1OCC2
Agent: Cl
Agent: O=C([O-])O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C(Nc1ccccc1Cl)c1cc2c(s1)-c1cnccc1OCC2
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 66.2 %

Procedure:
1.6 M of n-Butyllithium in hexane (0.6302 mL) was added dropwise to a solution of 2-bromo-4,5-dihydropyrido[4,3-b]thieno[2,3-d]oxepine (0.227 g, 0.804 mmol) in tetrahydrofuran (6.00 mL, 74.0 mmol) at −75° C. The dark brown mixture was stirred at −78° C. for 20 min. 1-Chloro-2-isocyanato-benzene (0.1421 g, 0.9252 mmol) in 2 ml of tetrahydrofuran was added dropwise and the mixture was kept at −78° C. for 20 min. 4N aq. HCl (1 ml) was added and the mixture was poured into 50 ml of sat. aq NaHCO3. The mixture was extracted twice with methylene chloride, combined, and washed with water and brine, and dried over MgSO4. After concentrating under vacuum, the residue was triturated with ethyl acetate. The collected precipitate was N-(2-chlorophenyl)-4,5-dihydropyrido[4,3-b]thieno[2,3-d]oxepin-2-carboxamide (0.19 g, 66% yield). MS (ESI+) 357.0.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=2[C:9]([OH:11])=O)=[C:4]([NH:18][C:19]([NH:21][C:22]2[S:23][CH:24]=[CH:25][N:26]=2)=[O:20])[CH:3]=1.[CH3:27][NH2:28].C1COCC1>>[F:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=2[C:9]([NH:28][CH3:27])=[O:11])=[C:4]([NH:18][C:19]([NH:21][C:22]2[S:23][CH:24]=[CH:25][N:26]=2)=[O:20])[CH:3]=1
Reactant: CN
Reactant: O=C(Nc1nccs1)Nc1cc(F)ccc1Oc1ccccc1C(=O)O
Solvent: C1CCOC1
Product: CNC(=O)c1ccccc1Oc1ccc(F)cc1NC(=O)Nc1nccs1

Procedure:
2-[4-Fluoro-2-(3-thiazol-2-yl-ureido)-phenoxy]-N-methyl-benzamide was prepared from 2-[4-fluoro-2-(3-thiazol-2-yl-ureido)-phenoxy]-benzoic acid and 1N solution of methyl amine in THF (0.5 mL, 0.5 mmol) following the general procedure K.
Reaction SMILES: [C:1]([C:5]1[C:6]([O:35][CH3:36])=[C:7]([CH:24]=[C:25]([N:27]2[CH:32]=[CH:31][C:30](=[O:33])[NH:29][C:28]2=[O:34])[CH:26]=1)/[CH:8]=[CH:9]/[C:10]1[CH:18]=[CH:17][C:16]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])=[CH:15][C:11]=1[C:12](Cl)=[O:13])([CH3:4])([CH3:3])[CH3:2].[NH:37]1[CH:41]=[CH:40]N=N1.C(=O)([O-])[O-].[K+].[K+]>C1S(=O)(=O)CCC1>[C:1]([C:5]1[C:6]([O:35][CH3:36])=[C:7]([CH:24]=[C:25]([N:27]2[CH:32]=[CH:31][C:30](=[O:33])[NH:29][C:28]2=[O:34])[CH:26]=1)/[CH:8]=[CH:9]/[C:10]1[CH:18]=[CH:17][C:16]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])=[CH:15][C:11]=1[C:12]1[O:13][CH:40]=[CH:41][N:37]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1c(/C=C/c2ccc(NS(C)(=O)=O)cc2C(=O)Cl)cc(-n2ccc(=O)[nH]c2=O)cc1C(C)(C)C
Reactant: c1c[nH]nn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=S1(=O)CCCC1
Product: COc1c(/C=C/c2ccc(NS(C)(=O)=O)cc2-c2ncco2)cc(-n2ccc(=O)[nH]c2=O)cc1C(C)(C)C
Temperature: 130 °C
Yield: 46 %

Procedure:
To a solution of the product from Example 126, Part A (80 mg, 0.15 mmol) in tetramethylene sulfone (1.5 ml) was added 1H-1,2,3-triazole (10 μL, 0.17 mmol) and potassium carbonate (73 mg, 0.53 mmol). The mixture was heated for 35 min at 130° C. in a microwave reactor. After cooling to room temperature, the mixture was partitioned between 1 N aqueous HCl (10 ml) and EtOAc (2×10 ml). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel using 3% MeOH in CH2Cl2 as the eluent to give the title compound (37 mg, 46%). 1H NMR (300 MHz, DMSO-d6) δ 11.41 (d, J=1.84 Hz, 1H) 10.10 (s, 1H) 8.29 (d, J=1.10 Hz, 1H) 8.05 (d, J=16.18 Hz, 1H) 7.95 (d, J=8.82 Hz, 1H) 7.82 (d, J=2.21 Hz, 1H) 7.74 (d, J=8.09 Hz, 1H) 7.51 (d, J=2.57 Hz, 1H) 7.46 (d, J=0.74 Hz, 1H) 7.39 (dd, J=8.64, 2.39 Hz, 1H) 7.20-7.30 (m, 2H) 5.65 (dd, J=7.91, 2.02 Hz, 1H) 3.80 (s, 3H) 3.07 (s, 3H) 1.38 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[C:16]([F:18])[C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([C:13]([NH2:15])=[O:14])[CH:8]=2)=[C:4]([F:19])[CH:3]=1.COC1C=CC(CNC2N=CN=C(OC3C=CC(N[C:42]([NH:44][C:45](=[O:54])[CH2:46][C:47]4[CH:52]=[CH:51][C:50]([F:53])=[CH:49][CH:48]=4)=[O:43])=CC=3F)C=2)=CC=1>>[C:13]([C:9]1[CH:8]=[C:7]([O:6][C:5]2[C:16]([F:18])=[CH:17][C:2]([NH:1][C:42]([NH:44][C:45](=[O:54])[CH2:46][C:47]3[CH:52]=[CH:51][C:50]([F:53])=[CH:49][CH:48]=3)=[O:43])=[CH:3][C:4]=2[F:19])[CH:12]=[CH:11][N:10]=1)(=[O:14])[NH2:15]
Reactant: COc1ccc(CNc2cc(Oc3ccc(NC(=O)NC(=O)Cc4ccc(F)cc4)cc3F)ncn2)cc1
Reactant: NC(=O)c1cc(Oc2c(F)cc(N)cc2F)ccn1
Product: NC(=O)c1cc(Oc2c(F)cc(NC(=O)NC(=O)Cc3ccc(F)cc3)cc2F)ccn1
Yield: 52 %

Procedure:
4-(4-Amino-2,6-difluorophenoxy)picolinamide (104 mg, 0.39 mmol) was converted to the title compound (91 mg, 52%) in a manner similar to the preparation of Compound D of Example 112. 1H NMR (DMSO-d6) δ 11.07 (s, 1H), 10.62 (s, 1H), 8.50 (d, 1H, J=5.6 Hz), 8.11 (br s, 1H), 7.72 (br s, 1H), 7.61 (m, 2H), 7.36-7.37 (d, 1H, J=2.3 Hz), 7.23-7.31 (m, 3H), 7.11 (m, 2H), 3.69 (s, 2H); HRMS(ESI+), 445.1124 (M+H)+ calcd., 445.1117 (M+H)+ found.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[CH3:6][O:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]2)[C:11]([NH2:21])=[CH:10][C:9]=1[NH:22][C:23]1[N:28]=[C:27]([C:29]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[N:31]([CH3:38])[CH:30]=2)[CH:26]=[CH:25][N:24]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:6][O:7][C:8]1[C:9]([NH:22][C:23]2[N:28]=[C:27]([C:29]3[C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[N:31]([CH3:38])[CH:30]=3)[CH:26]=[CH:25][N:24]=2)=[CH:10][C:11]([NH:21][C:1](=[O:4])[CH:2]=[CH2:3])=[C:12]([N:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]2)[CH:13]=1
Reactant: COc1cc(N2CCN(C)CC2)c(N)cc1Nc1nccc(-c2cn(C)c3ccccc23)n1
Reactant: C=CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CC(=O)Nc1cc(Nc2nccc(-c3cn(C)c4ccccc34)n2)c(OC)cc1N1CCN(C)CC1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 17.3 %

Procedure:
A solution of acryloyl chloride (58.4 mg, 0.64 mmol) in CH2Cl2 (1 mL) was added dropwise to a mixture of 4-methoxy-N′-[4-(1-methylindol-3-yl)pyrimidin-2-yl]-6-(4-methylpiperazin-1-yl)benzene-1,3-diamine (Intermediate 110, 286 mg, 0.64 mmol) and DIPEA (0.134 mL, 0.77 mmol) in CH2Cl2 (20 mL), which was cooled in an ice/water bath. The mixture was stirred for 1.5 h at 0° C. More DIPEA was added (30 μL) then more acryloyl chloride (20 mg) was added dropwise as a solution in CH2Cl2 (1 mL). This mixture was stirred for 2 h and then diluted with CH2Cl2 (50 mL). This solution was washed with sat. NaHCO3 solution (2×25 mL) and then the combined aqueous washes were extracted with CH2Cl2 (2×25 mL). The combined organic solutions were washed with brine, dried (MgSO4) and concentrated in vacuo. The resulting gum was triturated with diethyl ether to give a solid which was collected by filtration and dried in vacuo. Purification by FCC, eluting with 0-8% 7N methanolic ammonia in CH2Cl2 gave the title compound (55 mg, 17%) as a light grey solid after trituration with diethyl ether (with a few drops of CH3OH); 1H NMR: 2.27 (3H, s), 2.53-2.59 (4H, m), 2.85-2.91 (4H, m), 3.87 (3H, s), 3.91 (3H, s), 5.75 (1H, d), 6.24 (1H, d), 6.67 (1H, dd), 6.89 (1H, s), 7.15-7.28 (3H, m), 7.53 (1H, d), 7.89 (1H, s), 8.28 (1H, d), 8.32 (1H, d), 8.58 (1H, s), 8.81 (1H, s), 9.07 (1H, s); m/z: ES+ MH+ 498.58.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].Br[CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH3:15].O>CN(C=O)C>[CH3:15][O:14][CH2:13][CH2:12][O:11][CH2:10][CH2:9][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: COCCOCCBr
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCOCCn1ccnc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
Imidazole 1 g (0.015 mol) was dissolved in dry DMF 50 mL under argon atmosphere. After a NaH mineral oil dispersion (60%) 0.68 g (0.017 mol) was added, the mixture was heated at 80° C. for 70 min. After cooling to room temperature, 1-Bromo-2-(2-methoxyethoxy)-ethane (1), 2.75 g (0.015 mol), was added, then stirred overnight. The reaction was poured into water, extracted by CHCl3, washed by water, dried over Na2SO4, then dried (Rotavap) until an oily residue remained. The crude product was purified with silica gel flash column chromatography with an eluant of CHCl3: CH3OH=20:1. 1.69 g (70% yield) of the product (2) was obtained as a colorless oil. As an alternative to column chromatography, product (2) is purified by vacuum distillation.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:9]2[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10]2)[S:5][C:6]=1[CH:7]=O.[CH3:15][N:16]([CH3:36])[C:17]([C@@H:19]1[C@H:24]([NH:25][C:26]2[C:31]([Cl:32])=[CH:30][N:29]=[C:28]([NH2:33])[C:27]=2[NH2:34])[C@@H:23]2[CH2:35][C@H:20]1[CH:21]=[CH:22]2)=[O:18].C([O-])(=O)C.[NH4+]>>[CH3:15][N:16]([CH3:36])[C:17]([C@@H:19]1[C@H:24]([NH:25][C:26]2[C:31]([Cl:32])=[CH:30][N:29]=[C:28]3[NH:33][C:7]([C:6]4[S:5][C:4]([N:9]5[CH2:13][CH2:12][C@@H:11]([OH:14])[CH2:10]5)=[N:3][C:2]=4[Cl:1])=[N:34][C:27]=23)[C@@H:23]2[CH2:35][C@H:20]1[CH:21]=[CH:22]2)=[O:18]
Reactant: O=Cc1sc(N2CCC(O)C2)nc1Cl
Reactant: CN(C)C(=O)[C@@H]1[C@H](Nc2c(Cl)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: CN(C)C(=O)[C@@H]1[C@H](Nc2c(Cl)cnc3[nH]c(-c4sc(N5CC[C@@H](O)C5)nc4Cl)nc23)[C@H]2C=C[C@@H]1C2
Yield: 10.8 %

Procedure:
In a similar fashion to Compound LXXXVII, 4-Chloro-2-(3-hydroxy-pyrrolidin-1-yl)-thiazole-5-carbaldehyde (180.77 mg, 0.77687 mmol), (1S,2S,3R,4R)-3-(2,3-Diamino-5-chloro-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid dimethylamide (200.00 mg, 0.62149 mmol) and Ammonium acetate (95.813 mg, 1.2430 mmol) were reacted to produce 35.95 mg (11%) of the title compound. (300 MHz, DMSO-d6) 12.70 (s, 1H), 7.95 (s, 1H), 6.66 (s, 1H), 6.42-6.34 (m, 2H), 5.76 (s, 1H), 5.13 (m, 2H), 4.44 (s, 1H), 3.54 (m, 3H), 3.03 (d, J=9 Hz, 1H), 2.95 (s, 3H), 2.86 (m, 4H), 2.83 (m, 4H), 2.11 (d, J=9 Hz, 1H), 1.96 (m, 1H), 1.42 (d, J=9 Hz, 1H). MS=533 (M+H), HPLC: 2.33 min. (G Method)
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[CH2:3][NH:4][C:5]([NH:7][C:8]1[CH:9]=[C:10]([C:14]2[N:18]3[N:19]=[CH:20][C:21]([C:23]4[CH:28]=[CH:27][C:26]([CH:29]([CH3:33])[C:30]([OH:32])=O)=[CH:25][CH:24]=4)=[CH:22][C:17]3=[N:16][CH:15]=2)[CH:11]=[CH:12][CH:13]=1)=[O:6].[CH3:36][NH:37][CH3:38]>>[CH3:36][N:37]([CH3:38])[C:30](=[O:32])[CH:29]([C:26]1[CH:25]=[CH:24][C:23]([C:21]2[CH:20]=[N:19][N:18]3[C:14]([C:10]4[CH:11]=[CH:12][CH:13]=[C:8]([NH:7][C:5]([NH:4][CH2:3][C:2]([F:34])([F:35])[F:1])=[O:6])[CH:9]=4)=[CH:15][N:16]=[C:17]3[CH:22]=2)=[CH:28][CH:27]=1)[CH3:33]
Reactant: CC(C(=O)O)c1ccc(-c2cnn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)cc1
Reactant: CNC
Product: CC(C(=O)N(C)C)c1ccc(-c2cnn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)cc1

Procedure:
This compound was prepared by using procedure analogous to those described for the synthesis of Example 98, Step 9 starting from 2-(4-{3-[3-({[(2,2,2-trifluoroethyl)amino]-carbonyl}amino)phenyl]imidazo[1,2-b]pyridazin-7-yl}phenyl)propanoic acid and N,N-dimethylamine. LCMS (M+H)+: m/z=511.2
Reaction SMILES: [CH:1]1[C:10]2[C:9]3[CH2:11][CH2:12][CH:13]=[CH:14][C:8]=3[N:7]=[CH:6][CH2:5][C:4]=2[S: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>[CH:1]1[C:10]2[C:9]3[CH2:11][CH:12]([C:25]([C:24]4[CH:23]=[CH:22][C:21]([NH:20][C:18](=[O:19])[C:17]5[CH:30]=[CH:31][CH:32]=[CH:33][C:16]=5[CH3:15])=[CH:29][CH:28]=4)=[O:26])[CH:13]=[CH:14][C:8]=3[N:7]=[CH:6][CH2:5][C:4]=2[S:3][CH:2]=1
Reactant: C1=CC2=C(CC1)c1ccsc1CC=N2
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)C2C=CC3=C(C2)c2ccsc2CC=N3)cc1
Yield: 59.4 %

Procedure:
A mixture of 400 mg of 9,10-dihydro-4H-thieno[2,3-d][1]benzazepine and 600 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 water and chloroform. 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 518 mg of the desired product. M+1=439.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1.[Cl:15][CH2:16][C:17](Cl)=[O:18].C(N(C(C)C)CC)(C)C.C(NC(C)C)(C)C>C(Cl)Cl.C(OCC)(=O)C>[C:11]([O:10][C:8]([N:5]1[CH2:6][CH2:7][CH:3]([CH2:2][NH:1][C:17](=[O:18])[CH2:16][Cl:15])[CH2:4]1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: O=C(Cl)CCl
Reactant: CC(C)(C)OC(=O)N1CCC(CN)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(CNC(=O)CCl)C1
Reaction time: 1 h

Procedure:
3-(RS)-aminomethyl-1-tert-butoxycarbonylpyrrolidine (6.0 g, 30 mmol) in methylene chloride (15 mL) was added dropwise to a cold (0° C.) solution of chloroacetylchloride (2.4 mL, 30 mmol) and diisopropylethylamine (5.5 mL, 32 mmol) in methylene chloride under N2. After 1 h, an additional 0.5 equiv. of chloroacetyl chloride and diisopropylamine were added. After being left at 0° C. overnight, the reaction mixture was diluted with ethyl acetate and washed briefly with water and brine, then dried over sodium sulfate and concentrated to give N-(1-tert-butoxycarbonylpyrrolidin-3-(RS)-ylmethyl)-2-chloroacetamide as a dark brown oil which was used without further purification.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:28][C:29]1[CH:38]=[CH:37][C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=1)[C:3]([NH:5][CH2:6][CH2:7][CH2:8][CH2:9][C@H:10]([N:13]([S:18]([C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:11][OH:12])=[O:4].[CH:39]1([C:45](Cl)=[O:46])[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1>>[NH2:27][C:24]1[CH:23]=[CH:22][C:21]([S:18]([N:13]([CH2:14][CH:15]([CH3:17])[CH3:16])[C@H:10]([CH2:11][OH:12])[CH2:9][CH2:8][CH2:7][CH2:6][NH:5][C:3]([C@@H:2]([NH:1][C:45]([CH:39]2[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]2)=[O:46])[CH2:28][C:29]2[CH:38]=[CH:37][C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=2)=[O:4])(=[O:20])=[O:19])=[CH:26][CH:25]=1
Reactant: CC(C)CN([C@H](CO)CCCCNC(=O)[C@@H](N)Cc1ccc2ccccc2c1)S(=O)(=O)c1ccc(N)cc1
Reactant: O=C(Cl)C1CCCCC1
Product: CC(C)CN([C@H](CO)CCCCNC(=O)[C@H](Cc1ccc2ccccc2c1)NC(=O)C1CCCCC1)S(=O)(=O)c1ccc(N)cc1

Procedure:
The title compound was prepared from (2S,S)-2-amino-N-{5-[(4-amino-benzenesulfonyl)-isobutyl-amino]-6-hydroxy-hexyl}-3-naphthalen-2-yl-propionamide (product of example 49) as described in general procedure D using cyclohexanecarbonyl chloride. The final product was obtained in 56% yield.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8].C(N(CC)CC)C.[C:16]1([CH3:25])[CH:21]=[CH:20][C:19]([C:22](O)=[O:23])=[CH:18][CH:17]=1.P(Cl)(OCC)(OCC)=O>C(OCC)(=O)C>[C:6]1(=[O:7])[N:2]([O:1][C:22]([C:19]2[CH:20]=[CH:21][C:16]([CH3:25])=[CH:17][CH:18]=2)=[O:23])[C:3](=[O:8])[CH2:4][CH2:5]1
Reactant: O=C1CCC(=O)N1O
Reactant: Cc1ccc(C(=O)O)cc1
Agent: CCOP(=O)(Cl)OCC
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1ccc(C(=O)ON2C(=O)CCC2=O)cc1
Temperature: 25 °C

Procedure:
Analogous example 3 2,76 g (0.024 mol) of N-hydroxysuccinimide and 5.06 g (0,050 mol) of triethylamine were initially introduced into 5 ml of ethyl acetate and stirred at room temperature. 2.72 g (0.020 mol) of solid 4-toluic acid were added to this suspension in the course of 5 min. and then a solution of 3.47 g (0,020 mol) of diethyl chlorophosphate was added dropwise in the course of 20 min., the reaction mixture warming to about 35° C. The mixture was stirred at room temperature for 3 hours until the reaction was complete. The further proceeding was performed analogous example 3. 2.8 g of crude 4-toluic acid succinimidyl ester were isolated.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:14]=1.[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH:30]=O>O1CCCC1.O>[CH3:25][O:26][C:27]1[CH:28]=[C:29](/[CH:30]=[C:19](/[C:15]2[CH:14]=[N:13][CH:18]=[CH:17][CH:16]=2)\[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:32]=[CH:33][C:34]=1[O:35][CH3:36]
Reactant: COc1ccc(C=O)cc1OC
Reactant: CCOC(=O)Cc1cccnc1
Agent: [Li]CCCC
Solvent: O
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)/C(=C\c1ccc(OC)c(OC)c1)c1cccnc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 36.5 %

Procedure:
n-Butyllithium (1.6M hexane solution, 99.2 ml) was dropped into a solution of diisopropylamine (23.4 ml, 166.6 mmol) in tetrahydrofuran (320 ml). The obtained mixture was stirred at 0° C. for 30 minutes. A solution of ethyl 3-pyridylacetate (24.0 ml, 158.9 mmol) in tetrahydrofuran (20 ml) was dropped into the resulting mixture at -70° C. and the obtained mixture was stirred at 0° C. for 15 minutes. A solution of 3,4-dimethoxybenzaldehyde (27.6 g, 166.0 mmol) in tetrahydrofuran (100 ml) was dropped into the mixture at 0° C. The obtained mixture was stirred at room temperature overnight, followed by the addition of water. The obtained mixture was extracted with ether. The organic layer was washed with water and a saturated aqueous solution of common salt, dried over magnesium sulfate and concentrated. The oily residue was purified by flash column chromatography (ethyl acetate/hexane=3:2) to give the title compound as a pale yellow oil (18.19 g, yield: 37%).
Reaction SMILES: [CH2:1]([NH2:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH3:9][S:10](Cl)(=[O:12])=[O:11].Cl>C1COCC1>[CH2:1]([NH:8][S:10]([CH3:9])(=[O:12])=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCCCCN
Agent: Cl
Solvent: C1CCOC1
Product: CCCCCCCNS(C)(=O)=O
Reaction time: 0.75 h

Procedure:
A solution of 7.5 ml (50 mmol) of n-heptylamine in 50 ml of THF was cooled in an ice-water bath. Methanesulfonyl chloride (1.93 ml, 25 mmol) was added dropwise, with stirring to the amine solution over a 4 minute period. After stirring for an additional 45 minutes the mixture was poured into dilute HCl, and the product was extracted with ethyl acetate. The extract was washed with brine, dried (Na2SO4) and evaporated in vacuo. The resulting yellow solid was recrystallized from hexane. Yield: 4.03 gm. 'H-NMR (CDCl3) δ 4.48 (1H, br t); 3.13 (2H, q, J=6H2); 2.96 (3H, s); 1.57 (2H, m); 1.30 (8H, br m); 0.89 (3H, br t).
Reaction SMILES: [CH2:1]([S-:3])[CH3:2].[Na+].Cl[C:6]1[C:7]([C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)=[O:13])=[N:8][CH:9]=[CH:10][CH:11]=1.CN(C=O)C>O>[CH2:1]([S:3][C:6]1[C:7]([C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:23])([F:24])[F:22])=[CH:17][CH:16]=2)=[O:13])=[N:8][CH:9]=[CH:10][CH:11]=1)[CH3:2]
Reactant: CC[S-]
Reactant: O=C(Nc1ccc(C(F)(F)F)cc1)c1ncccc1Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCSc1cccnc1C(=O)Nc1ccc(C(F)(F)F)cc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 97.8 %

Procedure:
0.91 g of sodium ethanethiolate was added to a mixture of 1.29 g of 3-chloro-N-(4-trifluoromethylphenyl)picolinamide and 3 mL of DMF, and the mixture was stirred at 60° C. for 2 hours. The reaction mixture cooled to room temperature was poured to water, and the precipitated solid was taken by filtration. The resulting solid was dissolved in ethyl acetate, and the mixture was extracted with water and ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain 1.37 g of 3-ethylsulfanyl-N-(4-trifluoromethylphenyl)picolinamide (hereinafter, referred to as Compound of Present Invention 9).
Reaction SMILES: [C:1]([N:9]1[C@@H:13]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12](=[O:18])OC1=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]1([CH3:29])[CH:25]=[CH:24][C:23]([C@@H:26]([NH2:28])[CH3:27])=[CH:22][CH:21]=1.Cl>C(OCC)(=O)C>[C:20]1([CH3:29])[CH:25]=[CH:24][C:23]([C@@H:26]([NH:28][C:12](=[O:18])[C@H:13]([C:14]([CH3:15])([CH3:16])[CH3:17])[NH:9][C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH3:27])=[CH:22][CH:21]=1
Reactant: Cc1ccc([C@H](C)N)cc1
Reactant: CC(C)(C)[C@H]1C(=O)OC(=O)N1C(=O)c1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1ccc([C@H](C)NC(=O)[C@@H](NC(=O)c2ccccc2)C(C)(C)C)cc1
Reaction time: 0.5 h
Yield: 49.3 %

Procedure:
(S)-3-Benzoyl-4-tert-butyl-2,5-oxazolidinedione (N-benzoyl-L-tert-leucine-NCA)(100 mg, 0.38 mmol) was dissolved in ethyl acetate (2.0 mL), followed by the addition of a solution of (S)-1-(p-tolyl)ethylamine (52 mg, 0.38 mmol) in ethyl acetate (2.0 mL) at 0° C. The resulting mixture was stirred for 30 minutes. The reaction mixture was poured into 1 N hydrochloric acid (10 mL), followed by extraction with ethyl acetate (10 mL). The organic layer was washed successively with a saturated aqueous solution of sodium hydrogencarbonate (10 mL) and a saturated aqueous solution of sodium chloride (10 mL), and was then dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure to afford the title compound (66 mg, 49%) as white crystals.