Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:10]=1B(O)O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br.Br[C:30]1[CH:35]=[CH:34][N:33]=[N:32][CH:31]=1>O1CCOCC1.O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:10]=1[C:30]1[CH:35]=[CH:34][N:33]=[N:32][CH:31]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1cc(C(F)(F)F)ccc1OCc1ccccc1
Reactant: Brc1ccnnc1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: FC(F)(F)c1ccc(OCc2ccccc2)c(-c2ccnnc2)c1
Reaction time: 3 h

Procedure:
([2-(benzyloxy)-5-(trifluoromethyl)phenyl]boronic acid (3.72 g, 0.0126 mol) and caesium carbonate (8.9 g, 0.0273 mol) were suspended in 1,4 dioxane (40.0 mL) and water (20.0 mL). The reaction was degassed twice before being brought to 80° C. under nitrogen. Then 4-bromopyridazine hydrobromide (Preparation see above, 2.52 g, 0.0105 mol) and palladium tetrakistriphenylphosphine (0.62 g, 0.000537 mol) were added to the reaction and it was stirred for three hours. The reaction was concentrated in vacuo to 20.0 mL, and partitioned between ethyl acetate (70.0 mL) and saturated aqueous brine (50.0 mL). The two layers were filtered over arbocel™ to remove a fine black solid. Then the organic layer was washed with more saturated aqueous brine (2×50.0 mL) and it was dried over sodium sulphate. The solvents were concentrated in vacuo and crude was purified using ISCO™ (using a gradient of 0-50% ethyl acetate in heptane, 80 g SiO2) to afford the title compound as a light orange solid.
Reaction SMILES: [Cl:1][C:2]([Cl:30])([Cl:29])[CH2:3][O:4][C:5](=[O:28])[C:6]([N:10]1[C@H:13]([S:14]SC2SC3C=CC=CC=3N=2)[C@@H:12]([O:25][CH3:26])[C:11]1=[O:27])=[C:7]([CH3:9])[CH3:8].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CC=CC=1.[C:56](OC(=O)C)(=[O:58])[CH3:57]>C(O)(=O)C>[Cl:30][C:2]([Cl:1])([Cl:29])[CH2:3][O:4][C:5](=[O:28])[C:6]([N:10]1[C@H:13]([S:14][C:56](=[O:58])[CH3:57])[C@@H:12]([O:25][CH3:26])[C:11]1=[O:27])=[C:7]([CH3:8])[CH3:9]
Reactant: CC(=O)OC(C)=O
Reactant: CO[C@H]1C(=O)N(C(C(=O)OCC(Cl)(Cl)Cl)=C(C)C)[C@@H]1SSc1nc2ccccc2s1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: CC(=O)O
Product: CO[C@H]1C(=O)N(C(C(=O)OCC(Cl)(Cl)Cl)=C(C)C)[C@@H]1SC(C)=O
Reaction time: 1.25 h

Procedure:
A solution of 3.26 g of 2-[(3S,4R)-4-(benzthiazol-2-yldithio)-3-methoxy-2-oxoazetidin-1-yl]-3-methylcrotonic acid 2,2,2-trichloroethyl ester in 36.3 ml of acetic anhydride and 12.4 ml of acetic acid is cooled to -15° and 1.7 g of triphenylphosphine are added. After stirring under nitrogen at the same temperature for 75 minutes, 24.8 ml of pyridine are added to the mixture. After stirring for a further 3 hours at 0°, the reaction mixture is concentrated by evaporation under reduced pressure and the resulting residue is purified by chromatography over silica gel with toluene and toluene/ethyl acetate (19:1). IR spectrum (in methylene chloride): characteristic absorption bands at 3.40, 5.63, 5.77, 5.80, 6.13, 7.25, 7.35, 8.26, 9.0, 9.52 and 11.90μ.
Reaction SMILES: [C:1]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][C:4]([C:7](=[N:9][O:10][CH2:11][CH2:12][OH:13])[CH3:8])=[CH:3][CH:2]=1.O[C:21]1[CH:53]=[CH:52][C:24]([CH2:25][CH:26]2[O:30][C:29](=[O:31])[N:28]([C:32]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]2=[O:51])=[CH:23][CH:22]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCNCC1)=O)=NC(N1CCNCC1)=O>>[C:1]1([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:6]=[CH:5][C:4]([C:7](=[N:9][O:10][CH2:11][CH2:12][O:13][C:21]2[CH:53]=[CH:52][C:24]([CH2:25][CH:26]3[O:30][C:29](=[O:31])[N:28]([C:32]([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)([C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=4)[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[C:27]3=[O:51])=[CH:23][CH:22]=2)[CH3:8])=[CH:3][CH:2]=1
Reactant: O=C1OC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(=NOCCO)c1ccc(-c2ccccc2)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCNCC1)N1CCNCC1
Product: CC(=NOCCOc1ccc(CC2OC(=O)N(C(c3ccccc3)(c3ccccc3)c3ccccc3)C2=O)cc1)c1ccc(-c2ccccc2)cc1
Yield: 50.7 %

Procedure:
Following a procedure similar to that described in Example 3(a), but using 0.23 g of 2-[1-(4-biphenylyl)-ethylideneaminooxy]ethanol (prepared as described in Preparation 15), 0.40 g of 5-(4-hydroxybenzyl)-3-trityloxazolidine-2,4-dione, 0.40 g of tributylphosphine and 0.50 g of 1,1'-(azodicarbonyl)dipiperazine, 0.31 g of the title compound was obtained as a crystalline powder, melting at 193°-195° C.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([C:22]2[CH:27]=[CH:26][C:25]([S:28][CH:29]3[CH2:31][CH2:30]3)=[CH:24][CH:23]=2)[C:8](N([C@H](C)[C@H](O)C2C=CC=CC=2)C)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.S(=O)(=O)(O)[OH:33]>O1CCOCC1.O>[CH:1]1([CH2:6][C@H:7]([C:22]2[CH:27]=[CH:26][C:25]([S:28][CH:29]3[CH2:31][CH2:30]3)=[CH:24][CH:23]=2)[C:8]([OH:9])=[O:33])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=S(=O)(O)O
Reactant: C[C@H]([C@H](O)c1ccccc1)N(C)C(=O)[C@H](CC1CCCC1)c1ccc(SC2CC2)cc1
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)[C@H](CC1CCCC1)c1ccc(SC2CC2)cc1
Temperature: 105 °C
Yield: 59 %

Procedure:
A solution of (R)-3-cyclopentyl-2-(4-cyclopropylsulfanyl-phenyl)-N-((1R,2R)-2-hydroxy-1-methyl-2-phenyl-ethyl)-N-methyl-propionamide (715 mg, 1.63 mmol) in dioxane (5 mL) was treated with a 9 N aqueous sulfuric acid solution (1.3 mL). The resulting solution was then heated at 105° C. for 16 h. The reaction was then cooled and diluted with water (13 mL) and extracted with a chloroform/methanol solution (3:2, 3×20 mL) and then combined the organic extracts dried over magnesium sulfate, filtered and concentrated. Purification on an AnaLogix Intelliflash system (12 g column, 10% ethyl acetate/hexanes to 80% ethyl acetate/hexanes) afforded (R)-3-cyclopentyl-2-(4-cyclopropylsulfanyl-phenyl)-propionic acid (278 mg, 59%) as a white solid: [α]25589=−52.6° (c=0.19, methanol); ES-HRMS m/e calcd for C17H22O2S (M−H)− 289.1268, observed 289.1268; 1H NMR (300 MHz, CDCl3) δ 1.61-2.05 (m, 4H, 2×CH2), 2.45 (s, 3 H, ArCH3), 3.76 (m, 2H, OCH2), 4.00 (m, 2H, SO3CH2), 4.08 (m, 1H, OCH), 7.35 (brd, 2H, Ar), 7.81 (brd, 2H, Ar).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Se:5]1[C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=[C:6]1[C:13]([OH:15])=[O:14].S(=O)(=O)(O)O>>[N+:1]([C:7]1[CH:8]=[C:9]([C:10]([OH:12])=[O:11])[Se:5][C:6]=1[C:13]([OH:15])=[O:14])([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)c1ccc(C(=O)O)[se]1
Agent: O=S(=O)(O)O
Product: O=C(O)c1cc([N+](=O)[O-])c(C(=O)O)[se]1
Reaction time: 2 h

Procedure:
Nitric acid (5.65 mL, 125.55 mmol, 70%) was added slowly to a mixture of selenophene-2,5-dicarboxylic acid (11 g, 50.2 mmol) in sulfuric acid (21.87 mL, 401.77 mmol) at 0-5° C. for 15 min. The mixture was allowed to rt with stifling slowly for 2 h, poured into ice cold water and stirred for 30 min. The solution was extracted with ethyl acetate (3×200 mL) and the combined organic layer was washed with water, brine and dried over sodium sulfate. The solution was filtered and evaporated the solvent to give the product as pale yellow color solid (10 g, 76%, it is a mixture of 2 compounds).
Reaction SMILES: C([O:3][C:4](=[O:28])[CH2:5][S:6][C:7]1[S:11][C:10]([NH:12][C:13]([N:15]([CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[O:14])=[N:9][CH:8]=1)C.[C:29]([N:36]1[CH2:41]CCC[C:37]1=O)(OC(C)(C)C)=[O:30].C1(N)CCCCC1.C(OC(=O)CSC1SC(N)=NC=1)C.CN(C)C(Cl)=O>>[CH:22]1([N:15]([CH:16]2[CH2:21][CH2:20][N:19]([C:29](=[O:30])[N:36]([CH3:41])[CH3:37])[CH2:18][CH2:17]2)[C:13](=[O:14])[NH:12][C:10]2[S:11][C:7]([S:6][CH2:5][C:4]([OH:3])=[O:28])=[CH:8][N:9]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: CC(C)(C)OC(=O)N1CCCCC1=O
Reactant: CCOC(=O)CSc1cnc(NC(=O)N(C2CCCCC2)C2CCNCC2)s1
Agent: CCOC(=O)CSc1cnc(N)s1
Agent: CN(C)C(=O)Cl
Solvent: NC1CCCCC1
Product: CN(C)C(=O)N1CCC(N(C(=O)Nc2ncc(SCC(=O)O)s2)C2CCCCC2)CC1

Procedure:
{2-[3-Cyclohexyl-3-piperidin-4-yl-ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester was pre-pared in a similar manner to the synthesis of example 12 from N-Boc piperidone, cyclohexyl-amine and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester, Boc deprotection, reaction with dimethylcarbamoyl chloride and hydrolysis of the ester moiety as described in general procedure (I) gave the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([S:8][CH2:9][C:10](OCC)=[O:11])[N:5]=[C:4]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[CH:3]=1.O.[NH2:25][NH2:26].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:5]=[C:6]([S:8][CH2:9][C:10]([NH:25][NH2:26])=[O:11])[N:7]=1
Reactant: NN
Reactant: CCOC(=O)CSc1nc(Cl)cc(NCc2ccc(Cl)cc2)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: NNC(=O)CSc1nc(Cl)cc(NCc2ccc(Cl)cc2)n1

Procedure:
A stirred mixture of 1.1 g of (6-chloro-4-p-chlorobenzylamino-2pyrimidinylthio)acetic acid, ethyl ester 0.18 g of hydrazine hydrate (98%) and 0.3 g of sodium carbonate in 15 ml. of ethanol was heated under reflux for 3 hr. The reaction mixture was filtered and the filtrate diluted with water until a precipitate appeared. The solid was washed with aqueous (10%) sodium carbonate then recrystallized from ethanol to a mp. of 178-182°C.
Reaction SMILES: [CH3:1][O:2][CH2:3]Cl.O1CCCC1.[Br:10][C:11]1[N:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1.[H-].[Na+]>O>[Br:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:1][O:2][CH3:3])=[CH:15][N:16]=1
Reactant: Oc1ccc(Br)nc1
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COCOc1ccc(Br)nc1

Procedure:
Methoxymethyl chloride (73 ml) was added to a tetrahydrofuran (1.3 L) solution of the obtained 6-bromo-3-pyridinol (129 g), and sodium hydride (30% liquid paraffin added) (32 g) was added at an inner temperature not to be over −10° C. Water was added, extracted with ethyl acetate, and the organic layer was washed with saturated saline water. After dried, the solvent was evaporated away under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate=9/1 to 8/1) to obtain the entitled compound (105 g) as a colorless oil.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([CH3:13])([CH3:12])[C:9]([NH2:11])=[O:10])[CH:5]=[CH:4][CH:3]=1.[NH2:14][C:15]1[S:16][C:17]([C:23]2[C:28]([F:29])=[CH:27][C:26]([C:30]([OH:33])([CH3:32])[CH3:31])=[CH:25][C:24]=2[F:34])=[CH:18][C:19]=1[C:20]([NH2:22])=[O:21]>>[NH2:11][C:9](=[O:10])[C:8]([C:6]1[N:7]=[C:2]([NH:14][C:15]2[S:16][C:17]([C:23]3[C:24]([F:34])=[CH:25][C:26]([C:30]([OH:33])([CH3:31])[CH3:32])=[CH:27][C:28]=3[F:29])=[CH:18][C:19]=2[C:20]([NH2:22])=[O:21])[CH:3]=[CH:4][CH:5]=1)([CH3:13])[CH3:12]
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Reactant: CC(C)(C(N)=O)c1cccc(Br)n1
Product: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(Nc3cccc(C(C)(C)C(N)=O)n3)s2)c(F)c1

Procedure:
The title compound was prepared according to the procedure described in Example 1 using 2-(6-bromopyridin-2-yl)-2-methylpropanamide (117 mg, 0.48 mmol) and 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (150 mg, 0.48 mmol) as starting materials.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].Cl.[CH2:8]([O:15][CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C([O-])([O-])=O.[K+].[K+].O>C(Cl)(Cl)Cl>[CH2:5]([O:4][C:2]([N:19]1[CH2:18][CH2:17][CH:16]([O:15][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:21][CH2:20]1)=[O:3])[CH3:6]
Reactant: c1ccc(COC2CCNCC2)cc1
Reactant: CCOC(=O)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCOC(=O)N1CCC(OCc2ccccc2)CC1
Reaction time: 1 h

Procedure:
3,4 g (0.033 mol) of ethyl chloroformate are added dropwise to a stirred mixture of 6.83 g (0.03 mol) of 4-benzyloxypiperidine hydrochloride, 7.74 g (0.056 mol) of dry K2CO3, 26 ml of water and 26 ml of chloroform. After stirring for 1 hour, the organic phase is decanted after dilution with 54 ml of chloroform, and washed 3 times with 20 ml of water and dried (MgSO4). Evaporation of the solvent in vacuo gives a liquid, which is distilled in vacuo.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH:30]=O)=[C:5]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:6]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=2)[C:7]=1[C:8]([O:10][CH2:11][CH2:12][O:13][CH2:14][CH3:15])=[O:9].Cl.[NH2:33]O.C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>C(O)(=O)C>[CH3:1][C:2]1[NH:3][C:4]([C:30]#[N:33])=[C:5]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:6]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=2)[C:7]=1[C:8]([O:10][CH2:11][CH2:12][O:13][CH2:14][CH3:15])=[O:9]
Reactant: CCOCCOC(=O)C1=C(C)NC(C=O)=C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CCOCCOC(=O)C1=C(C)NC(C#N)=C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.3 %

Procedure:
A mixture of 2-ethoxyethyl 2-methyl-4-(3-nitrophenyl)-5-ethoxycarbonyl-6-formyl-1,4-dihydropyridine-3-carboxylate (3.00 g), hydroxylamine hydrochloride (0.5547 g), sodium acetate (1.1382 g) in acetic acid (10 ml) was stirred for 30 minutes at room temperature. To this mixture was added acetic anhydride (1.4 ml) and the resultant mixture was stirred for an hour at room temperature and refluxed for an hour. The acetic acid was distilled off under reduced pressure, and to the residue was added water. The resultant mixture was neutrallized with an aqueous solution of sodium bicarbonate and extracted with ethyl acetate twice. The extract was washed with water and an aqueous solution saturated with sodium chloride and dried. The solvent was distilled off and thus obtained viscous oily substance (3.19 g) was subjected to column chromatography on silica gel with an eluent [a mixture of 5 parts of benzene and one part of ethyl acetate by volume] and a yellow oil (1.74 g) was obtained from the fraction which contained the designated product. The oil turned into crystals (1.56 g). These crystals were recrystallized from benzene to give yellow powder (1.5 g) of 2-ethoxyethyl 2-methyl-4-(3-nitrophenyl)-5-ethoxycarbonyl-6-cyano-1,4-dihydropyridine-3-carboxylate.1/3benzene, m.p. 89° to 91° C. Thus obtained yellow powder was further recrystallized from a mixture of diethyl ether and n-hexane to give crystals of 2-ethoxyethyl 2-methyl-4-(3-nitrophenyl)-5-ethoxycarbonyl-6-cyano-1,4-dihydropyridine-3-carboxylate, m.p. 115° to 116° C.
Reaction SMILES: [Br:1][C:2]1[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[CH:8]=[C:7]2[C:3]=1[CH2:4][N:5]([CH2:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[CH:19][CH:18]=1)[C:6]2=[O:15].[C:26]1([NH2:33])[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[NH2:32].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C>[NH2:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[NH:33][C:21](=[O:22])[C:20]1[CH:24]=[CH:25][C:17]([CH2:16][N:5]2[CH2:4][C:3]3[C:7](=[CH:8][C:9]([O:13][CH3:14])=[C:10]([O:11][CH3:12])[C:2]=3[Br:1])[C:6]2=[O:15])=[CH:18][CH:19]=1
Reactant: COc1cc2c(c(Br)c1OC)CN(Cc1ccc(C(=O)O)cc1)C2=O
Reactant: Nc1ccccc1N
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc2c(c(Br)c1OC)CN(Cc1ccc(C(=O)Nc3ccccc3N)cc1)C2=O
Temperature: 25 °C
Yield: 29.6 %

Procedure:
4-((4-Bromo-5,6-dimethoxy-1-oxoisoindolin-2-yl)methyl)benzoic acid (380 mg, 0.92 mmol) in the step 3, 1,2-phenylene diamine (199 mg, 1.84 mmol, 2 equiv.), and BOP (610 mg, 1.38 mmol, 1.5 equiv.) were dissolved in DMF (4 mL). Triethylamine (0.25 mL, 1.8 mmol, 2 equiv.) was added thereto, and stirred at room temperature for 1 night. The reaction proceeded until no starting material is detectable by TLC. The resulting mixture thus obtained was distilled under a reduced pressure to remove DMF. The resulting material was dissolved in methylene chloride and washed with saturated sodium bicarbonate solution. The isolated organic layer was collected, dried over anhydrous MgSO4, and distilled under a reduced pressure to remove solvent. The resulting residue was subjected to a silica gel column chromatography (EtOAc/hexane=9:1) to obtain the title compound (135 mg, 29%).
Reaction SMILES: [C:1](Cl)(=[O:17])[O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[Na].[CH3:20][N:21]1[C:26]([CH3:28])([CH3:27])[CH2:25][CH:24]([OH:29])[CH2:23][C:22]1([CH3:31])[CH3:30]>C1(C)C=CC=CC=1>[C:1](=[O:17])([O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[O:29][CH:24]1[CH2:23][C:22]([CH3:30])([CH3:31])[N:21]([CH3:20])[C:26]([CH3:28])([CH3:27])[CH2:25]1
Reactant: CN1C(C)(C)CC(O)CC1(C)C
Reactant: CCCCCCCCCCCCCCOC(=O)Cl
Agent: [Na]
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCOC(=O)OC1CC(C)(C)N(C)C(C)(C)C1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
27.7 g (0.1 mol) of tetradecyl chlorocarbonate are added slowly to a solution of 19.3 g (0.1 mol) of the sodium salt of 1,2,2,6,6-pentamethyl-4-piperidinol in 150 ml of toluene, maintaining the temperature at 0° C. After the end of the addition, the mixture is stirred for 2 hours at ambient temperature, washed with water, dried over Na2SO4 and evaporated. The residue is distilled in vacuo. The product obtained has a boiling point of 172°-174° C./0.3 mbar and solidifies with melting point 32°-34° C.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:15]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])(=[O:18])[NH:16][NH2:17]>>[C:4]([O:3][C:1]([N:8]1[CH2:13][CH2:12][C:11](=[N:17][NH:16][C:15]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:10][CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)NN
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Product: CC(C)(C)OC(=O)NN=C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Yield: 94.3 %

Procedure:
To a three-neck flask equipped with a mechanical stirrer and a condenser was loaded 1-Boc-4-piperidone (10.0 g, 50.2 mmol), tert-butyl carbazate (7.30 g, 55.2 mmol) and hexanes (20 mL). The mixture was heated to reflux for 3 h, then cooled to room temperature and filtered. The solid was washed with hexanes and dried at room temperature to give 4-(tert-butoxycarbonyl-hydrazono)piperidine-1-carboxylic acid tert-butyl ester (14.84 g, 94%) as a white powder. 1H NMR (CDCl3) δ 1.46 (s, 9H), 1.50 (s, 9H), 2.32 (m, 2H), 2.52 (m, 2H), 3.55 (m, 4H), 7.48 (br, 1H).
Reaction SMILES: [CH2:1]([C:3](=[CH2:6])[CH:4]=O)[CH3:2].[NH2:7][C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11]>Cl.CNC.O>[CH2:1]([C:3]1[CH:4]=[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:7][CH:6]=1)[CH3:2]
Reactant: C=C(C=O)CC
Reactant: CCOC(=O)C=C(N)C(=O)OCC
Agent: CNC
Agent: Cl
Solvent: O
Product: CCOC(=O)c1cc(CC)cnc1C(=O)OCC
Temperature: 50 °C
Reaction time: 4 h
Yield: 45.7 %

Procedure:
In a 500 ml four neck distillation flask with a reflux condenser were placed 2-ethyl-2-propenal 100 g (1.19 mol) and dimethylamine hydrochloride 2.0 g, and heated on an oil bath. When the inside temperature reached 90° C., ethyl β-amino-β-ethoxycarbonylacrylate 200 g (1.07 mol) was added dropwise thereto at 90° to 95° C. over a period of 4 hours. After completion of the dropping, the mixture was heated at 90° to 95° C. for 10 hours. Then, the reaction mixture was cooled to 50° C., and 30 ml of water was added thereto. The mixture was then allowed to stand still to separate into a water layer and an oil layer. The oil layer was distilled to give 123.0 g of 5-ethyl-2,3-diethoxycarbonylpyridine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]=[C:10]([C:18]([NH:20][OH:21])=[NH:19])[N:9]=2)=[CH:4][CH:3]=1.[S:22]([C:26]1[S:27][C:28]([C:31](O)=O)=[CH:29][CH:30]=1)(=[O:25])(=[O:24])[NH2:23]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:15])([F:16])[F:17])[N:11]=[C:10]([C:18]3[N:19]=[C:31]([C:28]4[S:27][C:26]([S:22]([NH2:23])(=[O:25])=[O:24])=[CH:30][CH:29]=4)[O:21][N:20]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: N=C(NO)c1nc(-c2ccc(Cl)cc2)cc(C(F)(F)F)n1
Reactant: NS(=O)(=O)c1ccc(C(=O)O)s1
Product: NS(=O)(=O)c1ccc(-c2nc(-c3nc(-c4ccc(Cl)cc4)cc(C(F)(F)F)n3)no2)s1

Procedure:
The title compound was prepared from 4-(4-chloro-phenyl)-N-hydroxy-6-trifluoromethyl-pyrimidine-2-carboxamidine (example C.1) (0.16 g, 0.5 mmol) and commercially available 2-sulfamoyl-thiophene-5-carboxylic acid [CAS-No. 7353-87-9] (104 mg, 0.5 mmol) according to the general procedure VI. Obtained as a light yellow solid (0.085 g, 35%). MS (ISN) 486.1 [(M−H)−]; mp 236.5° C.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH:6]([NH:9][C:10]1[C:11]([CH3:41])=[C:12]([C:16]2[C:28]3[C:27]4[C:22](=[CH:23][C:24]([C:29]([N:31]5[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]5)=[O:30])=[CH:25][CH:26]=4)[NH:21][C:20]=3[C:19]([C:38]([NH2:40])=[O:39])=[CH:18][CH:17]=2)[CH:13]=[CH:14][CH:15]=1)([CH3:8])[CH3:7].Cl>N1C=CC=CC=1.CO>[CH:6]([N:9]([C:10]1[C:11]([CH3:41])=[C:12]([C:16]2[C:28]3[C:27]4[C:22](=[CH:23][C:24]([C:29]([N:31]5[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]5)=[O:30])=[CH:25][CH:26]=4)[NH:21][C:20]=3[C:19]([C:38]([NH2:40])=[O:39])=[CH:18][CH:17]=2)[CH:13]=[CH:14][CH:15]=1)[S:2]([CH3:1])(=[O:4])=[O:3])([CH3:8])[CH3:7]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1c(NC(C)C)cccc1-c1ccc(C(N)=O)c2[nH]c3cc(C(=O)N4CCN(C)CC4)ccc3c12
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Product: Cc1c(-c2ccc(C(N)=O)c3[nH]c4cc(C(=O)N5CCN(C)CC5)ccc4c23)cccc1N(C(C)C)S(C)(=O)=O
Reaction time: 0.5 h

Procedure:
Methanesulfonyl chloride (1.3 μL, 0.016 mmol) was added to a stirred solution of 4-(3-(isopropylamino)-2-methylphenyl)-7-(4-methylpiperazine-1-carbonyl)-9H-carbazole-1-carboxamide, TFA salt (Example 9-1, 13 mg, 0.016 mmol) in pyridine (0.2 mL) at rt. After 30 min, additional methanesulfonyl chloride (2.4 μL) was added and the mixture was stirred overnight. The mixture was treated with 1 M hydrochloric acid (0.56 mL), dissolved in methanol and purified by preparative HPLC to provide two rotational isomers of 4-(3-(N-isopropylmethylsulfonamido)-2-methylphenyl)-7-(4-methylpiperazine-1-carbonyl)-9H-carbazole-1-carboxamide, isolated separately as TFA salts after lyophilization. Isomer A (3.3 mg, 31%) 1H NMR (400 MHz, chloroform-d) δ 9.58 (1H, s), 7.81 (1H, d, J=7.70 Hz), 7.68 (1H, s), 7.41-7.47 (1H, m), 7.32-7.37 (2H, m), 7.11 (1H, d, J=7.70 Hz), 7.05 (1H, d, J=8.14 Hz), 6.86 (1H, d, J=8.14 Hz), 4.60-4.72 (1H, m), 3.66 (3H, br. s.), 3.05 (8H, br. s.), 2.90 (3H, s), 1.91 (3H, s), 1.40 (3H, d, J=6.60 Hz), 1.12 (3H, d, J=6.82 Hz). Mass spectrum m/z 562.1 (M+H)+. Isomer B (2.9 mg, 27%) 1H NMR (400 MHz, chloroform-d) δ 9.41 (1H, br. s.), 7.84 (1H, d, J=7.70 Hz), 7.69 (1H, s), 7.46 (1H, t, J=7.81 Hz), 7.36 (2H, t, J=8.25 Hz), 7.13 (1H, d, J=7.70 Hz), 7.05 (1H, dd, J=8.25, 1.21 Hz), 6.92 (1H, d, J=8.36 Hz), 4.71-4.82 (1H, m), 3.67 (3H, br. s.), 2.59-3.07 (11H, m), 1.90 (3H, s), 1.43 (3H, d, J=6.60 Hz), 1.10 (3H, d, J=6.60 Hz). Mass spectrum m/z 562.2 (M+H)+.