Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([C:14]1[CH:19]=[CH:18][C:17]3[O:20][CH2:21][O:22][C:16]=3[CH:15]=1)[N:8]=[CH:7]2)([O-:3])=[O:2].[CH3:23]COC(C)=O>>[N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([C:14]1[CH:19]=[CH:18][C:17]3[O:20][CH2:21][CH2:23][O:22][C:16]=3[CH:15]=1)[N:8]=[CH:7]2)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2nc(-c3ccc4c(c3)OCO4)ncc2c1
Reactant: CCOC(C)=O
Product: O=[N+]([O-])c1ccc2nc(-c3ccc4c(c3)OCCO4)ncc2c1
Yield: 70 %

Procedure:
This compound was synthesized in 70% yield, according to the procedure described in example 3 for 6-nitro-2-(3,4-methylendioxy-phenyl)-quinazoline. C16H11N3O4, MW: 309, 28; mp: 263-265; TLC (tol/AcOEt 7/3) Rf=0.80.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].C(O)[C@@H]([C@H]([C@@H]([C@H](CO)O)O)O)O>>[OH:1][CH2:2][C:3]([C@H:5]([C@@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])=[O:4]
Reactant: OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)CO
Agent: OC[C@H](O)[C@@H](O)[C@H](O)[C@@H](O)CO
Product: O=C(CO)[C@@H](O)[C@H](O)[C@@H](O)CO

Procedure:
According to another advantageous embodiment of the method of the invention, the solution of D-sorbitol and of L-iditol subjected to fermentation is obtained by catalytic hydrogenation of L-sorbose.
Reaction SMILES: [CH2:1]([N:8]([CH3:26])[C:9]1[CH:14]=[CH:13][N:12]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23]O)=[CH:19][CH:18]=2)[C:11](=[O:25])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Br)(Br)[Br:28]>C(Cl)Cl.C([O-])(O)=O.[Na+].O>[CH2:1]([N:8]([CH3:26])[C:9]1[CH:14]=[CH:13][N:12]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][Br:28])=[CH:19][CH:18]=2)[C:11](=[O:25])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(Cc1ccccc1)c1ccn(CCc2ccc(CO)cc2)c(=O)c1
Reactant: BrP(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CN(Cc1ccccc1)c1ccn(CCc2ccc(CBr)cc2)c(=O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 280 mg (0.80 mmol, 74% purity) 4-(benzyl-methyl-amino)-1-[2-(4-hydroxymethyl-phenyl)-ethyl]-1H-pyridin-2-one (preparation 14c) in 5.0 mL of DCM is added at 0° C. 53 μL (0.56 mmol) phosphorus tribromide. The mixture is stirred overnight at RT and is diluted with aqueous NaHCO3-solution and water. The layers are separated and the organic phase is dried over MgSO4, filtered and the solvent is removed. The residue is used directly without further purification.
Reaction SMILES: [C:1](=[O:18])([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[O:2][CH:3](Cl)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:19]([NH:22][C:23]1[C:24]([I:39])=[C:25]([N:34]([C:36](=[O:38])[CH3:37])[CH3:35])[C:26]([I:33])=[C:27]([C:30]([O-:32])=[O:31])[C:28]=1[I:29])(=[O:21])[CH3:20].[K+].[I-].[Na+]>CN(C=O)C>[C:19]([NH:22][C:23]1[C:24]([I:39])=[C:25]([N:34]([C:36](=[O:38])[CH3:37])[CH3:35])[C:26]([I:33])=[C:27]([C:30]([O:32][CH:3]([O:2][C:1]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:18])[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[O:31])[C:28]=1[I:29])(=[O:21])[CH3:20]
Reactant: O=C(Oc1ccccc1)OC(Cl)c1ccccc1
Reactant: CC(=O)Nc1c(I)c(C(=O)[O-])c(I)c(N(C)C(C)=O)c1I
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1c(I)c(C(=O)OC(OC(=O)Oc2ccccc2)c2ccccc2)c(I)c(N(C)C(C)=O)c1I
Temperature: 60 °C
Reaction time: 2 h

Procedure:
1-Chloro-1-phenylmethyl phenyl carbonate (0.63 g, 2.4 mmol) was added at room temperature to a solution of potassium 5-(N-acetylamino)-3-(N-acetyl-N-methylamino)-2,4,6-triiodobenzene carboxylate (1.44 g, 2.2 mmol) and sodium iodide (0.034 g, 0.23 mmol) in dry DMF (12 ml). After stir ring at 60° C. for 2 hours and at room temperature for 18 hours the solvent was removed at reduced pressure. The residue was suspended in chloroform (20 ml) and washed four times with a saturated sodium hydrogen carbonate solution and finally twice with water. After drying with magnesium sulfate the solution was evaporated to dryness. Yield: 0.90 g. Purity by HPLC: 96.6% 1H-NMR(DMSO-d6): delta=1.67 (NCH3COCH3 ); 2.05 (NHCOCH3); 2.96 (NCH3); 7.29-7.54 (phenyl); 7.71 (CH); 10.13 ppm (NH). FAB/MS: 854 (M+).
Reaction SMILES: C[O:2][C:3](=[O:26])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:5]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(Cl)(=O)CC>>[CH2:11]([O:10][C:6]1[C:5]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:4]([CH:9]=[CH:8][CH:7]=1)[C:3]([OH:26])=[O:2])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COC(=O)c1cccc(OCc2ccccc2)c1OCc1ccccc1
Agent: CCC(=O)Cl
Product: O=C(O)c1cccc(OCc2ccccc2)c1OCc1ccccc1

Procedure:
In another embodiment the compounds can be prepared as shown in Scheme III. A nitroaniline (1) can be reacted with propionyl chloride to yield nitro-phenyl-propionamide (2). NaH can then be added to a solution of (2) in anhydrous THF followed by iodomethane to give pure product nitro-phenyl-N-methyl-propionamide (3).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([F:19])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:20](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:21][CH:22]([CH3:24])[CH3:23])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:36][O:37][C:38](=[O:55])[C:39]1[CH:44]=[CH:43][C:42](B2OC(C)(C)C(C)(C)O2)=[CH:41][C:40]=1[F:54].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:36][O:37][C:38](=[O:55])[C:39]1[CH:44]=[CH:43][C:42]([C:20]([C:11]2[N:10]([S:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:8])=[O:9])[C:14]3=[N:15][CH:16]=[C:17]([F:19])[CH:18]=[C:13]3[CH:12]=2)=[CH:21][CH:22]([CH3:24])[CH3:23])=[CH:41][C:40]=1[F:54]
Reactant: Cc1ccc(S(=O)(=O)OC(=CC(C)C)c2cc3cc(F)cnc3n2S(=O)(=O)c2ccccc2)cc1
Reactant: COC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COC(=O)c1ccc(C(=CC(C)C)c2cc3cc(F)cnc3n2S(=O)(=O)c2ccccc2)cc1F
Yield: 83.9 %

Procedure:
To a mixture of toluene-4-sulfonic acid 1-(1-benzenesulfonyl-5-fluoro-1H-pyrrolo[2,3-b]pyridin-2-yl)-3-methyl-but-1-enyl ester (prepared as in Example 99, 3.09 g, 6 mmol), 2-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid methyl ester (prepared as in Example 95, 5.88 g, 21 mmol) and dichlorobis(triphenylphosphine)palladium (II) (420 mg, 0.6 mmol) in dioxane (24 mL) was added an aqueous sodium carbonate solution (2 M, 7.5 mL). The resulting mixture was subjected to microwave irradiation for 4 h at 100° C. The mixture was diluted with ethyl acetate (200 mL), washed with a saturated aqueous sodium bicarbonate solution (3×50 mL), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company, 25% ethyl acetate/hexanes) afforded 4-[1-(1-benzenesulfonyl-5-fluoro-1H-pyrrolo[2,3-b]pyridin-2-yl)-3-methyl-but-1-enyl]-2-fluoro-benzoic acid methyl ester (2.50 g, 83%) as a white solid: LC/MS m/e calcd for C26H22F2N2O4S [M+H]+ 497.54, observed 496.7.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]#[C:10][Si](C)(C)C)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[OH-].[K+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]#[CH:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: C[Si](C)(C)C#Cc1cc(Cl)cc(Cl)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: C#Cc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (3,5-dichloro-phenylethynyl)-trimethylsilane (4.85 g, 19.9 mmol) in methanol (50 mL) was added 1M potassium hydroxide (30 mL). The reaction mixture was stirred 1 h at room temperature and evaporated. The residue was treated with water (10 mL) and extracted with 3×40 mL diethyl ether. The tried organic phases were evaporated to give the desired 1,3-dichloro-5-ethynyl-benzene product in 2.3 g yield.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[C:3]=1[N+:9]([O-:11])=[O:10].CO[CH:14]1[CH2:18][CH2:17][CH:16](OC)O1>CC(O)=O>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[CH:14]=[CH:18][CH:17]=[CH:16]2)[C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: Cc1ccnc(N)c1[N+](=O)[O-]
Reactant: COC1CCC(OC)O1
Solvent: CC(=O)O
Product: Cc1ccnc(-n2cccc2)c1[N+](=O)[O-]
Yield: 90.4 %

Procedure:
11.82 g (0.0581 mol; yield: 90.4%) of a yellow powder, which turns red in air, are obtained by carrying out the reaction in the same way as in Stage B of Example 92 but starting from 9.85 g (0.0643 mol) of 4-methyl-3nitro-2-aminopyridine and using 10.2 g (0.0772 mol; 1.2 eq) of 2,5-dimethoxytetrahydrofuran and 200 cm3 of glacial CH3CO2H, and bringing the solution to reflux for 3 h.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[N:9][C:10]([O:12][Si](C)(C)C)=[CH2:11])[CH:5]=[CH:6][CH:7]=1.[CH2:17]([O:19][C:20]([N:22]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([Cl:31])[CH:29]=2)/[C:24](=[CH:32]/[C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[CH:34]=2)/[C:23]1=[O:40])=[O:21])[CH3:18].CO>C1(C)C=CC=CC=1>[CH2:17]([O:19][C:20]([N:22]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([Cl:31])[CH:29]=2)[C:24]2([CH:32]([C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[CH:34]=3)[CH2:12][C:10](=[O:11])[NH:9][CH:8]2[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[C:23]1=[O:40])=[O:21])[CH3:18]
Reactant: CCOC(=O)N1C(=O)/C(=C\c2cccc(Cl)c2)c2ccc(Cl)cc21
Reactant: C=C(N=Cc1cccc(Cl)c1)O[Si](C)(C)C
Solvent: CO
Solvent: Cc1ccccc1
Product: CCOC(=O)N1C(=O)C2(c3ccc(Cl)cc31)C(c1cccc(Cl)c1)CC(=O)NC2c1cccc(Cl)c1
Temperature: 135 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of 1-(3-chlorophenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene prepared in example 1b in toluene (20 mL) was added E/Z-6-chloro-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid ethyl ester prepared in example 6b (0.3 g, 0.83 mmol). The reaction mixture was stirred under nitrogen in a sealed tube at 135° C. for 1 h. After the solution was cooled to room temperature, methanol (50 mL) was added, and then the mixture was concentrated. The residue was purified by chromatography (EtOAc:CH2Cl2=1:3) to give racemic (2′R,3R,4′S)-6-chloro-2′,4′-bis(3-chlorophenyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxylic acid ethyl ester as a yellow oil (Yield 0.45 g, 100%).
Reaction SMILES: [CH2:1]([C@H:8]([NH:19][C:20](=[O:43])[O:21][NH:22][C:23](=[O:42])[C@@H:24]([NH:29][C:30]([C:32]1[CH:41]=[CH:40][C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:33]=1)=[O:31])[CH2:25][C:26]([NH2:28])=[O:27])[C@H:9]([OH:18])[CH2:10][NH:11][O:12][CH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[S:45]([C:48]1[CH:61]=[CH:60][C:51]2[NH:52][C:53]([NH:55][C:56](=[O:59])[O:57][CH3:58])=[N:54][C:50]=2[CH:49]=1)(=[O:47])=[O:46].C(N(C(C)C)CC)(C)C>O1CCCC1.CO>[CH2:1]([C@H:8]([NH:19][C:20](=[O:43])[O:21][NH:22][C:23](=[O:42])[C@@H:24]([NH:29][C:30]([C:32]1[CH:41]=[CH:40][C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:33]=1)=[O:31])[CH2:25][C:26]([NH2:28])=[O:27])[C@H:9]([OH:18])[CH2:10][N:11]([O:12][CH:13]1[CH2:14][CH2:15][CH2:16][CH2:17]1)[S:45]([C:48]1[CH:61]=[CH:60][C:51]2[NH:52][C:53]([NH:55][C:56]([O:57][CH3:58])=[O:59])=[N:54][C:50]=2[CH:49]=1)(=[O:47])=[O:46])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)Nc1nc2cc(S(=O)(=O)Cl)ccc2[nH]1
Reactant: NC(=O)C[C@H](NC(=O)c1ccc2ccccc2n1)C(=O)NOC(=O)N[C@@H](Cc1ccccc1)[C@H](O)CNOC1CCCC1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: COC(=O)Nc1nc2cc(S(=O)(=O)N(C[C@@H](O)[C@H](Cc3ccccc3)NC(=O)ONC(=O)[C@H](CC(N)=O)NC(=O)c3ccc4ccccc4n3)OC3CCCC3)ccc2[nH]1
Reaction time: 24 h
Yield: 17 %

Procedure:
(2S)-4-Amino-4-oxo-2-[(2-quinolinylcarbonyl)amino]butanamido N-(1S,2R)-1-benzyl-3-[(cyclopentyloxy)-amino]-2-hydroxypropylcarbamate (Step 1, above), (44 mg, 0.0825 mmol), methyl N-[5-(chlorosulfonyl)-1H-benzimidazol-2-yl]carbamate (24 mg, 0.0825 mmol), and anhydrous diisopropylethylamine (0.05 mL, 0.280 mmol) were combined in anhydrous tetrahydrofuran (3 mL) in a 25 mL round bottomed flask under nitrogen. The reaction was stirred for 24 hours and concentrated in vacuo. Ethyl acetate (30 mL) and water (10 mL) were added and the layers were separated. The organic layer was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative silica gel TLC using 90:10 chloroform:methanol as an eluent to provide the desired product as a white solid (11 mg, 0.014 mmol, 17%). 1HNMR (d6-DMSO) δ: 8.86 (d, J=8.4 Hz, 1H), 8.62 (d, J=8.4 Hz, 1H), 8.22-6.94 (m, 12H), 5.19 (d, J=6.2 Hz, 1H), 4.77-4.72 (m, 2H), 4.02-1.35 (m, 17H), 3.80 (s, 3H). MS(ES): 787 (M+1), 785 (M−1).
Reaction SMILES: C(OC(=O)[N:7]([CH2:9][C:10]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])[N:12]([S:22]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH:32]3[CH2:37]CCCO3)=[CH:27][CH:26]=2)(=[O:24])=[O:23])[CH:11]=1)[CH3:8])(C)(C)C.[F:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[C:46]1[N:50]([S:51]([C:54]2[CH:59]=[CH:58][C:57]([OH:60])=[CH:56][CH:55]=2)(=[O:53])=[O:52])[CH:49]=[C:48]([CH2:61][N:62]([CH3:70])[C:63](=[O:69])[O:64][C:65]([CH3:68])([CH3:67])[CH3:66])[CH:47]=1.C1(C)C=CC(S(O)(=O)=[O:78])=CC=1>CO>[F:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:13]1[N:12]([S:22]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:37]([NH:50][CH3:49])=[O:78])=[CH:27][CH:26]=2)(=[O:24])=[O:23])[CH:11]=[C:10]([CH2:9][NH:7][CH3:8])[CH:14]=1.[F:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[C:46]1[N:50]([S:51]([C:54]2[CH:55]=[CH:56][C:57]([OH:60])=[CH:58][CH:59]=2)(=[O:52])=[O:53])[CH:49]=[C:48]([CH2:61][N:62]([CH3:70])[C:63](=[O:69])[O:64][C:65]([CH3:66])([CH3:67])[CH3:68])[CH:47]=1
Reactant: CN(Cc1cc(-c2ccccc2F)n(S(=O)(=O)c2ccc(OC3CCCCO3)cc2)c1)C(=O)OC(C)(C)C
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: CN(Cc1cc(-c2ccccc2F)n(S(=O)(=O)c2ccc(O)cc2)c1)C(=O)OC(C)(C)C
Solvent: CO
Product: CNCc1cc(-c2ccccc2F)n(S(=O)(=O)c2ccc(OCC(=O)NC)cc2)c1
Reaction time: 3 h

Procedure:
tert-Butyl ((5-(2-fluorophenyl)-1-((4-hydroxyphenyl)sulfonyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate tert-Butyl ((5-(2-fluorophenyl)-1-((4-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)sulfonyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate 4c (2.3 g, 4.28 mmol) was dissolved in 30 mL of methanol, followed by addition of p-toluenesulfonic acid (148 mg, 0.86 mmol), and then the reaction solution was stirred for 3 h. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with elution system B to obtain the title product tert-butyl ((5-(2-fluorophenyl)-1-((4-hydroxyphenyl)sulfonyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate 4d (2.0 g, a colorless oil) in 80% yield.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]([N:10]=[C:11]=[O:12])[CH2:7][CH2:8][CH2:9][C:2]1=2.[C:13]([NH2:16])(=[O:15])[CH3:14]>>[C:13]([NH:16][C:11]([NH:10][CH:6]1[C:3]2[CH:4]=[CH:5][S:1][C:2]=2[CH2:9][CH2:8][CH2:7]1)=[O:12])(=[O:15])[CH3:14]
Reactant: CC(N)=O
Reactant: O=C=NC1CCCc2sccc21
Product: CC(=O)NC(=O)NC1CCCc2sccc21

Procedure:
A 2.94 g sample of benzoyl isocyanate in 5 ml of CH2Cl2 is added to 3.04 g of 4,5,6,7-tetrahydrobenzo[b]thiophen-4-amine in 50 ml of CH2Cl2 under N2 atmosphere. After stirring overnight at room temperature, the reaction mixture is evaporated to dryness in vacuo. The residue is then stirred in 100 ml of Et2O and filtered to afford 1-benzoyl-3-(4,5,6,7-tetrahydrobenzo[b]thien-4-yl)urea, m.p. 189° C. to 194° C. Substitution of trichloroacetyl isocyanate for benzoyl isocyanate affords 1-trichloroacetyl-3-(4,5,6,7-tetrahydrobenzo[b]thien-4-yl)urea. Use of 4,5,6,7-tetrahydrobenzo[b]thien-4-ylisocyanate and acetamide in the above manner affords 1-acetyl-3-(4,5,6,7-tetrahydrobenzo[b]thien-4-yl)urea.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:10]1[N:11]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:12]2[C:13]([N:18]=1)=[N:14][CH:15]=[CH:16][CH:17]=2)[CH3:9])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:19]1([N:11]2[C:12]3[C:13](=[N:14][CH:15]=[CH:16][CH:17]=3)[N:18]=[C:10]2[C@@H:8]([NH2:7])[CH3:9])[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1nc2ncccc2n1-c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H](N)c1nc2ncccc2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 53 %

Procedure:
To a solution of [(S)-1-(1-phenyl-1H-imidazo[4,5-b]pyridin-2-yl)ethyl]carbamic acid tert-butyl ester (910 mg, 2.69 mmol) in DCM (5 mL) was added TFA (15 mL) and the mixture stirred at RT for 15 min. The volatiles were removed in vacuo and the resulting residue dissolved in DCM and washed with a saturated aqueous solution of NaHCO3. The aqueous phase was further extracted with DCM (×3) and the combined organic fractions dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% 2M NH3/MeOH in DCM) to afford the title compound as a brown solid (340 mg, 53%). 1H NMR (CDCl3, 400 MHz): δ 8.55 (1H, dd, J=4.78, 1.56 Hz), 7.65-7.53 (3H, m), 7.45-7.37 (3H, m), 7.15 (1H, dd, J=8.04, 4.78 Hz), 4.18 (1H, q, J=6.71 Hz), 3.49 (2H, s), 1.48 (3H, d, J=6.71 Hz).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C@@H:4]1[CH2:8][C@@H:7](OS(C)(=O)=O)[CH2:6][N:5]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].[C-:22]#[N:23].[Na+]>CS(C)=O.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:21])[C@@H:4]1[CH2:8][C@@H:7]([C:22]#[N:23])[CH2:6][N:5]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]
Reactant: COC(=O)[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OC(C)(C)C
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H]1C[C@@H](C#N)CN1C(=O)OC(C)(C)C
Temperature: 55 °C
Reaction time: 24 h

Procedure:
A mixture of (4R)-1-(tert-butyloxycarbonyl)-4-(methane-sulfonyloxy)-L-proline methyl ester (2.31 g, 7.14 mmol) and sodium cyanide (3.5 g, 71.4 mmol) in dry dimethylsulfoxide (46 mL) was stirred for 24 hours at 55° C. under a nitrogen atmosphere. The cooled reaction mixture was diluted with ethyl acetate, washed with water (2×), saturated brine solution, dried (MgSO4), and evaporated. The crude product mixture was subjected to flash silica gel chromatography eluting with 15% acetone/hexane. Fractions containing the desired nitrile were combined and evaporated to afford a colorless oil; yield 205 mg (11%).
Reaction SMILES: Cl.[CH2:2]([N:5]([CH2:37][CH2:38][CH3:39])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]([CH2:33][C:34]([OH:36])=[O:35])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][N:19]([CH2:27][C:28]2[NH:29][CH:30]=[CH:31][N:32]=2)[CH2:20][C:21]2[N:22]([CH3:26])[CH:23]=[CH:24][N:25]=2)=[CH:14][CH:13]=1)[CH2:3][CH3:4].[CH2:40](O)[CH:41]=[CH:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>CN(C=O)C>[CH2:40]([O:35][C:34](=[O:36])[CH2:33][N:10]([CH2:9][CH2:8][CH2:7][CH2:6][N:5]([CH2:2][CH2:3][CH3:4])[CH2:37][CH2:38][CH3:39])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][N:19]([CH2:27][C:28]2[NH:29][CH:30]=[CH:31][N:32]=2)[CH2:20][C:21]2[N:22]([CH3:26])[CH:23]=[CH:24][N:25]=2)=[CH:14][CH:13]=1)[CH:41]=[CH:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: OCC=Cc1ccccc1
Reactant: CCCN(CCC)CCCCN(CC(=O)O)Cc1ccc(CN(Cc2ncc[nH]2)Cc2nccn2C)cc1
Agent: Cl
Solvent: CN(C)C=O
Product: CCCN(CCC)CCCCN(CC(=O)OCC=Cc1ccccc1)Cc1ccc(CN(Cc2ncc[nH]2)Cc2nccn2C)cc1

Procedure:
The hydrochloride (203 mg) of the compound obtained in Example 65-1 was dissolved in DMF (3.0 ml) and added with cinnamyl alcohol (73.9 μl) and the whole was refluxed overnight under heating. After completion of the reaction, the solvent was distilled off. The resultant was dissolved in chloroform and added with a saturated aqueous sodium hydrogen carbonate solution and the whole was stirred for a while. The solution was subjected to extraction with chloroform and washed with a saturated saline solution. The organic layer was dried with anhydrous sodium sulfate. The solvent was distilled off. The residue was purified through silica gel column chromatography (chloroform/ethyl acetate) and treated with hydrochloric acid, thereby obtaining a hydrochloride (19.1 mg) of the subject compound as a brownish-red solid.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH:10]([Mg]Br)=[CH2:11]>O1CCCC1>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]([OH:7])[CH:10]=[CH2:11])=[CH:4][CH:3]=1
Reactant: C=C[Mg]Br
Reactant: O=Cc1ccc(F)cc1
Solvent: C1CCOC1
Product: C=CC(O)c1ccc(F)cc1
Temperature: 25 °C

Procedure:
A solution of 4-fluorobenzaldehyde (8.5 g, 68.2 mmol, Aldrich) in 50 mL of tetrahydrofuran was added dropwise to a solution of vinylmagnesium bromide (9.84 g, 75 mmol, Aldrich) in 150 mL of tetrahydrofuran at 0° C. The mixture was stirred for min and then allowed to warm to room temperature. The reaction was stirred overnight and quenched by the addition of water (100 mL). The resulting precipitate was removed by filtration. The filtrate was concentrated in vacuo and then dissolved in 200 mL of ethyl acetate. This solution was washed with water, brine, dried over sodium sulfate, and concentrated in vacuo to 10.3 g of an amber oil as product. NMR (300 MHz, CDCl3) δ 7.37-7.29 (m, 2H), 7.04 (dd, 2H, J=9 Hz, 9 Hz), 6.08-5.97 (m, 1H), 5.35 (d, 1H, J=17 Hz), 5.21 (d, 2H, J=10 Hz), 1.90 (d, 1H, J=4 Hz).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[CH3:11])[NH:7][C:6](=[O:12])[C:5]2=O.[CH:14]1[C:19]([NH:20][NH2:21])=[CH:18][CH:17]=[C:16]([S:22]([NH2:25])(=[O:24])=[O:23])[CH:15]=1.Cl>>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[CH3:11])[NH:7][C:6](=[O:12])[C:5]2=[N:21][NH:20][C:19]1[CH:18]=[CH:17][C:16]([S:22]([NH2:25])(=[O:23])=[O:24])=[CH:15][CH:14]=1
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Reactant: Cc1cc2c(cc1C)C(=O)C(=O)N2
Agent: Cl
Product: Cc1cc2c(cc1C)C(=NNc1ccc(S(N)(=O)=O)cc1)C(=O)N2
Yield: 32 %

Procedure:
The title compound was prepared from 5,6-dimethyl-1H-indole-2,3-dione and 4-sulfonamidophenylhydrazine hydrochloride according to Procedure G in 32% yield: 1H NMR (DMSO-d6): δ 2.22 (s, 3H), 2.24 (s, 3H), 6.72 (s, 1H), 7.23 (s, 2H), 7.36 (s, 1H), 7.52 (d, J=8.8 Hz, 2H), 7.77 (d, J=8.8 Hz, 2H), 10.93 (s, 1H), 12.71 (s, 1H). APCI−MS m/z 343 (M−H)−. Anal. Calcd for C16H16N4O3S: C, 55.80, H. 4.68; N, 16.27; S, 9.31. Found C, 55.78, H, 4.74; N,16.37; S, 9.22.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3([O:26][C:27](=[O:28])[C:4]=2[CH:3]=1)[CH2:13][CH2:12][N:11]([C:14]([C:16]1[C:24]2[C:19](=[CH:20][C:21]([Cl:25])=[CH:22][CH:23]=2)[NH:18][CH:17]=1)=[O:15])[CH2:10][CH2:9]3.[F:29][C:30]1[CH:31]=[C:32]([S:37](Cl)(=[O:39])=[O:38])[CH:33]=[C:34]([F:36])[CH:35]=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3([O:26][C:27](=[O:28])[C:4]=2[CH:3]=1)[CH2:9][CH2:10][N:11]([C:14]([C:16]1[C:24]2[C:19](=[CH:20][C:21]([Cl:25])=[CH:22][CH:23]=2)[N:18]([S:37]([C:32]2[CH:31]=[C:30]([F:29])[CH:35]=[C:34]([F:36])[CH:33]=2)(=[O:39])=[O:38])[CH:17]=1)=[O:15])[CH2:12][CH2:13]3
Reactant: O=S(=O)(Cl)c1cc(F)cc(F)c1
Reactant: O=C1OC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccc(Br)cc21
Product: O=C1OC2(CCN(C(=O)c3cn(S(=O)(=O)c4cc(F)cc(F)c4)c4cc(Cl)ccc34)CC2)c2ccc(Br)cc21

Procedure:
Following the general procedure VII as described above, the sulphonylation of 5-bromo-1′-[(6-chloro-1H-indol-3-yl)carbonyl]-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one with commercially available 3,5-difluorobenzenesulfonyl chloride gave the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:10])[NH2:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1B(O)O)#[N:12].C(N(CC)CC)C>ClCCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:1]([O:5][C:6]([N:8]([CH3:10])[NH:9][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:11]#[N:12])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: N#Cc1ccccc1B(O)O
Reactant: CN(N)C(=O)OC(C)(C)C
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CN(Nc1ccccc1C#N)C(=O)OC(C)(C)C
Temperature: 60 °C
Yield: 29.3 %

Procedure:
A mixture of N-methyl-hydrazinecarboxylic acid tert-butyl ester (Intermediate 1; 890 mg, 6.06 mmol), 2-cyanophenylboronic acid (CombiBlock; 1.00 g, 6.8 mmol), copper(II) acetate (1.25 g, 6.9 mmol) and triethylamine (2 mL, 14.4 mmol) in 1,2-dichloroethane (30 mL) was heated in an oil bath at 60° C. for 3 h. The mixture was allowed to cool, and it was then adsorbed onto silica gel and purified by chromatography using an ISCO 40 g column, eluting with 10-20% ethyl acetate/hexanes, to give N′-(2-cyano-phenyl)-N-methyl-hydrazinecarboxylic acid tert-butyl ester (439 mg, 29%) as a pale yellow oil.