Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:17]([N:27]1[CH2:34][CH2:33][CH2:32][C@@H:28]1[C:29](O)=[O:30])([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18].C(OC1C=CC(NC(C2C=CC=CN=2)=O)=CC=1)C1C=CC=CC=1>>[CH2:20]([O:19][C:17]([N:27]1[CH2:34][CH2:33][CH2:32][C@@H:28]1[C:29](=[O:30])[NH:14][C:13]1[CH:12]=[CH:11][C:10]([O:9][CH2:2][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)=[CH:16][CH:15]=1)=[O:18])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Nc1ccc(OCc2ccccc2)cc1
Reactant: O=C(O)[C@H]1CCCN1C(=O)OCc1ccccc1
Agent: Cl
Agent: O=C(Nc1ccc(OCc2ccccc2)cc1)c1ccccn1
Product: O=C(Nc1ccc(OCc2ccccc2)cc1)[C@H]1CCCN1C(=O)OCc1ccccc1

Procedure:
This compound was prepared from 4-benzyloxyaniline hydrochloride (4.0 g, 17.0 mmol) and (+)-N-carbobenzyloxy-d-proline (4.44 g, 17.8 mmol), using the same method to prepare pyridine-2-carboxylic acid (4-benzyloxyphenyl)amide, to give the product as a colorless solid, which was used without further purification in the subsequent step. 1H NMR(DMSO-d6) δ61.80-1.95 (m, 3H), 2.10-2.27 (m, 1H), 3.35-3.55 (m, 2H), 4.33 (m, 1H), 5.0 (m, 4H), 6.95 (d, 2H), 7.12-7.53 (m, 12H) and 9.95 (d, 1H).
Reaction SMILES: C(N(C(C)C)[CH:4]([CH3:6])[CH3:5])C.[CH2:10](Br)[CH2:11][CH3:12].[NH2:14][CH2:15][C:16]1[O:20][C:19]([C:21]2[N:22]=[CH:23][N:24]3[C:30]4[CH:31]=[CH:32][S:33][C:29]=4[C:28](=[O:34])[N:27]4[CH2:35][CH2:36][C@H:26]4[C:25]=23)=[N:18][N:17]=1>CN(C)C=O>[CH2:10]([N:14]([CH2:15][C:16]1[O:20][C:19]([C:21]2[N:22]=[CH:23][N:24]3[C:30]4[CH:31]=[CH:32][S:33][C:29]=4[C:28](=[O:34])[N:27]4[CH2:35][CH2:36][C@H:26]4[C:25]=23)=[N:18][N:17]=1)[CH2:5][CH2:4][CH3:6])[CH2:11][CH3:12]
Reactant: CCCBr
Reactant: CCN(C(C)C)C(C)C
Reactant: NCc1nnc(-c2ncn3c2[C@@H]2CCN2C(=O)c2sccc2-3)o1
Solvent: CN(C)C=O
Product: CCCN(CCC)Cc1nnc(-c2ncn3c2[C@@H]2CCN2C(=O)c2sccc2-3)o1
Reaction time: 12 h
Yield: 43.3 %

Procedure:
3 ml (17.25 mmol) of N-ethyldiisopropylamine and 0.8 ml (8.8 mmol) of propyl bromide were added to a solution of 0.550 g (1.68 mmol) of (S)-1-(5-aminomethyl-1,3,4-oxadiazol-2-yl)-11,11a-dihydro-8H, 10H-azeto[1,2-a]imidazo[5,1-c]thieno[3,2-e][1,4]diazepin-8-one in 30 ml of dimethylformamide, whereupon the mixture was stirred at 70° for 12 hours. The dimethylformamide was evaporated and the residue was partitioned between methylene chloride and 2N sodium carbonate solution. The aqueous phase was washed twice with methylene chloride and the organic phases were dried with sodium sulfate, filtered and evaporated. Chromatography (silica gel, ethyl acetate/methanol 20:1) yielded 0.300 g (43%) of (S)-1-(5-dipropylaminomethyl-1,3,4-oxadiazol-2-yl)-11,11a-dihydro-8H,10H-azeto[1,2-a]imidazo[5,1-c]thieno[3,2-e][1,4]diazepin-8-one as a colourless foam, Rf=0.28 (silica gel, ethyl acetate/methanol 20:1).
Reaction SMILES: [Mg:1].[CH:2]([NH:5][CH:6]([CH3:8])[CH3:7])([CH3:4])[CH3:3].BrCC.CC.CC[Mg+].[Br-:17]>C1COCC1>[CH:2]([N:5]([Mg:1][Br:17])[CH:6]([CH3:8])[CH3:7])([CH3:4])[CH3:3]
Reactant: CC(C)NC(C)C
Reactant: [Mg]
Reactant: [Br-]
Agent: CC
Agent: CC[Mg+]
Solvent: C1CCOC1
Solvent: CCBr
Product: CC(C)N([Mg]Br)C(C)C

Procedure:
Into a 1 liter round bottom flask equipped with an addition funnel and a reflux condenser were placed magnesium turnings (24.3 g, 1.0 mol), diisopropylamine (20.2 g, 0.2 mol) and THF (500 ml). Bromoethane (120.0 g, 1.1 mol) was added dropwise to this mixture via the addition funnel at such a rate as to maintain a refluxing solution. Ethane was evolved during the addition. The reaction was determined to be complete once all of the magnesium was consumed. This process produced a solution containing EtMgBr and DAMB.
Reaction SMILES: P(Br)(Br)[Br:2].[CH:5]1([C:11]2[CH:36]=[CH:35][C:14]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[CH2:23][CH2:24][CH:25](O)[CH2:26][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH3:33])=[O:31])=[CH:13][CH:12]=2)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.O>C(OCC)C>[Br:2][CH:25]([CH2:24][CH2:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[O:16][CH2:15][C:14]1[CH:35]=[CH:36][C:11]([CH:5]2[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)=[CH:12][CH:13]=1)[CH2:26][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH3:33])=[O:31]
Reactant: COC(=O)CCCCC(O)CCc1ccccc1OCc1ccc(C2CCCCC2)cc1
Reactant: BrP(Br)Br
Solvent: CCOCC
Solvent: O
Product: COC(=O)CCCCC(Br)CCc1ccccc1OCc1ccc(C2CCCCC2)cc1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
At 0° C., 140 mg (0.51 mmol) of phosphorus tribromide were added to a solution of 500 mg (1.14 mmol) of methyl 8-{2-[(4-cyclohexylbenzyl)oxy]phenyl}-6-hydroxyoctanoate XVI in 5 ml of diethyl ether. The mixture was stirred at 0° C. for 1 h and at room temperature for another 16 h. Water was added, the mixture was extracted with cyclohexane and the combined organic phases were dried over Na2SO4. The product was purified chromatographically (silica gel, cyclohexane(ethyl acetate 10:1).
Reaction SMILES: [OH:1][C:2]1[C:3]2[O:21][N:20]=[C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:4]=2[C:5]([C:13]#[C:14][Si](C)(C)C)=[N:6][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].C(=O)([O-])[O-].[Cs+].[Cs+]>CCO.C(Cl)Cl>[C:13]([C:5]1[C:4]2[C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:20][O:21][C:3]=2[C:2]([OH:1])=[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1)#[CH:14]
Reactant: CCOC(=O)c1nc(C#C[Si](C)(C)C)c2c(-c3ccccc3)noc2c1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCO
Solvent: ClCCl
Product: C#Cc1nc(C(=O)OCC)c(O)c2onc(-c3ccccc3)c12
Temperature: 25 °C
Reaction time: 14 h
Yield: 111.1 %

Procedure:
Ethyl 7-hydroxy-3-phenyl-4-((trimethylsilyl)ethynyl)isoxazolo[4,5-c]pyridine-6-carboxylate (205 mg, 0.54 mmol) was dissolved in a 1:1 mixture of EtOH/CH2Cl2 (6 mL). Cesium carbonate (211 mg, 0.65 mmol) was added and the resulting slurry was stirred at room temperature for 14 h. The solvent was evaporated and the residue was partitioned between EtOAc (25 mL) and 1 M hydrochloric acid (25 mL). The aqueous layer was extracted with CH2Cl2 and the combined organic layer was dried over MgSO4 and concentrated to give 185 mg of the title compound. MS: (+) m/z 309.29 (M+1).
Reaction SMILES: [CH3:1][C@H:2]([OH:10])[C@@H:3]([OH:9])[C@@H:4]([NH2:8])[CH2:5][CH:6]=[O:7].FC(F)(F)C([O:15][C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])=O.[ClH:24]>C(OCC)C>[Cl:24][C@:6]1([O:10][C@@H:2]([CH3:1])[C@@:3]([O:15][C:16](=[O:21])[C:17]([F:18])([F:19])[F:20])([OH:9])[C@@H:4]([NH:8][C:16](=[O:15])[C:17]([F:20])([F:19])[F:18])[CH2:5]1)[OH:7]
Reactant: Cl
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: C[C@H](O)[C@@H](O)[C@@H](N)CC=O
Solvent: CCOCC
Product: C[C@@H]1O[C@](O)(Cl)C[C@H](NC(=O)C(F)(F)F)[C@@]1(O)OC(=O)C(F)(F)F
Reaction time: 1 h

Procedure:
One gram of daunosamine (II) hydrochloride was suspended in anhydrous diethyl ether and treated at 0° C. with 8 ml. of trifluoroacetic anhydride. After allowing the suspension to stand for two hours at 0° C. and one hour at room temperature, the solvent was removed under reduced pressure and the residue was crystallized from dichloromethane to yield 1.1 g. of 2,3,6-trideoxy-1-trifluoroacetoxy-3-trifluoroacetamido-4-trifluoroacetoxy-L-lyxopyranose (IIA), having a m.p. of 132°-134° C. and a mass spectrum m/e 391 (M-44), 322 (M-113). 0.5 g of (IIA) in anhydrous diethyl ether was treated at 0° C. with anhydrous gaseous hydrogen chloride. After standing at +5° C. overnight, the solvent was removed in vacuo to yield 1-chloro-2,3,6-trideoxy-3-trifluoroacetamido-4-trifluoroacetoxy-α-L-lyxohexopyranose (IIB) as crystalline product. The NMR spectrum of (IIB) in CDCl3 was as follows:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[F:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[CH:21]([CH3:25])[NH:20][CH2:19][CH2:18]2>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:20]3[CH2:19][CH2:18][C:17]4[C:22](=[CH:23][CH:24]=[C:15]([F:14])[CH:16]=4)[CH:21]3[CH3:25])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CC1NCCc2cc(F)ccc21
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Product: CC1c2ccc(F)cc2CCN1C(=O)c1cc2ncc(Cl)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 6-fluoro-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH3:11][N:12]1[CH:20]=[C:19]2[C:14]([CH:15]=[CH:16][CH:17]=[C:18]2[CH2:21][OH:22])=[N:13]1.C(N(CC)CC)C.[NH4+].[Cl-]>ClCCl>[CH3:11][N:12]1[CH:20]=[C:19]2[C:14]([CH:15]=[CH:16][CH:17]=[C:18]2[CH:21]=[O:22])=[N:13]1
Reactant: Cn1cc2c(CO)cccc2n1
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1cc2c(C=O)cccc2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.8 %

Procedure:
Under nitrogen atmosphere, dimethyl sulfoxide (70.0 mL, 987 mmol) was added to a solution of oxalyl chloride (43.2 mL, 493 mmol) in dichloromethane (2.47 L) at −78° C., and the mixture was stirred for 2 hr. To the reaction mixture was added (2-methyl-2H-indazol-4-yl)methanol (40.0 g, 247 mmol), and the mixture was stirred for 1 hr. To the reaction mixture was added triethylamine (139 mL, 987 mmol) at −78° C., and the mixture was stirred for 1 hr and warmed to room temperature over 4 hr. To the reaction mixture was added aqueous ammonium is chloride solution, and the mixture was extracted with dichloromethane. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by recrystallization (dichloromethane/hexane) to give the title compound (36.3 g, yield 92%).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][CH:16]=[CH:15]4)=[N:9][N:10]=2)[N:7]=1.[NH:22]1[CH:26]=[CH:25][N:24]=[CH:23]1.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C=O)C>[N:22]1([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([CH2:11][C:12]4[CH:13]=[C:14]5[C:19](=[CH:20][CH:21]=4)[N:18]=[CH:17][CH:16]=[CH:15]5)=[N:9][N:10]=3)[N:7]=2)[CH:26]=[CH:25][N:24]=[CH:23]1
Reactant: Clc1ccc2nnc(Cc3ccc4ncccc4c3)n2n1
Reactant: c1c[nH]cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1cnc2ccc(Cc3nnc4ccc(-n5ccnc5)nn34)cc2c1

Procedure:
A mixture of 6-(6-Chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-ylmethyl)-quinoline, imidazole, and potassium carbonate were stirred in DMF (3 mL) for 8 h at 100° C. Aqueous HCl (0.5 N) was added and the volatiles were removed in vacuo. Purification by HPLC (5-35% B over 45 min) yielded the product as a TFA salt. The residue was dissolved in aq 1N HCl (5 mL) and the volatiles removed in vacuo. After two repetitions, the product-dihydrochloride was dried under high vacuum to yield a glassy solid (53 mg, 44% yield). 1H-NMR (CD3OD): δ 9.60 (1H, s), 9.17 (1H, dd, J=1.5, 5.3 Hz), 9.10 (1H, m), 8.58 (1H, d, J=9.9 Hz), 8.38 (1H, m), 8.36 (1H, m), 8.27 (1H, m), 8.23 (1H, m), 8.05 (1H, dd, J=5.3, 8.3 Hz), 7.98 (1H, d, J=9.9 Hz), 7.72 (1H, s), 5.12 (2H, s), 4.98 (2H, m). ESI-MS (m/z): Calcd. for C18H13N7: 327.1; found: 328.3 (M+H).
Reaction SMILES: [OH:1][CH:2]([CH2:23][O:24][C:25]1[CH:26]=[CH:27][C:28]2[S:32][C:31]([CH3:33])=[N:30][C:29]=2[CH:34]=1)[CH2:3][N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][N:12]2C(=O)C3C=CC=CC=3C2=O)[CH2:6][CH2:5]1.O.NN.Cl>CO>[NH2:12][CH2:11][CH2:10][N:7]1[CH2:8][CH2:9][N:4]([CH2:3][C@@H:2]([OH:1])[CH2:23][O:24][C:25]2[CH:26]=[CH:27][C:28]3[S:32][C:31]([CH3:33])=[N:30][C:29]=3[CH:34]=2)[CH2:5][CH2:6]1
Reactant: Cc1nc2cc(OCC(O)CN3CCN(CCN4C(=O)c5ccccc5C4=O)CC3)ccc2s1
Agent: Cl
Agent: NN
Solvent: CO
Solvent: O
Product: Cc1nc2cc(OC[C@H](O)CN3CCN(CCN)CC3)ccc2s1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A solution of 2-(2-{4-[2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}ethyl)benzo[c]azoline-1,3-dione (101 mg, 0.21 mmol) in MeOH (0.84 mL) was treated with hydrazine hydrate (0.07 mL) and stirred at RT for 14 hours. HCl (1 mL, conc) was added and the solution was heated to 88° C. for 14 hours. Upon cooling, the resulting solid was filtered off and washed with H2O and EtOAc. The filtrate was pH adjusted to >12 (NaOH) and extracted with EtOAc. The combined organic layers were then concentrated to afford (2R)-1-[4-(2-aminoethyl)piperazinyl]-3-(2-methylbenzothiazol-5-yloxy)propan-2-ol as an oil.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:38][C@@H:39]1[CH2:44][NH:43][CH2:42][CH2:41][NH:40]1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:43]3[CH2:42][CH2:41][NH:40][C@H:39]([CH3:38])[CH2:44]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: C[C@@H]1CNCCN1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN[C@H](C)C1

Procedure:
In a manner analogous to the method described in examples 8, (4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 51) was coupled with (R)-2-methyl-piperazine (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C34H42Cl2N5O2 [(M+H)+] 622.271, observed 622.2714.
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]2[C:10]([CH2:11][CH3:12])=[C:9]([C:13]([O:15][CH:16]([O:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH3:17])=[O:14])[N:8]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[C:37]4[N:41](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[N:40]=[N:39][N:38]=4)=[CH:27][CH:26]=3)[N:6]2[N:7]=1)[CH3:2].CO>C(O)(=O)C>[CH2:1]([C:3]1[N:4]=[C:5]2[C:10]([CH2:11][CH3:12])=[C:9]([C:13]([O:15][CH:16]([O:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH3:17])=[O:14])[N:8]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[C:37]4[NH:41][N:40]=[N:39][N:38]=4)=[CH:27][CH:26]=3)[N:6]2[N:7]=1)[CH3:2]
Reactant: CCOC(=O)OC(C)OC(=O)c1c(CC)c2nc(CC)nn2n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(=O)OC(C)OC(=O)c1c(CC)c2nc(CC)nn2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 95.6 %

Procedure:
A mixture consisting of 5.64 g of 1-ethoxycarbonyloxyethyl 2,7-diethyl-5-[[2'-(N-triphenylmethyl-tetrazol-5-yl)biphenyl-4-yl]methyl]-5H-pyrazolo[1,5-b][1,2,4]triazole-6-carboxylate, 230 ml of methanol and 12 ml of acetic acid was heated under reflux for 3 hours. After removing the solvent by distillation under a reduced pressure, the resulting residue was subjected to silica gel column chromatography. Elution was conducted with a methanol-chloroform (1:19, v/v) mixed solvent to give 3.76 g of 1-ethoxycarbonyloxyethyl 2,7-diethyl-5-[[2'-(tetrazol-5-yl)biphenyl-4-yl]methyl]-5H-pyrazolo[1,5-b][1,2,4]triazole-6-carboxylate in the form of amorphous foamy material.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH2:6][C:5]2[CH:9]=[CH:10][S:11][C:4]=2[S:3]1(=[O:13])=[O:12].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]=[C:22]=[O:23])=[CH:17][CH:16]=1.C(N(CC)CC)C.Cl>CS(C)=O>[OH:8][C:7]1[N:2]([CH3:1])[S:3](=[O:13])(=[O:12])[C:4]2[S:11][CH:10]=[CH:9][C:5]=2[C:6]=1[C:22](=[O:23])[NH:21][C:18]1[CH:19]=[CH:20][C:15]([Cl:14])=[CH:16][CH:17]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: CN1C(=O)Cc2ccsc2S1(=O)=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CN1C(O)=C(C(=O)Nc2ccc(Cl)cc2)c2ccsc2S1(=O)=O
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
1 g (4.6 mmol) of 3,4-dihydro-2-methyl-3-oxo-2H-thieno[3,2-e]-1,2-thiazine 1,1-dioxide are stirred at room temperature for 3 hours under nitrogen with 0.71 g (4.6 mmol) of p-chlorophenylisocyanate and 0.47 g (4.6 mmol) of triethylamine in 10 ml of absolute dimethylsulfoxide. Thereafter, the mixture is poured into 40 ml of 2-N hydrochloric acid and 25 g of ice and stirred for 20 minutes. The separated precipitate is filtered off under suction and washed neutral with water. The precipitate is dissolved in 200 ml of methylene chloride, the turbid solution is dried over sodium sulfate, stirred with 0.3 g of active carbon and filtered. The filtrate is extracted with five 100 ml portions of saturated sodium carbonate solution, each of the aqueous phases being re-extracted with a small amount of methylene chloride. The combined aqueous phases are acidified to pH 1 with concentrated hydrochloric acid. The separated product is extracted with two 150 ml portions of methylene chloride. The combined organic phases are dried over sodium sulfate, whereupon the solvent is distilled off. For purification, the product is recrystallized from ca 50 ml of methanol. There is obtained 3-hydroxy-2-methyl-4-(4-chlorophenylcarbamoyl)-2H-thieno[3,2-e]-1,2-thiazine 1,1-dioxide of melting point 202°-204° C.
Reaction SMILES: [C:1]([CH2:3][C@H:4]1[O:9][C:8]([CH3:11])([CH3:10])[O:7][C@@H:6]([CH2:12][C:13]([N:15]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[CH2:5]1)#[N:2].N.[H][H]>CO.[Ni]>[NH2:2][CH2:1][CH2:3][C@H:4]1[O:9][C:8]([CH3:11])([CH3:10])[O:7][C@@H:6]([CH2:12][C:13]([N:15]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:14])[CH2:5]1
Reactant: CC1(C)O[C@H](CC#N)C[C@H](CC(=O)N(Cc2ccccc2)Cc2ccccc2)O1
Reactant: [H][H]
Agent: [Ni]
Agent: N
Solvent: CO
Product: CC1(C)O[C@H](CCN)C[C@H](CC(=O)N(Cc2ccccc2)Cc2ccccc2)O1
Temperature: 20 °C
Reaction time: 3 h
Yield: 94.8 %

Procedure:
A solution of (4R-cis)-6-(cyanomethyl)-2,2-dimethyl-N,N-bis(phenylmethyl)-1,3-dioxane-4-acetamide (10.0 g, 0.025 mol) in methanol (150 mL) containing anhydrous ammonia (2.25 g) is reacted with hydrogen gas in a Parr shaker at 30° C. in a presence of a slurry of Raney nickel A-7000 (3.7 g). After 3 hours, uptake of hydrogen has ceased, the mixture is cooled to 20° C., the atmosphere is vented and exchanged for nitrogen, the slurry is filtered through celite, and concentrated at reduced pressure to give 9.4 g of (4R-cis)-6-(2-aminoethyl)-2,2-dimethyl-N,N-bis (phenylmethyl)-1,3-dioxane-4-acetamide as an oil;
Reaction SMILES: [CH3:1][S:2]([OH:5])(=[O:4])=[O:3].C([NH:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][C:15]=1[S:23]([NH2:26])(=[O:25])=[O:24])C1C=CC=CC=1.O1CCCC1.[H][H]>[Pd].C(O)C.O>[CH3:1][S:2]([OH:5])(=[O:4])=[O:3].[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][C:15]=1[S:23]([NH2:26])(=[O:24])=[O:25]
Reactant: [H][H]
Reactant: NS(=O)(=O)c1cc([N+](=O)[O-])ccc1NCc1ccccc1
Agent: [Pd]
Agent: CS(=O)(=O)O
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: Nc1ccc(N)c(S(N)(=O)=O)c1
Temperature: 23 °C
Reaction time: 22 h
Yield: 92.7 %

Procedure:
Methanesulfonic acid (465 mL, 7.16 mol) was added slowly to a solution of 2-benzylamino-5-nitro-benzenesulfonamide (2.20 kg, 7.16 mol) and tetrahydrofuran (11.0 L). The resulting solution was added to a mixture of 10% palladium on carbon (220 g of 50% water wet catalyst) and water (1.1 L) in a hydrogenation reactor. The mixture was further diluted with absolute ethanol (21.0 L) and was then hydrogenated with 55 psi hydrogen at 50° C. for 21 h. Additional 10% palladium on carbon (55 g of 50% water wet catalyst) was added, and hydrogenation at 55 psi and 50° C. was continued for 22 h. The resulting suspension was diluted with water (1.1 L) and the suspension was then filtered through a pad of Celite. The filtrate was partially concentrated in vacuo and was then diluted with acetonitrile (15.4 L). The solution was again partially concentrated in vacuo and diluted with acetonitrile (15.4 L). The resulting suspension was partially concentrated in vacuo and was allowed to stir at 23° C. for 2 h. The suspension was filtered and the solid was then washed with acetonitrile (3 L). The solid was further dried in vacuo at 45° C. to afford the desired product, 2,5-diamino-benzenesulfonamide methanesulfonate (1.88 kg, 6.64 mol, 93%), as a purple solid. 1H NMR (400 MHz, DMSO-d6) δ: 2.34 (3H, s), 6.05 (2H, b), 6.87 (1H, d, J=8.6 Hz), 7.20 (1H, dd, J1=8.6 Hz, J2=2.3 Hz), 7.38 (2H, s), 7.53 (1H, d, J=2.3 Hz), 9.62 (3H, b). LC-MS (ESI) calcd for C6H9NO2S 187.04, found 187.9 [M+H+].
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:13]=1[I:14])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].FC(F)(F)S(O[CH2:24][C:25]([F:28])([F:27])[F:26])(=O)=O.C([O-])(O)=O.[Na+]>CN(C=O)C.CCOC(C)=O>[C:1]([O:5][C:6](=[O:15])[N:7]([C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:13]=1[I:14])[CH2:24][C:25]([F:28])([F:27])[F:26])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cnccc1I
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(CC(F)(F)F)c1cnccc1I
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (4-iodo-pyridin-3-yl)-carbamic acid tert-butyl ester (280 mg, 875 μmol) in DMF (4 mL) was added NaH (42.0 mg, 962 μmol, 60% dispersion in mineral oil) at 0° C. The reaction mixture was stirred at room temperature for 30 minutes. 2,2,2-Trifluoroethyl trifluoromethanesulphonate (203 mg, 126 μL, 875 μmol, CAS RN 6226-25-1) was added and the reaction stirred at room temperature for 2 hours. The reaction mixture was poured on 30 mL 10% aqueous NaHCO3 solution and 30 mL EtOAc and the layers were separated. The aqueous layer was extracted a second time with 30 mL EtOAc and the combined organic layers were washed with 30 mL brine, dried over MgSO4, filtered and concentrated under vacuum. The compound was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:EtOAc (100:0 to 30:70). Colorless solid (207 mg, 59%). MS (ESI): m/z=403.012 [M+H]+.
Reaction SMILES: C(OP([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][N:18]=2)[CH:11]=1)(=O)OCC)C.[H-].[Na+].[C:29]([O:33][C:34]([N:36]1[CH2:41][CH2:40][C:39](=O)[CH2:38][CH2:37]1)=[O:35])([CH3:32])([CH3:31])[CH3:30].O>C1COCC1.O1CCOCCOCCOCCOCC1>[CH:17]([O:16][CH:12]([CH3:11])[CH3:13])([CH3:22])[CH3:29].[C:29]([O:33][C:34]([N:36]1[CH2:41][CH2:40][C:39](=[CH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:24])([F:25])[F:26])=[CH:19][N:18]=3)[CH:11]=2)[CH2:38][CH2:37]1)=[O:35])([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CCOP(=O)(Cc1cccc(Oc2ccc(C(F)(F)F)cn2)c1)OCC
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(=Cc2cccc(Oc3ccc(C(F)(F)F)cn3)c2)CC1
Product: CC(C)OC(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 144.2 %

Procedure:
[3-(5-Trifluoromethyl-pyridin-2-yloxy)-benzyl]-phosphonic acid diethyl ester (2.3 g, 6.0 mmol) from Step 3 and 1,4,7,10,13-pentaoxacyclopentadecane (15-Crown-5, 0.03 mL, 0.15 mmol) were combined in THF (10 mL). The mixture was cooled to 0° C. and sodium hydride (240 mg, 60% dispersion in mineral oil, 6.0 mmol) was added. The reaction was warmed to room temperature, stirred for 30 minutes and then cooled back to 0° C. A solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (1.2 g, 6.0 mmol) in THF (6 mL) was added and the reaction was warmed to room temperature. After 16 hours, water was added and the layers were separated. The aqueous layer was extracted with EtOAc (2×200 mL) and the combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to a thick oil. Treatment of the oil with hot isopropyl ether (45 mL) provided the title compound as a white solid (1.88 g). 1H NMR (400 MHz, CD3OD) δ ppm 1.46 (s, 9H) 2.34 (td, J=5.85, 1.18 Hz, 2H) 2.46 (td, J=5.87, 1.07 Hz, 2H) 3.37-3.44 (m, 2H) 3.45-3.57 (m, 2H) 6.41 (s, 1H) 6.92-7.04 (m, 2H) 7.06-7.17 (m, 2H) 7.31-7.54 (m, 1H) 8.08 (ddd, J=8.74, 2.59, 0.56 Hz, 1H) 8.42 (td, J=1.73, 0.90 Hz, 1H).