Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][NH:13][C:14]([C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH2:25][CH2:26][CH3:27])[N:17]=2)=O)[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:37])=CC=1>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[CH2:1]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][NH:13][C:14]([C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH2:25][CH2:26][CH3:27])[N:17]=2)=[S:37])[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1CCN(CCNC(=O)c2nn(CCC)c3ccccc23)CC1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: CCCCN1CCN(CCNC(=S)c2nn(CCC)c3ccccc23)CC1
Temperature: 25 °C
Yield: 88.5 %

Procedure:
To a solution of N-[2-(4-n-butyl-1-piperazinyl)-ethyl]-1-n-propylindazole-3-carboxamide (0.39 g) obtained in Example 3 in toluene (10 ml) was added Lawesson reagent (0.64 g) at room temperature, and the mixture was heated under reflux for one hour. The reaction solution was cooled to room temperature, diluted with chloroform (50 ml), and then washed with saturated aqueous sodium hydrogencarbonate (50 ml). The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by thin-layer chromatography on silica gel (chloroform:methanol:aqueous ammonia=8:2:0.2) to give the title compound (0.36 g) as a pale yellow oily substance. Yield=88%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:14][CH2:15][OH:16])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].CN1CCOCC1.[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:32]=[C:33]([O:37][CH3:38])[C:34]=1[O:35][CH3:36])[C:29](Cl)=[O:30]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:14][CH2:15][OH:16])[CH2:13][CH2:12][N:11]([C:29](=[O:30])[C:28]3[CH:27]=[C:26]([O:25][CH3:24])[C:34]([O:35][CH3:36])=[C:33]([O:37][CH3:38])[CH:32]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Reactant: OCCC1(c2ccc(Cl)c(Cl)c2)CCNC1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COc1cc(C(=O)N2CCC(CCO)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Temperature: 0 °C
Reaction time: 1 h
Yield: 70.6 %

Procedure:
3-(3,4-Dichloro-phenyl)-3-(2-hydroxy-ethyl)-pyrrolidine (288 mg, 1.1 mmol) was dissolved in dichloromethane at -78° C. and treated with 4-methylmorpholine (0.25 mL, 2.27 mmol, 2 eq.) and 3,4,5-trimethoxy-benzoyl chloride (250 mg, 1.1 mmol, 1 eq) in dichloromethane (3 mL). The solution was allowed to warm to 0° C. and stir for 1 hour. The solution was washed with 1N HCl and 5% sodium bicarbonate and the organic phase was dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel (30 g) with a gradient of 50% ethyl acetate in hexane to 6% methanol in dichloromethane to give 353 mg (71%) of the title compound.
Reaction SMILES: CN([CH:4]=[O:5])C.P(Cl)(Cl)(Cl)=O.[CH2:11]([CH:13]1[N:22]([S:23]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([CH3:34])[CH:27]=2)(=[O:25])=[O:24])[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([F:35])[CH:20]=2)[N:15]2[CH:36]=[CH:37][CH:38]=[C:14]12)[CH3:12].O>C(Cl)Cl>[CH2:11]([CH:13]1[N:22]([S:23]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([CH3:34])[CH:27]=2)(=[O:25])=[O:24])[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([F:35])[CH:20]=2)[N:15]2[C:36]([CH:4]=[O:5])=[CH:37][CH:38]=[C:14]12)[CH3:12]
Reactant: CN(C)C=O
Reactant: CCC1c2cccn2-c2ccc(F)cc2N1S(=O)(=O)c1ccc(OC)c(C)c1
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: CCC1c2ccc(C=O)n2-c2ccc(F)cc2N1S(=O)(=O)c1ccc(OC)c(C)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a 25 ml round bottom flask under nitrogen charged with 10 ml of methylene chloride was added 0.1 ml (1.25 mmol) of DMF and cooled to 0° C. Added 0.12 ml of phosphorous oxychloride and stirred for 15 minutes. 0.40 g (1 mmol) of the product from Example 18 was added and the mixture was stirred at room temperature for 16 hours. At the end of this time added 5 ml of water and stirred vigorously an additional 0.5 hr. The solution was diluted with methylene chloride and the layers separated. The aqueous phase was extracted with methylene chloride and combined with the previous layer. After drying (MgSO4) and concentrating the crude solid was subjected to column chromatography on silica gel, eluting with 30% ethyl acetate:hexane. The product was collected and briefly characterized, then used in the next step without further purification.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][CH:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]([C:17](=[O:34])[C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:33])[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[CH3:32])=[CH:20][CH:19]=2)[CH2:9][CH2:8][CH2:7]1)=[O:4].Cl.[CH3:36][NH:37][CH3:38].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:36][N:37]([CH3:38])[CH2:2][C:3]([NH:5][CH:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]([C:17](=[O:34])[C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:33])[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[CH3:32])=[CH:20][CH:19]=2)[CH2:9][CH2:8][CH2:7]1)=[O:4]
Reactant: CNC
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(NC(=O)CCl)c3ccccc32)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(NC(=O)CN(C)C)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 39.3 %

Procedure:
To a solution of 5-(2-chloroacetylamino)-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.6 g) in dimethylformamide (20 ml) are added dimethylamine hydrochloride (0.21 g) and potassium carbonate (0.54 g), and the mixture is stirred at room temperature for 2 days. The reaction solution is concentrated and water is added to the resulting residue. The precipitated crystal is collected by filtration, and recrystallized from ethyl acetate to give 5-(2-dimethylaminoacetylamino)-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.24 g) as colorless prisms, m.p. 214-216° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C@H:4]([NH:8][S:9]([C:12]1[CH:23]=[CH:22][C:15]2[N:16]=[C:17]([S:19][CH2:20][CH3:21])[S:18][C:14]=2[CH:13]=1)(=[O:11])=[O:10])[CH:5]([CH3:7])[CH3:6].C([O-])([O-])=O.[K+].[K+].[CH2:31](Br)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(OC(=O)C)C>CN(C=O)C.O>[CH3:1][O:2][C:3](=[O:24])[C@H:4]([N:8]([S:9]([C:12]1[CH:23]=[CH:22][C:15]2[N:16]=[C:17]([S:19][CH2:20][CH3:21])[S:18][C:14]=2[CH:13]=1)(=[O:11])=[O:10])[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH:5]([CH3:7])[CH3:6]
Reactant: CCSc1nc2ccc(S(=O)(=O)N[C@@H](C(=O)OC)C(C)C)cc2s1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCSc1nc2ccc(S(=O)(=O)N(Cc3ccccc3)[C@@H](C(=O)OC)C(C)C)cc2s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(2R)-3-methyl-2-[(2-ethylthiobenzthiazol-6-sulfonyl)amino]butanoic acid methylester (0.16 g, 0.376 mmol) prepared in a similar manner as in Example 14 was dissolved in DMF (1 mL). K2CO3 (150 mg, 3 equi.) and benzylbromide (0.056 mL, 1.3 equi.) were added at RT. After stirring the reaction solution for 1 hour at RT, ethylacetate (5 mL) and H2O were added to afford the phase separation, when starting material was exhausted. The separated organic phase was washed with H2O for several times, dried over MgSO4 and distilled under reduced pressure to prepare the titled compound, (2R)-3-methyl-2-[(ethylthio-6-benzthiazolsulfonyl)benzylamino]butanoic acid methylester (180 mg, 100%).
Reaction SMILES: CS[C:3]1[C@@:8]([O:14][C:15]2[CH:20]=[C:19]([F:21])[C:18]([F:22])=[C:17]([F:23])[CH:16]=2)([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:7][CH2:6][CH2:5][N:4]=1.CO[C:26]1[CH:35]=[C:34]([C:36]2[O:40][C:39]([CH3:41])=[N:38][CH:37]=2)[CH:33]=[CH:32][C:27]=1[C:28]([NH:30][NH2:31])=O.[C:42](O)(=[O:44])C>C(OCC)(=O)C>[CH3:42][O:44][C:33]1[CH:32]=[C:27]([C:28]2[N:4]3[CH2:5][CH2:6][CH2:7][C@:8]([O:14][C:15]4[CH:20]=[C:19]([F:21])[C:18]([F:22])=[C:17]([F:23])[CH:16]=4)([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:3]3=[N:31][N:30]=2)[CH:26]=[CH:35][C:34]=1[C:36]1[O:40][C:39]([CH3:41])=[N:38][CH:37]=1
Reactant: CCOC(=O)[C@@]1(Oc2cc(F)c(F)c(F)c2)CCCN=C1SC
Reactant: CC(=O)O
Reactant: COc1cc(-c2cnc(C)o2)ccc1C(=O)NN
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@@]1(Oc2cc(F)c(F)c(F)c2)CCCn2c(-c3ccc(-c4cnc(C)o4)c(OC)c3)nnc21
Temperature: 100 °C
Reaction time: 3 h

Procedure:
To ethyl (3S)-2-(methylsulfanyl)-3-(3,4,5-trifluorophenoxy)-3,4,5,6-tetrahydropyridine-3-carboxylate (702 mg) and 3 methoxy-4-(2-methyl-1,3-oxazol-5-yl)benzohydrazide (500 mg) was added acetic acid (3 mL), and the mixture was stirred at 100° C. for 3 hr. The reaction mixture was diluted with ethyl acetate, and the mixture was washed with 10% aqueous potassium carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (NH, ethyl acetate). The crudely-purified product was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (933 mg).
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6](C)([C:7]3[CH:15]=[CH:14][C:13]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[CH:17]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:24].N1C=CC=C[CH:26]=1.ClCCl.[C:34](Cl)(=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36]>C(Cl)(Cl)Cl>[CH3:1][N:2]1[C@H:11]2[C@@H:6]([C:7]3[C:15]([CH3:26])=[CH:14][C:13]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:34](=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36])[CH:17]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:24]
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(-c4cccc(N)c4)cc3CC[C@@H]12
Reactant: c1ccncc1
Reactant: CC(C)(C)C(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: Cc1cc(-c2cccc(NC(=O)C(C)(C)C)c2)cc2c1[C@H]1CCC(=O)N(C)[C@@H]1CC2
Temperature: 25 °C
Yield: 64 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-(3-aminophenyl)-10b-methyl 1,2,3,4,4a,-5,6,10b octahydrobenzo[f]quinolin-3-one (31 mg, 0.097 mmol), N,N-dimethylaminopyridine (3 mg, 0.024 mmol), 1 mL of pyridine and 0.5 mL of dichloromethane. The solution was cooled to 0°, and excess pivaloyl chloride (0.086 mL, 0.69 mmol) was added. The stirred mixture was allowed to warm to room temperature over 2 h. The mixture was diluted with chloroform, and washed with 5% aqueous hydrochloric acid solution, water, 5% aqueous sodium hydroxide solution, water, and the combined organic extracts were dried over sodium sulfate, concentrated and chromatographed on silica gel (ethyl acetate eluent) to give 25 mg (64%) of the title compound as a yellow solid. mp 95°-98°. FDMS m/e=404. α[D]589 =+62.50 (c=0.16, chloroform).
Reaction SMILES: ONC(=N)C1C2C(C=CC=1)=NN(CCC(OCC)=O)C=2.[OH:21][NH:22][C:23](=[NH:40])[C:24]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:25]=1[CH:26]=[N:27][N:28]2[CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36].[Cl:41][C:42]1[CH:43]=[C:44]([CH:48]=[CH:49][C:50]=1[O:51][CH:52]([CH3:54])[CH3:53])[C:45](O)=O.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C)C=O.C(OCC)(=O)C>[Cl:41][C:42]1[CH:43]=[C:44]([C:45]2[O:21][N:22]=[C:23]([C:24]3[CH:32]=[CH:31][CH:30]=[C:29]4[C:25]=3[CH:26]=[N:27][N:28]4[CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[N:40]=2)[CH:48]=[CH:49][C:50]=1[O:51][CH:52]([CH3:53])[CH3:54]
Reactant: CCOC(=O)CCn1ncc2c(C(=N)NO)cccc21
Reactant: CC(C)Oc1ccc(C(=O)O)cc1Cl
Agent: CCOC(=O)CCn1cc2c(C(=N)NO)cccc2n1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CCn1ncc2c(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)cccc21
Temperature: 120 °C
Yield: 65.8 %

Procedure:
A mixture of ethyl 3-{4-[(hydroxyamino)(imino)methyl]-2H-indazol-2-yl}propanoate & ethyl 3-{4-[(hydroxyamino)(imino)methyl]-1H-indazol-1-yl}propanoate (D55) (700 mg, 1.27 mmol) (a 3:1 mix of 1 and 2-isomers), 3-chloro-4-[(1-methylethyl)oxy]benzoic acid (D3) (0.544 g, 2.53 mmol), EDC (0.534 g, 2.79 mmol) and HOBT (0.427 g, 2.79 mmol) in N,N-dimethylformamide (10 ml) was heated at 120° C. for 2 hrs, cooled, diluted with ethyl acetate (60 ml) and washed with water (3×20 ml). The organic layer was dried (MgSO4), evaporated and purified by flash chromatography eluting with EtOAc/hexane 1:4 to give the title compound (380 mg) as a white solid. δH (CDCl3, 400 MHz): 1.17 (3H, t), 1.46 (6H, d), 3.02 (2H, t), 4.10 (2H, q), 4.70-4.77 (3H, m), 7.08 (1H, d), 7.53 (1H, dd), 7.69 (1H, d), 8.05-8.12 (2H, m), 8.29 (1H, d), 8.71 (1H, d). MS (ES): C23H2335ClN4O4 requires 454; found (MH+) 455.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[N:10][N:11]([CH3:18])[C:12]=1[C:13]1[N:14]=[CH:15][NH:16][CH:17]=1.Cl[C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][N:21]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[N:10][N:11]([CH3:18])[C:12]=1[C:13]1[N:14]=[CH:15][N:16]([C:20]2[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][N:21]=2)[CH:17]=1
Reactant: Cn1nnc(-c2ccccc2Cl)c1-c1c[nH]cn1
Reactant: COC(=O)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(-n2cnc(-c3c(-c4ccccc4Cl)nnn3C)c2)nc1
Temperature: 120 °C
Yield: 75.6 %

Procedure:
A mixture of 4-(2-chlorophenyl)-5-(1H-imidazol-4-yl)-1-methyl-1H-1,2,3-triazole (322 mg, 1.24 mmol), methyl 6-chloronicotinate (213 mg, 1.24 mmol) and potassium carbonate (343 mg, 2.48 mmol) in DMF (7 mL) was stirred under Ar in a sealed flask and heated at 120° C. for 3 h. After cooling to room temperature the mixture was poured into water and extracted with ethyl acetate and the combined extracts washed with water, brine, dried over sodium sulphate, filtered and evaporated. Purification by chromatography (silica, 30 to 100% ethyl acetate in heptane) afforded the title compound (370 mg, 76%) as a white solid. MS: m/e=395.1 [M+H]+.
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC(OCC(C)C)=O.CN1CCOCC1.[Br:27][C:28]1[CH:29]=[C:30]([NH:34][C:35]2[C:44]3[C:39](=[CH:40][CH:41]=[C:42]([NH2:45])[CH:43]=3)[N:38]=[CH:37][N:36]=2)[CH:31]=[CH:32][CH:33]=1>O1CCCC1.N1C=CC=CC=1>[Br:27][C:28]1[CH:29]=[C:30]([NH:34][C:35]2[C:44]3[C:39](=[CH:40][CH:41]=[C:42]([NH:45][C:9](=[O:11])[C:8]#[C:7][C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH:43]=3)[N:38]=[CH:37][N:36]=2)[CH:31]=[CH:32][CH:33]=1
Reactant: O=C(O)C#Cc1ccccc1
Reactant: Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Agent: CC(C)COC(=O)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: O=C(C#Cc1ccccc1)Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Yield: 0.7 %

Procedure:
A solution of 0.93 g of 3-phenyl-2-propynoic acid in 10 ml of tetrahydrofuran was cooled in an ice bath. A 0.82 ml portion of isobutyl chloroformate followed by a 0.69 ml portion of N-methyl morpholine were added. After about 1 minute a solution of 1.0 g of N-(3-bromophenyl)-4,6-quinazolindiamine in 7 ml of pyridine was added. The reaction at 0° C. for 1 hr. The solvents were removed at reduced pressure and the solid was purified by chromatography on silica gel to give 0.01 g of N-[4-[(3-bromophenyl)amino]-6-quinazolinyl]-(3-phenyl-2-propynamide): mass spectrum (m/e): 443.2, 445.2 (M+H, electrospray).
Reaction SMILES: [CH3:1][N:2]1[C:6]([S:7][CH2:8][CH2:9][CH2:10][N:11]2C(=O)C3=CC=CC=C3C2=O)=[N:5][N:4]=[N:3]1.O.NN>C(O)C>[CH3:1][N:2]1[C:6]([S:7][CH2:8][CH2:9][CH2:10][NH2:11])=[N:5][N:4]=[N:3]1
Reactant: Cn1nnnc1SCCCN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Solvent: CCO
Product: Cn1nnnc1SCCCN
Yield: 50 %

Procedure:
1-Methyl-5-[3-(phthalimido)propylthio]-1,2,3,4-tetrazole (3.5 g) is dissolved in ethanol (50 ml). To the mixture is added hydrazine hydrate (85%, 2 g) and the mixture is refluxed for 1 hour. After cooling, the precipitate is filtered off and ethanol is distilled off. The residue is dissolved in ethyl acetate and dried over magnesium sulfate. Ethyl acetate is distilled off, and then the residue is purified by column chromatography (Alminium oxide 60, made by Merk & Co.), followed by eluting with chloroform to give 1-Methyl-5-(3-aminopropylthio)-1,2,3,4-tetrazole (1 g), colorless liquid, nD21.5 =1.5384.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].[CH2:15]1[C:23]2[C:18](=[CH:19][C:20]([N:24]3[CH2:28][CH2:27][CH:26]([C:29](O)=[O:30])[C:25]3=[O:32])=[CH:21][CH:22]=2)[CH2:17][CH2:16]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:29]([CH:26]1[CH2:27][CH2:28][N:24]([C:20]2[CH:19]=[C:18]3[C:23](=[CH:22][CH:21]=2)[CH2:15][CH2:16][CH2:17]3)[C:25]1=[O:32])=[O:30]
Reactant: O=C(O)C1CCN(c2ccc3c(c2)CCC3)C1=O
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)C1CCN(c2ccc3c(c2)CCC3)C1=O
Yield: 43 %

Procedure:
This compound was prepared according to method A with 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.100 g; 0.424 mmol), 1-(2,3-dihydro-1H-inden-5-yl)-2-oxopyrrolidine-3-carboxylic acid (0.111 g; 0.445 mmol), HATU (0.166 g; 0.437 mmol) and N,N-diisopropylethylamine (0.186 mL; 1.06 mmol) in DMF (5 mL). The crude material was purified by flash chromatography on silica gel (eluent: 2 to 20% of ethyl acetate in dichloromethane) to give 0.077 g (43%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-1-(2,3-dihydro-1H-inden-5-yl)-2-oxopyrrolidine-3-carboxamide as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C:16]2[N:17]=[N:18][N:19]([CH3:21])[CH:20]=2)[NH:9]S(C(C)(C)C)=O)=[CH:4][CH:3]=1.[ClH:22]>CO.C(OCC)C>[Cl-:22].[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C:16]2[N:17]=[N:18][N:19]([CH3:21])[CH:20]=2)[NH3+:9])=[CH:4][CH:3]=1
Reactant: Cn1cc([C@@H](NS(=O)C(C)(C)C)c2ccc(Br)cc2)nn1
Reactant: Cl
Solvent: CO
Solvent: CCOCC
Product: Cn1cc([C@@H]([NH3+])c2ccc(Br)cc2)nn1
Product: [Cl-]
Reaction time: 0.5 h

Procedure:
To a solution of 0.71 g (1.9 mmol) N-[(S)-(4-bromophenyl)(1-methyl-1H-1,2,3-triazol-4-yl)methyl]-2-methylpropane-2-sulfinamide in 5.0 ml MeOH was added 1.4 mL (2.8 mmol) 2.0M HCl in diethyl ether. After 30 min at room temperature, the reaction mixture was concentrated in vacuo to afford (S)-(4-bromophenyl)(1-methyl-1H-1,2,3-triazol-4-yl)methanaminium chloride. ES-MS [M+1]+=269.0.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH:4]1[O:24][C@:23]2([C:25]([CH2:27][OH:28])=[O:26])[C@@H:6]([CH2:7][C@@H:8]3[C@:22]2([CH3:29])[CH2:21][C@H:20]([OH:30])[C@H:19]2[C@H:9]3[CH2:10][CH2:11][C:12]3[C@:18]2([CH3:31])[CH:17]=[CH:16][C:14](=[O:15])[CH:13]=3)[O:5]1.Cl[C:33]([O:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])=[O:34].CCN(CC)CC.O>C(Cl)Cl>[CH3:1][CH2:2][CH2:3][CH:4]1[O:24][C@:23]2([C:25]([CH2:27][OH:28])=[O:26])[C@@H:6]([CH2:7][C@@H:8]3[C@:22]2([CH3:29])[CH2:21][C@H:20]([OH:30])[C@H:19]2[C@H:9]3[CH2:10][CH2:11][C:12]3[C@:18]2([CH3:31])[CH:17]=[CH:16][C:14](=[O:15])[CH:13]=3)[O:5]1.[CH2:36]([O:35][C:33](=[O:5])[O-:34])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47]
Reactant: CCCCCCCCCCCCOC(=O)Cl
Agent: CCCC1O[C@@H]2C[C@H]3[C@@H]4CCC5=CC(=O)C=C[C@]5(C)[C@H]4[C@@H](O)C[C@]3(C)[C@]2(C(=O)CO)O1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CCCCCCCCCCCCOC(=O)[O-]
Temperature: 25 °C
Reaction time: 7 h

Procedure:
To the solution of budesonide (750 mg, 1.74 mmol) in DCM (7.5 mL) was added dodecyl chloroformate (513 mL, 1.617 mmol) and Et3N (533 μL, 3.825 mmol) at room temperature. The reaction mixture was stirred at room temperature for 7 hours. During this 7 hours more dodecyl chloroformate (510 μL, 1.616 mmol) and Et3N (440 μL, 3.18 mmol) were added. The reaction was followed by HPLC. The reaction mixture was poured into water (20 mL) and DCM (10 mL); the aqueous phase was extracted with DCM (10 mL). The combined organic phases were washed with water (10 mL) and brine (10 mL), dried over Na2SO4, filtered, and concentrated in vacuo to provide crude budesonide dodecylcarbonate. The product was purified by chromatography, eluted with Hexane:AcOEt=9:1 to 3:1 to provide 983 mg of 1:1 mixture of epimers (originated from budesonide) (96.78 area % purity on HPLC). 1H NMR (CDCl3) δ 0.80-2.25 (m, 45H), 2.36 (d, 1H, 13.4 Hz), 2.58 (t, 1H, 13.2 Hz), 4.19 (t, 2H, 6.7 Hz), 4.52 (bs, 1H), 4.6-5.2 (m, 5H), 6.03 (s, 1H), 6.30 (d, 1H, 10.1 Hz), 7.29 (d, 1H, 10.1 Hz). 13C NMR (CDCl3) δ 14.21, 14.38, 17.22, 17.35, 17.50, 17.78, 21.35, 22.94, 25.86, 28.83, 29.45, 29.60, 29.74, 29.80, 29.88, 30.57, 31.24, 32.16, 33.18, 33.68, 34.26, 35.26, 37.36, 41.17, 41.41, 44.24, 46.18, 47.61, 50.01, 53.14, 55.41, 55.52, 69.12, 69.18, 70.11, 70.22, 82.32, 83.57, 97.76, 98.62, 104.88, 108.63, 122.83, 128.24, 156.14, 169.81, 169.92, 186.74, 202.16 and 203.46. Mass spectrum (m/e) 643 (M+).
Reaction SMILES: [OH:1]/[N:2]=[C:3](\Cl)/[CH:4]=[N:5]/O.S(Cl)(Cl)=O.[O:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1>>[CH2:13]([O:12][CH:16]1[O:1][N:2]=[C:3]([C:4]#[N:5])[CH2:15]1)[CH3:14]
Reactant: C1CCOC1
Reactant: O/N=C(Cl)/C=N/O
Solvent: O=S(Cl)Cl
Product: CCOC1CC(C#N)=NO1
Temperature: 2.5 °C
Reaction time: 6.5 h
Yield: 30.5 %

Procedure:
To a dried 10 L three-necked flask equipped with a thermometer controller, a mechanical stirrer, and a dropping funnel protected under nitrogen was charged 6966.7 g (7.3×) of tetrahydrofuran and 950.0 g (1.0×) of compound (1Z,2E)-N-hydroxy-2-(hydroxyimino)acetimidoyl chloride. The reaction mixture was cooled to 0-5° C. followed by drop wise addition of 1845.2 g (1.9×) thionyl chloride over 60-90 minutes at 0-5° C. After addition, the reaction mixture was stirred at 10-15° C. for 6-7 hours and deemed complete by HPLC. The reaction mixture was then concentrated under vacuum at 15-20° C. to about 1.0 L (1.0×) followed by addition of a total of 950 g (0.9×) of tetrahydrofuran and distillation to remove residual thionyl chloride. The resulting mixture was added drop wise into a solution of 2755 g (2.9×) of ethoxyethene, 6764 g (7.12×) of tetrahydrofuran and 715.0 g (0.75×) of sodium carbonate in 3200.0 g (3.4×) of water over 30-40 minutes at 0-5° C. After addition, the reaction mixture was stirred at 0-5° C. for 1-2 hours and deemed complete by HPLC. The resulting mixture was separated and the aqueous layer was extracted with 1900 g (2.0×) of methyl t-butyl ether, and then the combined organic layer was dried with 380 g (0.4×) of sodium sulfate, filtered and then concentrated to give 549.7 g yellow oil (Assay 60.3%, purity 97.0%, yield 30.5%). 1H NMR (CDCl3, 400 MHz) δ 5.76 (dd, J=2.0 Hz, 4.8 Hz, 1H), 3.86-3.90 (m, 1H), 3.60-3.65 (m, 1H), 3.21 (dd, J=6.8 Hz, 11.2 Hz, 1H), 3.00 (dd, J=2.0 Hz, 16 Hz, 1H), 1.21 (T, J=6.8 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:6][C:7]3[C:12]([C:13]=2[C:14]=1[O:15][CH2:16][C@@H:17]1[CH2:19][O:18]1)=[CH:11][CH:10]=[CH:9][CH:8]=3.NCC1CCN([C:28]2[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:29]=2[S:36]([NH2:39])(=[O:38])=[O:37])CC1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:6][C:7]3[C:12]([C:13]=2[C:14]=1[O:15][CH2:16][C@@H:17]([OH:18])[CH2:19][NH:6][CH2:5][CH:13]1[CH2:14][CH2:2][N:39]([S:36]([C:29]2[CH:28]=[CH:33][C:32]([O:34][CH3:35])=[CH:31][CH:30]=2)(=[O:37])=[O:38])[CH2:11][CH2:12]1)=[CH:11][CH:10]=[CH:9][CH:8]=3
Reactant: COc1ccc(S(N)(=O)=O)c(N2CCC(CN)CC2)c1
Reactant: Clc1ccc2[nH]c3ccccc3c2c1OC[C@@H]1CO1
Product: COc1ccc(S(=O)(=O)N2CCC(CNC[C@H](O)COc3c(Cl)ccc4[nH]c5ccccc5c34)CC2)cc1
Yield: 122.2 %

Procedure:
Prepared from 3-chloro-4-[(2S)-oxiranylmethoxy]-9H-carbazole (0.060 g, 0.22 mmol) and (4-aminomethyl-1-piperidinyl) 4-methoxybenzenesulfonamide (0.125 g, 0.5 mmol) according to procedure used for Example 2 to give 0.075 g of the title compound as a white solid.