Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH2:25][CH2:26][CH3:27])([CH2:22][CH2:23][CH3:24])[C:9]([CH:11](C(OCC)=O)[C:12]([O:14]CC)=O)=[O:10])=[CH:4][CH:3]=1.ClCCl.Cl>CS(O)(=O)=O.O1CCCC1.O>[F:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[C:8]([CH2:22][CH2:23][CH3:24])([CH2:25][CH2:26][CH3:27])[C:9](=[O:10])[CH:11]=[C:12]2[OH:14]
Reactant: CCCC(CCC)(C(=O)C(C(=O)OCC)C(=O)OCC)c1ccc(F)cc1
Agent: CS(=O)(=O)O
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: CCCC1(CCC)C(=O)C=C(O)c2cc(F)ccc21
Temperature: 50 °C
Yield: 69.9 %

Procedure:
The compound of Example 14F (6.0 g, 15.75 mmol) was dissolved in methanesulfonic acid (35 mL) and warmed at 50° C. for 5 h. The mixture was cooled and added to a mixture of ice and dichloromethane, followed by stirring until all ice had melted. The layers were separated and the aqueous phase was extracted again with dichloromethane. The combined organic layers were dried (Na2SO4) and concentrated in vacuo to afford an amber oil, which was dissolved in tetrahydrofuran (60 mL) and warmed at reflux with 1 N HCl solution (50 mL) for 18 h. The mixture was cooled and diluted with water and extracted with ethyl acetate. The organic layer was extracted with water and saturated NaCl solution. Drying (Na2SO4) and concentration in vacuo afforded a brown solid, which was triturated with ether-hexane and collected by filtration. These procedures afforded the title compound (2.89 g, 70%) as an off-white solid. 1H NMR (300 MHz, DMSO-d6): δ 0.51 (m, 2 H) 0.64 (m, 6 H) 0.84 (m, 2 H) 1.84 (m, 2 H) 1.99 (m, 2 H) 5.80 (s, 1 H) 7.43 (m, 1 H) 7.57 (dd, J=9.56, 2.57 Hz, 1 H) 7.67 (d, J=5.52 Hz, 1 H) 11.75 (s, 1 H).
Reaction SMILES: [NH2:1][C:2]1[N:34]=[C:5]2[N:6]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=3)[C:7]([CH3:23])=[C:8]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:9]([C:10]3[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][CH:11]=3)[N:4]2[N:3]=1.C1COCC1.Cl[C:41]([O:43][CH3:44])=[O:42]>N1C=CC=CC=1>[C:16]([C:13]1[CH:14]=[CH:15][C:10]([CH:9]2[N:4]3[N:3]=[C:2]([NH:1][C:41]([O:43][CH3:44])=[O:42])[N:34]=[C:5]3[N:6]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:31])([F:33])[F:32])[CH:25]=3)[C:7]([CH3:23])=[C:8]2[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:11][CH:12]=1)#[N:17]
Reactant: CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)c2nc(N)nn2C1c1ccc(C#N)cc1
Reactant: COC(=O)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)c2nc(NC(=O)OC)nn2C1c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Under an atmosphere of argon protective gas, ethyl 2-amino-7-(4-cyanophenyl)-5-methyl-4-[3-(trifluoromethyl)phenyl]-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxylate (10 mg, 21 μmol) was dissolved in a mixture of abs. THF (3 ml) and abs. pyridine (3 ml). At 0° C., methyl chloroformate (17 mg, 180 μmol, 8.5 eq.) was added in two portions and the mixture was stirred for 12 h with warming to RT. Once HPLC analysis showed substantial conversion, the reaction mixture was concentrated under reduced pressure and purified by preparative HPLC (Gromsil C18 column, 30×250 mm; mobile phase: acetonitrile-water-0.1% TFA). After lyophilization, the product was obtained as a solid (10.8 mg, 96% of theory).
Reaction SMILES: [CH2:1]([C@@H:8]([CH2:12][CH2:13][C@H:14]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][S:22][C@H:21]2[CH2:25][CH2:26][CH2:27][C@@H:28]([C:29]([O:31][CH3:32])=[O:30])[N:20]2[C:19]1=[O:33])=[O:16])[C:9](O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:42][C@H:43]1[CH2:49][CH2:48][CH2:47][CH2:46][N:45]([CH2:50][C:51]2[CH:56]=[CH:55][CH:54]=[C:53]([Cl:57])[CH:52]=2)[C:44]1=[O:58]>>[CH2:34]([C@@H:14]([CH2:13][CH2:12][C@H:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]([NH:42][C@H:43]1[CH2:49][CH2:48][CH2:47][CH2:46][N:45]([CH2:50][C:51]2[CH:56]=[CH:55][CH:54]=[C:53]([Cl:57])[CH:52]=2)[C:44]1=[O:58])=[O:10])[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][S:22][C@H:21]2[CH2:25][CH2:26][CH2:27][C@@H:28]([C:29]([O:31][CH3:32])=[O:30])[N:20]2[C:19]1=[O:33])=[O:16])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)O)Cc3ccccc3)C(=O)N21
Reactant: N[C@H]1CCCCN(Cc2cccc(Cl)c2)C1=O
Agent: Cl
Product: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)N[C@H]3CCCCN(Cc4cccc(Cl)c4)C3=O)Cc3ccccc3)C(=O)N21

Procedure:
(4S,7S,10aS)-Methyl 4-((2R,5R)-2,5-dibenzyl-6-((S)-1-(3-chlorobenzyl)-2-oxoazepan-3-ylamino)-6-oxohexanamido)-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepine-7-carboxylate was synthesized as described in General Procedure H using Intermediate 23 (7.0 mg, 0.012 mmol) and Intermediate 47 (3.6 mg, 0.012 mmol) to give a white solid (7.0 mg, 69% yield). Anal. Calcd. for C44H53ClN4O6S m/z 800.4. found: 801.4 (M+H)+; 1H NMR (500 MHz, CDCl3) δ ppm 7.25-7.19 (m, 7H), 7.18-7.12 (m, 6H), 7.10 (d, J=4.40 Hz, 1H), 6.96 (d, J=6.60 Hz, 1H), 6.92 (d, J=6.60 Hz, 1H), 5.33 (t, J=4.67 Hz, 1H), 5.17-5.12 (m, 1H), 5.03-4.93 (m, 1H), 4.64 (d, J=14.85 Hz, 1H), 4.59 (dd, J=10.45, 6.60 Hz, 1H), 4.42 (d, J=14.85 Hz, 1H), 3.67 (s, 3H), 3.49 (dd, J=15.40, 11.55 Hz, 1H), 3.24-3.09 (m, 2H), 2.90-2.78 (m, 3H), 2.77-2.68 (m, 2H), 2.45-2.34 (m, 3H), 2.02 (d, J=5.50 Hz, 2H), 1.90-1.79 (m, 2H), 1.72 (br. s., 4H), 1.68-1.49 (m, 8H).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.CC(C)=O.[SH2]=N.[C:17]1([NH:23][C:24](C2C=CC=CC=2C(O)=O)=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O>[C:17]1([NH:23][C:24]([N:2]2[CH2:3][CH2:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:1]2)=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(O)c1ccccc1C(=O)Nc1ccccc1
Reactant: c1ccc2c(c1)CCNC2
Agent: N=[SH2]
Solvent: O
Solvent: CC(C)=O
Product: O=C(Nc1ccccc1)N1CCc2ccccc2C1
Temperature: 5 °C
Reaction time: 0.75 h
Yield: 90.5 %

Procedure:
A solution of 1.35 g 1,2,3,4-tetrahydroisoquinoline with 5 ml aceton was added dropwise to a suspension of 1.5 g phenylcarbamoyl-benzoic acid sulfimide with 20 ml aceton, at ambient temperature. The reaction mixture was stirred for 45 minutes, then diluted with 150 ml water, cooled to 5° C. and the precipitated crystalline product was filtered, washed with water and dried. 1.18 g N-phenylcarbamoyl-1,2,3,4-tetrahydroisoquinoline was obtained with a melting point of 145°-146° C.
Reaction SMILES: C([O:8][CH2:9][CH2:10][CH2:11][C:12]1[N:13]=[C:14]([C:32]2[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][CH:33]=2)[S:15][C:16]=1[CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[NH:29][C:28](=[O:30])[O:27][N:26]=2)=[C:21]([F:31])[CH:20]=1)C1C=CC=CC=1.B(Br)(Br)Br.ClCCl.CC(C)=O.C([O-])(O)=O.[Na+]>ClCCl.CO>[F:31][C:21]1[CH:20]=[C:19]([O:18][CH2:17][C:16]2[S:15][C:14]([C:32]3[CH:37]=[CH:36][C:35]([C:38]([F:40])([F:41])[F:39])=[CH:34][CH:33]=3)=[N:13][C:12]=2[CH2:11][CH2:10][CH2:9][OH:8])[CH:24]=[CH:23][C:22]=1[C:25]1[NH:29][C:28](=[O:30])[O:27][N:26]=1
Reactant: O=c1[nH]c(-c2ccc(OCc3sc(-c4ccc(C(F)(F)F)cc4)nc3CCCOCc3ccccc3)cc2F)no1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: CC(C)=O
Product: O=c1[nH]c(-c2ccc(OCc3sc(-c4ccc(C(F)(F)F)cc4)nc3CCCO)cc2F)no1
Reaction time: 1 h

Procedure:
To a stirred solution of 100 mg of 3-{4-[4-(3-benzyloxy-propyl)-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-2-fluoro-phenyl}-4H-[1,2,4]oxadiazol-5-one in 3 mL of dichloromethane at −70° C. was added 0.34 mL of a 1M solution of boron tribromide in dichloromethane. After 1 h at −60° C., TLC monitoring (dichloromethane/acetone 8/2) showed remaining starting material so 1 mL of a 1M solution of boron tribromide in dichloromethane was added. After 10 min, the reaction mixture was poured into 30 mL of methanol and was neutralised with 5 mL of a saturated aqueous solution of NaHCO3. The suspension was filtered and the filtrate was concentrated under reduced pressure. The residue was taken up into dichloromethane then water added. The aqueous layer was separated and extracted three times with dichloromethane. The combined organic layers were dried over magnesium sulfate, filtered and concentrated under reduced pressure to give 60 mg of crude product. Purification by column chromatography on silica gel (dichloromethane 1/acetone 1) gave 13 mg of a first batch of the title compound (purity >95%) and 50 mg of a second batch of the title compound (purity >90%). The second batch was repurified by column chromatography on silica gel (dichloromethane 90/methanol 10). A total of 48 mg of 3-{2-fluoro-4-[4-(3-hydroxy-propyl)-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-phenyl}-4H-[1,2,4]oxadiazol-5-one was obtained.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5](=[O:8])[O:6][CH3:7].[Br:9][CH2:10][C:11](Br)=[O:12]>>[Br:9][CH2:10][C:11]([O:1][CH2:2][CH2:3][NH:4][C:5](=[O:8])[O:6][CH3:7])=[O:12]
Reactant: COC(=O)NCCO
Reactant: O=C(Br)CBr
Product: COC(=O)NCCOC(=O)CBr

Procedure:
by using methyl 2-hydroxyethylcarbamate and bromoacetyl bromide there is obtained methyl 2-bromoacetoxyethylcarbamate, nD20 1.4891;
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[I:9][C:10]1[CH:19]=[CH:18]C2C(=CC=CC=2)N=1.N1C2C(=CC=CC=2)C=CC=1>>[Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:3]=1[N:4]=[CH:18][CH:19]=[C:10]2[I:9]
Reactant: Ic1ccc2ccccc2n1
Reactant: Nc1ccccc1Br
Solvent: c1ccc2ncccc2c1
Product: Brc1cccc2c(I)ccnc12

Procedure:
8-bromo-4-iodoquinoline 43a is synthesized from 2-bromoaniline using the same protocols as those described for the preparation of iodoquinoline fragment 1i in Example 1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[N:8]2.[Sn](Cl)Cl>Cl>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([NH2:13])=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[N:8]2
Reactant: COc1ccc([N+](=O)[O-])c2ncccc12
Agent: Cl
Agent: Cl[Sn]Cl
Product: COc1ccc(N)c2ncccc12
Yield: 91.8 %

Procedure:
In a similar fashion using route 2 general procedure 4, 5-methoxy-8-nitroquinoline (Intermediate 66) (550 mg, 2.69 mmol), tin (II) chloride (1.53 mg, 8.07 mmol) and 6 N HCl (3 drops) gave the title compound (430 mg, 91%).
Reaction SMILES: [CH:1]1([NH:7][C:8]2[N:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:10]=[C:11]3[C:16]=2[CH:15]=[CH:14][CH:13]=[CH:12]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:23]([O:25][C:26](=[O:36])[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([N:33]=[C:34]=[O:35])[CH:28]=1)C>C1(C)C=CC=CC=1>[CH3:23][O:25][C:26](=[O:36])[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([NH:33][C:34]([N:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:8]2[N:9]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:10]=[C:11]3[C:16]=2[CH:15]=[CH:14][CH:13]=[CH:12]3)=[O:35])[CH:28]=1
Reactant: CCOC(=O)c1cccc(N=C=O)c1
Reactant: c1ccc(-n2nc3ccccc3c2NC2CCCCC2)cc1
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc(NC(=O)N(c2c3ccccc3nn2-c2ccccc2)C2CCCCC2)c1

Procedure:
In analogy to the procedure described in example 1.2, cyclohexyl-(2-phenyl-2H-indazol-3-yl)-amine (example 1.1) was reacted with 3-isocyanato-benzoic acid ethyl ester ([41221-47-0]) in toluene for 72 h under reflux conditions to give the title compound as yellow oil. MS: m/e=469.3 [M+H+].
Reaction SMILES: C([O:4][CH:5]1[CH2:10][N:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:8][CH:7]=[CH:6]1)(=O)C.[OH-].[Na+].C(O)(=O)C>CCO>[OH:4][CH:5]1[CH2:10][N:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:8][CH:7]=[CH:6]1
Reactant: CCOC(=O)N1CC=CC(OC(C)=O)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)N1CC=CC(O)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 100.9 %

Procedure:
To a solution of Compound 239B (10.5 g, 49.2 mmol) in 30 mL of EtOH was added a solution of 0.2N NaOH in EtOH (65 mL) and the mixture was stirred at 0° C. for 30 min. After warming to room temperature, the reaction mixture was neutralized with glacial acetic acid. Concentration in vacuo afforded 8.5 g of 239C as an oil. 1H-NMR (400 MHz, CDCl3): 5.90 (m, 1H), 5.82 (bs, 1H), 4.20 (bs, 1H), 4.18 (q, J=7.08, 2H), 4.04 (m, 1H), 3.85 (m, 1H), 3.55 (m, 2H), 1.28 (t, J=7.08, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:16]C)=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH:8]=[C:7]2[CH2:13][CH2:14][OH:15].B(Br)(Br)Br>O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:16])=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH:8]=[C:7]2[CH2:13][CH2:14][OH:15]
Reactant: COc1ccc(Br)c2[nH]c(=O)cc(CCO)c12
Agent: BrB(Br)Br
Solvent: O
Product: O=c1cc(CCO)c2c(O)ccc(Br)c2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.6 %

Procedure:
To a stirred solution of 8-bromo-4-(2-hydroxyethyl)-5-methoxyquinolin-2(1H)-one (2.7 g; 9.06 mmol) at −78° C. was added a solution of boron tribromide (1M in DCM) (55 ml; 55 mmol) dropwise. After 1 h the reaction mixture was allowed to warm up to room temperature and the stirring was carried out for 20 h. The reaction mixture was mixed with ice and water, the solid formed was isolated by filtration and dried over phosphorus pentoxide under reduced pressure to afford 1.56 g (45%) of 8-bromo-5-hydroxy-4-(2-hydroxyethyl)quinolin-2(1H)-one. The crude solid was used in the next step without further purification.
Reaction SMILES: [CH:1]1([S:4]([NH:7][C:8]([C@@:10]23[CH2:25][C@H:24]2[CH:23]=[CH:22][CH:21]([CH3:26])[CH2:20][CH2:19][CH2:18][C@@H:17]([CH3:27])[C@H:16]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[C:15](=[O:36])[N:14]2[CH2:37][C@H:38]([OH:40])[CH2:39][C@H:13]2[C:12](=[O:41])[NH:11]3)=[O:9])(=[O:6])=[O:5])[CH2:3][CH2:2]1.Cl[C:43]1[C:52]2[C:47](=[C:48]([Cl:53])[CH:49]=[CH:50][CH:51]=2)[C:46]([O:54][CH3:55])=[CH:45][N:44]=1.CC([O-])(C)C.[K+]>CS(C)=O>[Cl:53][C:48]1[CH:49]=[CH:50][CH:51]=[C:52]2[C:47]=1[C:46]([O:54][CH3:55])=[CH:45][N:44]=[C:43]2[O:40][C@H:38]1[CH2:37][N:14]2[C:15](=[O:36])[C@@H:16]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:33])([CH3:34])[CH3:32])[C@H:17]([CH3:27])[CH2:18][CH2:19][CH2:20][CH:21]([CH3:26])[CH:22]=[CH:23][C@@H:24]3[CH2:25][C@@:10]3([C:8](=[O:9])[NH:7][S:4]([CH:1]3[CH2:3][CH2:2]3)(=[O:6])=[O:5])[NH:11][C:12](=[O:41])[C@@H:13]2[CH2:39]1
Reactant: COc1cnc(Cl)c2cccc(Cl)c12
Reactant: CC1C=C[C@@H]2C[C@@]2(C(=O)NS(=O)(=O)C2CC2)NC(=O)[C@@H]2C[C@@H](O)CN2C(=O)[C@@H](NC(=O)OC(C)(C)C)[C@H](C)CCC1
Agent: CC(C)(C)[O-]
Agent: CC1/C=C\[C@@H]2C[C@@]2(C(=O)NS(=O)(=O)C2CC2)NC(=O)[C@@H]2C[C@@H](O)CN2C(=O)[C@@H](NC(=O)OC(C)(C)C)[C@H](C)CCC1
Agent: COc1cnc(O[C@@H]2C[C@H]3C(=O)N[C@]4(C(=O)NS(=O)(=O)C5CC5)C[C@H]4/C=C\C(C)CCC[C@@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N3C2)c2cccc(Cl)c12
Solvent: CS(C)=O
Product: COc1cnc(O[C@@H]2C[C@H]3C(=O)N[C@]4(C(=O)NS(=O)(=O)C5CC5)C[C@H]4C=CC(C)CCC[C@@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N3C2)c2cccc(Cl)c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl ((2R,6S,7R,13aS,14aR,16aS,Z)-14a-((cyclopropylsulfonyl)carbamoyl)-2-hydroxy-7,11-dimethyl-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate (500 mg, 0.8 mmol) and 1,5-dichloro-4-methoxyisoquinoline (230 mg, 1.0 mmol) in DMSO (5 mL) was added t-BuOK (1 M solution in THF, 450 mg, 4.0 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 2 h. The reaction mass was quenched with aqueous citric acid solution and extracted with ethyl acetate (150 mL×3). The combined organic layer was washed with water, brine solution, dried over anhydrous Na2SO4 and concentrated under reduced pressure to get crude compound as diastereomer mixture. MS: MS m/z 789.3 (M++1).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH2:11]([C:13]1[NH:14][C:15](=[O:18])[O:16][CH:17]=1)[CH3:12].C(N(CC)CC)C>C1C=CC=CC=1>[CH2:11]([C:13]1[N:14]([C:4](=[O:5])[C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=2[Cl:1])[C:15](=[O:18])[O:16][CH:17]=1)[CH3:12]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: CCc1coc(=O)[nH]1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCc1coc(=O)n1C(=O)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of o-chlorobenzoyl chloride (1.93 g.) and 4-ethyl-4-oxazolin-2-one (1.13 g.) in 30 ml. of benzene is cooled to 10° C. and reacted with 1.21 g. of triethylamine dissolved in 5 ml. of benzene. The reaction mixture is stirred at room temperature for 1 hour. The excess triethylamine and benzene is removed under reduced pressure to leave a light yellow oil (2.4 g.) which is triturated with ethanol whereupon a crystalline solid separates. The solid is removed and washed with a small amount of cold ethanol and dried. Yield 0.3 g.; m.p. 110°-112° C.
Reaction SMILES: Cl.[NH:2]1[CH2:6][CH2:5][C@@H:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[C:23]([F:25])[C:22]([O:26][CH3:27])=[CH:21][C:20]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3]1.[C:33](Cl)(=[O:35])[CH3:34]>>[C:33]([N:2]1[CH2:6][CH2:5][C@@H:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[C:23]([F:25])[C:22]([O:26][CH3:27])=[CH:21][C:20]=4[O:28][CH2:29][CH:30]4[CH2:31][CH2:32]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3]1)(=[O:35])[CH3:34]
Reactant: CC(=O)Cl
Reactant: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@@H]4CCNC4)c[nH]c23)cc1F
Agent: Cl
Product: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@@H]4CCN(C(C)=O)C4)c[nH]c23)cc1F

Procedure:
Starting from 4-(2-cyclopropylmethoxy-5-fluoro-4-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (R)-pyrrolidin-3-ylamide hydrochloride (example A169) and acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: Cl.C(OC1C=CC(S(Cl)(=O)=O)=CC=1[C:15]1[NH:20][C:19](=[O:21])[C:18]2=[C:22]([CH3:28])[N:23]=[C:24]([CH2:25][CH2:26][CH3:27])[N:17]2[N:16]=1)C>N1C=CC=CC=1.ClCCl>[CH3:28][C:22]1[N:23]=[C:24]([CH2:25][CH2:26][CH3:27])[N:17]2[C:18]=1[C:19](=[O:21])[NH:20][CH:15]=[N:16]2
Reactant: CCCc1nc(C)c2c(=O)[nH]c(-c3cc(S(=O)(=O)Cl)ccc3OCC)nn12
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCc1nc(C)c2c(=O)[nH]cnn12
Temperature: 0 °C
Reaction time: 8 h

Procedure:
110 mg (0.6 mmol) of 3-butylsydnoneimine hydrochoride are dissolved in 2.5 ml of pyridine and cooled to 0° C. 210 mg (0.5 mmol) of 4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonyl chloride are added, and the reaction mixture is stirred for 2 hours at 0° C. and overnight at room temperature. The mixture is diluted with dichloromethane, the organic phase is washed with water and dried over sodium sulphate and the solvent is removed under reduced pressure. Chromatography (dichloromethane/methanol) gives 16 mg (6%) of 2-[2-ethoxy-5-(3-butylsydnoneimine)-1-sulphonyl)-phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:11]2[CH:12]=[C:13]([Cl:16])[CH:14]=[CH:15][C:10]=2[O:9][C:8]2[CH:17]=[CH:18][CH:19]=[CH:20][C:7]=2[CH:6]=1)=[O:4].C(N=C(N(C)C)N(C)C)(C)(C)C.[N+:33]([CH3:36])([O-:35])=[O:34].Cl>C1COCC1.O.C(OC)(C)(C)C>[CH3:1][O:2][C:3]([C@@H:5]1[C:11]2[CH:12]=[C:13]([Cl:16])[CH:14]=[CH:15][C:10]=2[O:9][C:8]2[CH:17]=[CH:18][CH:19]=[CH:20][C:7]=2[C@H:6]1[CH2:36][N+:33]([O-:35])=[O:34])=[O:4]
Reactant: COC(=O)C1=Cc2ccccc2Oc2ccc(Cl)cc21
Reactant: C[N+](=O)[O-]
Agent: CN(C)C(=NC(C)(C)C)N(C)C
Agent: Cl
Solvent: COC(C)(C)C
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1c2cc(Cl)ccc2Oc2ccccc2[C@H]1C[N+](=O)[O-]

Procedure:
To a 5 L 3-neck round bottom flask was added 8-chloro-dibenz[b,f]-oxepin-10-carboxylic acid methyl ester (305 g, 1.06 mol, 1 eq) followed by THF (1.25 L) and t-butyl-tetramethylguanidine (27 g, 0.15 mol, 0.14 eq). To this solution was added nitromethane (576 g, 9.45 mol, 8.9 eq) in THF (0.5 L) while maintaining a temperature of less than 30° C. The resultant mixture was stirred at room temperature until judged complete by HPLC (overnight, <3% starting material). Once complete, methyl tertiary butyl ether (1.25 L), water (0.6 L) and 1 N HCl (0.6 L) were added, the layers were separated, and the aqueous layer was extracted a second time with MTBE (1 L). The combined organic layers were washed with 1 N HCl (2×0.6 L) and saturated sodium chloride (0.6 L). After addition of toluene (2 L) the organic fraction was concentrated under vacuum to a volume less than 2 L, toluene (1 L) was added, and the mixture was concentrated to minimum volume. Addition of THF (0.5 L) afforded the titled compound as a light colored solution which was used without further purification (368 g, 1.06 mol, theoretical). HPLC area %: 45% toluene, 48% trans-nitro ester, 6% cis-nitro ester, 1% starting material. HPLC conditions: column-3.5 μm Zorbax SB-Phenyl, 3 mm×150 mm; solvent- gradient from 55% water (0.1% HOCl4)/45% methanol (0.1% HOCl4) to 100% methanol (0.1% HOCl4) in 10 minutes and hold for 2 minutes; flow 0.5 mL/minute; detection at 210 nm.
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=3[O:20][CH3:21])[C:14](O)=[O:15])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[OH:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][C:30]=1[OH:31])[CH2:26][NH2:27]>>[C:1]12([C:11]3[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=3[O:20][CH3:21])[C:14]([NH:27][CH2:26][C:25]3[CH:28]=[CH:29][C:30]([OH:31])=[C:23]([OH:22])[CH:24]=3)=[O:15])[CH2:10][CH:5]3[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]3)[CH2:8]1)[CH2:2]2
Reactant: NCc1ccc(O)c(O)c1
Reactant: COc1ccc(C(=O)O)cc1C12CC3CC(CC(C3)C1)C2
Product: COc1ccc(C(=O)NCc2ccc(O)c(O)c2)cc1C12CC3CC(CC(C3)C1)C2

Procedure:
0.02 g of the target compound is obtained as solid of a light color in substantially the same manner as in (2) of Example 1, except for using 3-adamantan-1-yl-4-methoxybenzoic acid instead of 5-adamantan-1-yl-2,4-dihydroxybenzoic acid and using 3,4-dihydroxybenzylamine instead of dopamine.
Reaction SMILES: [CH3:1][N:2]1[C:6]([OH:7])=[C:5]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])[C:4]([CH3:16])=[N:3]1.[Cl:17][C:18]1[N:23]=[C:22](Cl)[CH:21]=[CH:20][N:19]=1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[CH3:1][N:2]1[C:6]([O:7][C:20]2[CH:21]=[CH:22][N:23]=[C:18]([Cl:17])[N:19]=2)=[C:5]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])[C:4]([CH3:16])=[N:3]1
Reactant: Cc1nn(C)c(O)c1Sc1ccccc1Cl
Reactant: Clc1ccnc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: Cc1nn(C)c(Oc2ccnc(Cl)n2)c1Sc1ccccc1Cl
Yield: 76.2 %

Procedure:
A mixture of 2.4 g (10 mmol) of 1,3-dimethyl-4-(2-chlorophenylthio)-5-hydroxypyrazole, 1.5 g (10 mmol) of 2,4-dichloropyrimidine and 1.5 g (11 mmol) of potassium carbonate was refluxed for 1 hour in 10 ml of acetonitrile. After completing the reaction, the reaction mixture was poured into water, extracted with ethyl acetate and dried. Then the organic layer was concentrated. The residue was purified by means of silica gel column chromatography (developing solution: ethyl acetate-hexane (3:1 v/v)) to give 2.8 g of 1,3-dimethyl-4-(2-chlorophenylthio)-5-(2-chloropyrimidine-4-yloxy)pyrazole
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][NH2:7].[C:11](OC(=O)C)(=[O:13])[CH3:12].O.C(OCC)(=O)C>N1C=CC=CC=1>[Br:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][NH:7][C:11](=[O:13])[CH3:12]
Reactant: NCc1cccc(Br)c1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(=O)NCc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 3-bromobenzylamine hydrochloride (5.20 g) in pyridine (30 ml) was added acetic anhydride (3.2 ml) at 0° C. and the mixture was stirred at room temperature for 24 h. Water and ethyl acetate were added to the reaction mixture for partitioning, and the organic layer was washed with 1N hydrochloric acid, aqueous sodium hydrogen carbonate and brine, dried (magnesium sulfate) and concentrated under reduced pressure. The residue was recrystallized from hexane-ethyl acetate to give the title compound (4.00 g) as colorless needle crystals.