Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[C:18]([O:20][CH3:21])=[O:19])[C:5]([O:7]N1C(=O)CCC1=O)=O.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:29]=[C:30]([O:32][CH3:33])[CH:31]=1)[CH2:27][NH2:28].C(N(CC)CC)C>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([NH:28][CH2:27][C:26]2[CH:29]=[C:30]([O:32][CH3:33])[CH:31]=[C:24]([O:23][CH3:22])[CH:25]=2)=[O:7])[CH:15]=[CH:16][C:17]=1[C:18]([O:20][CH3:21])=[O:19]
Reactant: COC(=O)c1ccc(C(=O)ON2C(=O)CCC2=O)cc1Cl
Reactant: COc1cc(CN)cc(OC)c1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C(=O)NCc2cc(OC)cc(OC)c2)cc1Cl
Yield: 72.6 %

Procedure:
A solution of 1-[[3-chloro-4-(methoxycarbonyl)benzoyl]oxy]-2,5-pyrrolidinedione (Example 5; 2.00 g, 6.4 mmol), 3,5-dimethoxybenzylamine (1.25 g, 7.5 mmol) and triethylamine (1.00 g, 9.9 mmol) in N,N-dimethylformamide (100 mL) was stirred at room temperature overnight. The solvent was evaporated (<0.5 mm Hg, 40° C.), ethyl acetate (200 mL) was added, and the solution was allowed to stand over the weekend at room temperature. The white solid was filtered off and discarded. Silica gel was added, the solvent was evaporated and the residue was chromatographed (30–50% ethyl acetate/hexanes) to give 2-chloro-4-[[[(3,5-dimethoxyphenyl)methyl]amino]carbonyl]benzoic acid, methyl ester (1.69 g, 72%) as a white solid, mp 101–103° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Cl:11][C:12]1[CH:13]=[C:14]([CH:19]([CH2:33][CH2:34][OH:35])[CH2:20][C:21]([N:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:26][CH2:25][CH2:24]2)=[O:22])[CH:15]=[CH:16][C:17]=1[Cl:18].CCN(CC)CC>C(Cl)Cl>[Cl:11][C:12]1[CH:13]=[C:14]([CH:19]([CH2:33][CH:34]=[O:35])[CH2:20][C:21]([N:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:26][CH2:25][CH2:24]2)=[O:22])[CH:15]=[CH:16][C:17]=1[Cl:18]
Reactant: O=C(CC(CCO)c1ccc(Cl)c(Cl)c1)N1CCCc2ccccc21
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=CCC(CC(=O)N1CCCc2ccccc21)c1ccc(Cl)c(Cl)c1
Reaction time: 0.25 h
Yield: 90.5 %

Procedure:
A solution of oxalyl chloride (1.15 mL) in CH2Cl2 (30 mL) was cooled to -78° C. whereupon DMSO (1.87 mL) was added dropwise over 15 mins. This mixture was stirred for 15 minutes. Whereupon a CH2Cl2 (30 mL) solution of 1-[3-(3,4-dichlorophenyl)-5-hydroxy-1-oxopentyl]-1,2,3,4-tetrahydroquinoline (1.0 g) was added over 20 minutes. The mixture was stirred for 30 minutes and then treated with Et3N (7.4 mL) and stirred for an additional 30 minutes at -78° C., followed by 1.5 hours at room temperature. The reaction mixture was quenched with water and diluted with CH2Cl2 (100 mL). The organic fraction was separated, washed sequentially with 1N HCl (1×50 mL), sat. NaHCO3 (1×50 mL) and brine (1×50 mL), dried over MgSO4, filtered and concentrated under reduced pressure to yield an oil. Silica gel chromatography eluting with 5-15% EtOAc/Hex gave the title compound (900 mg).
Reaction SMILES: C([O:3][C:4](=[O:22])[CH2:5][C:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:11][CH:10]=1)([OH:8])[CH3:7])C>C(O)C>[O:15]([C:12]1[CH:13]=[CH:14][C:9]([C:6]([OH:8])([CH3:7])[CH2:5][C:4]([OH:22])=[O:3])=[CH:10][CH:11]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CCOC(=O)CC(C)(O)c1ccc(Oc2ccccc2)cc1
Solvent: CCO
Product: CC(O)(CC(=O)O)c1ccc(Oc2ccccc2)cc1

Procedure:
10 g. of 3-p-phenoxyphenyl-3-hydroxybutyric acid ethyl ester are dissolved in 50 ml. of ethanol and the solution is boiled for 15 minutes with 2 g. of KOH, evaporated and subjected to standard working up to give 3-p-phenoxyphenyl-3-hydroxybutyric acid, m.p. 137°-138°. Cyclohexylamine salt, m.p. 188°-189°.
Reaction SMILES: [CH3:1][C:2]([CH3:27])([CH3:26])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][C:9]([C:13]3[CH:18]=[C:17]([C:19](O)([CH3:21])[CH3:20])[CH:16]=[CH:15][C:14]=3[CH3:23])=[CH:10][CH:11]=2)[N:6]([CH3:24])[C:5]1=[O:25].[N-:28]=[N+:29]=[N-:30].[Na+].FC(F)(F)C(O)=O>C(Cl)Cl.CCOC(C)=O>[N:28]([C:19]([C:17]1[CH:16]=[CH:15][C:14]([CH3:23])=[C:13]([C:9]2[N:8]=[C:7]3[N:6]([CH3:24])[C:5](=[O:25])[N:4]([CH2:3][C:2]([CH3:1])([CH3:26])[CH3:27])[C:12]3=[CH:11][CH:10]=2)[CH:18]=1)([CH3:20])[CH3:21])=[N+:29]=[N-:30]
Reactant: Cc1ccc(C(C)(C)O)cc1-c1ccc2c(n1)n(C)c(=O)n2CC(C)(C)C
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(C(C)(C)N=[N+]=[N-])cc1-c1ccc2c(n1)n(C)c(=O)n2CC(C)(C)C
Temperature: 25 °C

Procedure:
To a solution of 14-2 (1.2 g, 3.3 mmol) and sodium azide (0.42 g, 6.5 mmol) in DCM (8 mL) at −78 C was added a solution of trifluoroacetic acid (1.0 mL, 13 mmol) in DCM (0.25 mL). The reaction mixture was allowed to slowly warm to room temperature over 15 hours. The reaction was diluted in EtOAc and washed with water, brine, dried over sodium sulfate, filtered and concentrated to give product. HRMS (M+H)+: observed=393.2389, calculated=393.2397.
Reaction SMILES: C1(O)C=CC=CC=1.C1(C)C=CC(S([N:17]2[CH2:24][C:23]3[CH2:22][N:21](S(C4C=CC(C)=CC=4)(=O)=O)[CH2:20][C:19]=3[CH2:18]2)(=O)=O)=CC=1.[BrH:36]>>[BrH:36].[BrH:36].[C:19]12[CH2:20][NH:21][CH2:22][C:23]=1[CH2:24][NH:17][CH2:18]2
Reactant: Cc1ccc(S(=O)(=O)N2CC3=C(C2)CN(S(=O)(=O)c2ccc(C)cc2)C3)cc1
Agent: Br
Solvent: Oc1ccccc1
Product: C1NCC2=C1CNC2
Temperature: 25 °C

Procedure:
60 ml of 48% hydrobromic acid and 7 g of phenol were added to 10.8 g 3,7bis-p-toluenesulfonyl-3,7-diazabicyclo[3.3.0]oct-1-(5)-ene, prepared in Preparation 1. The mixture was refluxed for 4 hours and cooled to room temperature. The aqueous phase was separated by adding 100 ml of chloroform and 50 ml of water. The aqueous phase was washed with chloroform (100 ml×4) and decolorized with active carbon. The aqueous phase was concentrated under vacuum and the remained solid was washed with 1:1 methanol-ethyl ether solvent. 5 g of the title compound was obtained as white solid (yield 71%).
Reaction SMILES: CO.[CH2:3]([O:10][C:11]1[N:16]=[CH:15][C:14]([CH:17]=[O:18])=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[BH4-].[Na+]>O>[CH2:3]([O:10][C:11]1[N:16]=[CH:15][C:14]([CH2:17][OH:18])=[CH:13][CH:12]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=Cc1ccc(OCc2ccccc2)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: OCc1ccc(OCc2ccccc2)nc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 91.1 %

Procedure:
To a methanol (20.0 mL) solution of 6-benzyloxy-pyridine-3-carbaldehyde (2.00 g, 9.38 mmol) described in Manufacturing Example 12-1-2 was added sodium borohydride (426 mg, 11.3 mmol) on an ice bath (0° C.) under nitrogen atmosphere, which was stirred for 10 minutes at room temperature. Water was added to the reaction mixture at room temperature, which was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure to obtain the title compound (1.84 g, 91.1%).
Reaction SMILES: [CH3:1][N:2]([C:17]([NH:19][C@H:20]([C:24]([NH:26][C@H:27]([C@@H:35]([OH:72])[C@@H:36]([OH:71])[C@@H:37]([NH:45][C:46](=[O:70])[C@H:47]([CH:67]([CH3:69])[CH3:68])[NH:48][C:49]([N:51]([CH2:53][C:54]1[N:55]=[C:56]([NH:59]C(OC(C)(C)C)=O)[S:57][CH:58]=1)[CH3:52])=[O:50])[CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:25])[CH:21]([CH3:23])[CH3:22])=[O:18])[CH2:3][C:4]1[N:5]=[C:6]([NH:9]C(OC(C)(C)C)=O)[S:7][CH:8]=1.CO>C(Cl)(Cl)Cl>[CH3:52][N:51]([C:49]([NH:48][C@H:47]([C:46]([NH:45][C@H:37]([C@@H:36]([OH:71])[C@@H:35]([OH:72])[C@@H:27]([NH:26][C:24](=[O:25])[C@H:20]([CH:21]([CH3:22])[CH3:23])[NH:19][C:17]([N:2]([CH2:3][C:4]1[N:5]=[C:6]([NH2:9])[S:7][CH:8]=1)[CH3:1])=[O:18])[CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[CH2:38][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)=[O:70])[CH:67]([CH3:69])[CH3:68])=[O:50])[CH2:53][C:54]1[N:55]=[C:56]([NH2:59])[S:57][CH:58]=1
Reactant: CC(C)[C@H](NC(=O)N(C)Cc1csc(NC(=O)OC(C)(C)C)n1)C(=O)N[C@@H](Cc1ccccc1)[C@H](O)[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)N(C)Cc1csc(NC(=O)OC(C)(C)C)n1)C(C)C
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC(C)[C@H](NC(=O)N(C)Cc1csc(N)n1)C(=O)N[C@@H](Cc1ccccc1)[C@H](O)[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)N(C)Cc1csc(N)n1)C(C)C

Procedure:
Using the procedure of Example 58B but replacing the resultant compound of Example 58A with the resultant compound of Example 93 provided, after silica gel chromatography using first 5% then 10% methanol in chloroform followed by 2% isopropylamino/10% methanol in chloroform, 53 mg (38%) of the desired compound (Rf 0.15, 10% methanol in chloroform) as a white solid, m.p. 130°-134° C. Mass spectrum: (M+1)+ =837.
Reaction SMILES: C([N:4]([C:9]1[O:10][C:11]2[C:17]([N:18]3[C:23](=[O:24])[CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[N:20]([CH3:29])[C:19]3=[O:30])=[C:16]([F:31])[CH:15]=[C:14]([Cl:32])[C:12]=2[N:13]=1)[S:5]([CH3:8])(=[O:7])=[O:6])(=O)C>NN>[CH3:8][S:5]([NH:4][C:9]1[O:10][C:11]2[C:17]([N:18]3[C:23](=[O:24])[CH:22]=[C:21]([C:25]([F:26])([F:28])[F:27])[N:20]([CH3:29])[C:19]3=[O:30])=[C:16]([F:31])[CH:15]=[C:14]([Cl:32])[C:12]=2[N:13]=1)(=[O:7])=[O:6]
Reactant: CC(=O)N(c1nc2c(Cl)cc(F)c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c2o1)S(C)(=O)=O
Agent: NN
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(Cl)c3nc(NS(C)(=O)=O)oc23)c1=O
Reaction time: 18 h

Procedure:
A stirred solution of 4.5 grams (10 mmole) of 3-[2-(N-acetyl-N-methylsulfonylamino)-4-chloro-6-fluorobenzoxazol-7-yl]-1-methyl-6-trifluoromethyl-2,4-(1H,3H)pyrimidinedione in 25 mL of 85% hydrazine is heated to 60° C., where it stirs for about 18 hours. After this time the reaction mixture is concentrated under reduced pressure, yielding 3-(2-methylsulfonylamino-4-chloro-6-fluorobenzoxazol-7-yl)-1-methyl-6-trifluoromethyl-2,4-(1H,3H)-pyrimidinedione.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][CH3:9])[CH:3]=1.[O:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=2)[CH2:12][CH2:11]1>>[CH3:9][NH:8][C:4]1[CH:3]=[C:2]([NH:20][C:19]2[CH:18]=[CH:17][C:16]([N:13]3[CH2:14][CH2:15][O:10][CH2:11][CH2:12]3)=[CH:22][CH:21]=2)[N:7]=[CH:6][N:5]=1
Reactant: Nc1ccc(N2CCOCC2)cc1
Reactant: CNc1cc(Cl)ncn1
Product: CNc1cc(Nc2ccc(N3CCOCC3)cc2)ncn1

Procedure:
The title compound is prepared analogously as described in Example 114A from (6-chloro-pyrimidin-4-yl)-methylamine and 4-morpholinoaniline.
Reaction SMILES: [CH2:1]([NH:13][CH2:14][CH2:15][CH2:16][NH2:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[C:18]1(=O)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>>[CH:18]1([NH:17][CH2:16][CH2:15][CH2:14][NH:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: CCCCCCCCCCCCNCCCN
Reactant: O=C1CCCCC1
Product: CCCCCCCCCCCCNCCCNC1CCCCC1

Procedure:
Following the general procedure of Example 33, but starting with N-dodecyl-1,3-propanediamine and cyclohexanone, the title compound is produced; IR νmax (neat) 3292, 2925, 2854, 2810, 1466, 1450, 1367, 1130 and 721 cm-1. (PLA2)
Reaction SMILES: [C:1]([O:5]O)([CH3:4])([CH3:3])C.[Cl-].[Na+].[C:9]([O:32][CH:33]1[CH2:38][C:37]([CH3:40])([CH3:39])[NH:36][C:35]([CH3:42])([CH3:41])[CH2:34]1)(=[O:31])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH:21]1[CH2:26][C:25]([CH3:28])([CH3:27])[NH:24][C:23]([CH3:30])([CH3:29])[CH2:22]1)=[O:19]>C(C1C=CC=CC=1)C.CCCCCCC.[O-]CCCC.[O-]CCCC.[O-]CCCC.[O-]CCCC.[Ti+4]>[C:9]([O:32][CH:33]1[CH2:38][C:37]([CH3:40])([CH3:39])[N:36]([O:5][CH:1]([CH3:4])[C:3]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:35]([CH3:42])([CH3:41])[CH2:34]1)(=[O:31])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH:21]1[CH2:26][C:25]([CH3:27])([CH3:28])[N:24]([O:5][CH:1]([CH3:4])[C:3]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:23]([CH3:29])([CH3:30])[CH2:22]1)=[O:19]
Reactant: CC(C)(C)OO
Reactant: CC1(C)CC(OC(=O)CCCCCCCCC(=O)OC2CC(C)(C)NC(C)(C)C2)CC(C)(C)N1
Agent: [Ti+4]
Agent: CCCC[O-]
Agent: [Cl-]
Solvent: CCc1ccccc1
Solvent: CCCCCCC
Product: CC(ON1C(C)(C)CC(OC(=O)CCCCCCCCC(=O)OC2CC(C)(C)N(OC(C)c3ccccc3)C(C)(C)C2)CC1(C)C)c1ccccc1
Temperature: 136 °C
Yield: 13.3 %

Procedure:
A 2-phase mixture of 85.7 g (0.666 mol) of 70% aqueous tert-butyl hydroperoxide, 250 ml of ethylbenzene and 10 g of sodium chloride is agitated in a separatory funnel. The organic layer is dried over anhydrous magnesium sulfate. A mixture of 40.0 g (0.0832 mol) of bis-(2,2,6,6-tetramethylpiperidin-4-yl) sebacate and the tert-butyl hydroperoxideethylbenzene solution is heated to reflux (136° C.) under a nitrogen atmosphere. To this mixture is added over a 5-minute period, a solution of 5.0 g of titanium tetrabutoxide in 35 ml of ethylbenzene. The reaction mixture becomes red and water is collected in a Dean-Stark trap. The reaction mixture is heated at reflux for 18 hours. The red color remains. The solids are then removed by filtration, and the filtrate is concentrated under reduced pressure to give a red oil. The oil is dissolved in heptane (100 ml) and passed through a short column of silica gel with additional heptane. Further purification (Waters Prep 500A HPLC; 29:1 heptane:ethyl acetate) affords 4.0 g (7% yield) of the title compound as a cloudy, colorless syrup.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18]([CH3:22])[N:17]=3)=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1)=[O:4].[Br:23]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18]([CH2:22][Br:23])[N:17]=3)=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cccc2cc(Oc3ccnc(C)n3)ccc12
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cccc2cc(Oc3ccnc(CBr)n3)ccc12

Procedure:
A solution of 8.55 g (29.05 mMol) 6-(2-methyl-pyrimidin-4-yloxy)-naphthalene-1-carboxylic acid methyl ester, 13.5 g N-bromo-succinimide (95%; 72.6 mMol) and 3.31 g (20 mMol) α,α-azoisobytyronitrile in 1.85 l CCl4 is heated to 80° C. and irradiated (125 W lamp) for 2 days. Then 5.44 g N-bromo-succinimide and 1.66 g α,α-azoisobytyronitrile are added and irradiation at 80° C. is continued for another day. The reaction mixture is concentrated, the residue re-dissolved in EtOAc and water, the aq. layer separated off and extracted with EtOAc. The organic layers are washed with water and brine, dried (Na2SO4) and concentrated. Column chromatography (SiO2; hexane/EtOAc 1:1) gives the title compound: MS: [M+1]+=373/375; TLC(hexane/EtOAc 1:1): Rf=0.35.
Reaction SMILES: C1C2B3C(CCC2)CCCC3CC1.[Li].[C:15]12([CH3:25])[C:22]([CH3:24])([CH3:23])[CH:19]([CH2:20][CH2:21]1)[CH2:18][C:16]2=[O:17]>>[CH3:23][C:22]1([CH3:24])[C:15]2([CH3:25])[CH:16]([OH:17])[CH2:18][CH:19]1[CH2:20][CH2:21]2
Reactant: CC12CCC(CC1=O)C2(C)C
Agent: C1CC2CCCC3CCCC(C1)B23
Agent: [Li]
Product: CC1(C)C2CCC1(C)C(O)C2

Procedure:
A particularly preferred embodiment of the present invention is the use of the borohydrides described herein for the hydrogenation of ketones. Thus, the present compounds further react with ketones to give a predominance of one isomer. For example, lithium perhydro-9b-boraphenalylhydride reacts with camphor to give a quantitative yield of 99% isoborneol. The same hydride reacts with 2-methyleyclopentanone to give cis-2-methylcyclopentanol of 94% epimeric purity. In contrast, sodium borohydride reduction of 2-methylcyclopentanone gives only 31% of the cis-epimer while lithium tri-n-butylborohydride, which has the same number of carbon atoms as the phenalyl compound but as three long alkyl groups attached to the boron, gives only 67% of the cis-epimer.
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:6](=[CH:7][C:8]3[C:9]4[C:14]=2[C:13](=[O:16])[N:12]([CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])[C:11](=[O:22])[C:10]=4[CH:23]=[CH:24][CH:25]=3)[CH:5]=[CH:4][CH:3]=1.[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([N:32]=[C:33]=[S:34])[CH:27]=1>C(#N)C>[CH3:21][N:19]([CH3:20])[CH2:18][CH2:17][N:12]1[C:11](=[O:22])[C:10]2[CH:23]=[CH:24][CH:25]=[C:8]3[C:9]=2[C:14](=[C:15]2[C:2]([NH:1][C:33]([NH:32][C:28]4[CH:27]=[N:26][CH:31]=[CH:30][CH:29]=4)=[S:34])=[CH:3][CH:4]=[CH:5][C:6]2=[CH:7]3)[C:13]1=[O:16]
Reactant: CN(C)CCN1C(=O)c2cccc3cc4cccc(N)c4c(c23)C1=O
Reactant: S=C=Nc1cccnc1
Solvent: CC#N
Product: CN(C)CCN1C(=O)c2cccc3cc4cccc(NC(=S)Nc5cccnc5)c4c(c23)C1=O
Temperature: 25 °C

Procedure:
100 mg of 11-amino-2-[2-(dimethylamino)ethyl]-1H-dibenzo[de,h]isoquinoline-1,3(2H)-dione (obtained in example 3) (0.30 mmole) were dissolved in 8 ml of acetonitrile. 67 μl (2 molar equivalents) of 3-pyridyl isothiocyanate was added and the reaction mixture was maintained at room temperature for 16 hours. The solvent was then evaporated under reduced pressure and the residue was submitted to a flash chromatography (SiO2, CH2Cl2/MeOH 95/5). 132 mg of the desired product (formula shown hereinabove) were isolated as a red powder (yield=94%) which was characterized as follows:
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]3[C:13](=[C:14]([C:16]([NH2:18])=[O:17])[CH:15]=2)[NH:12][CH:11]=[C:10]3[CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:25][C:26]1[S:27][C:28]([S:32](Cl)(=[O:34])=[O:33])=[C:29]([CH3:31])[N:30]=1.C(N(CC)CC)C>>[CH3:25][C:26]1[S:27][C:28]([S:32]([N:22]2[CH2:23][CH2:24][CH:19]([C:10]3[C:9]4[C:13](=[C:14]([C:16]([NH2:18])=[O:17])[CH:15]=[C:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)[CH:8]=4)[NH:12][CH:11]=3)[CH2:20][CH2:21]2)(=[O:34])=[O:33])=[C:29]([CH3:31])[N:30]=1
Reactant: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCNCC3)c[nH]c12
Reactant: Cc1nc(C)c(S(=O)(=O)Cl)s1
Solvent: CCN(CC)CC
Product: Cc1nc(C)c(S(=O)(=O)N2CCC(c3c[nH]c4c(C(N)=O)cc(-c5ccccc5)cc34)CC2)s1

Procedure:
Following the general procedure in example 267, 5-phenyl-3-(4-piperidinyl)-1H-indole-7-carboxamide (32 mg, 0.1 mmol), 2,4-dimethyl-1,3-thiazole-5-sulfonyl chloride (24.8 mg, 0.15 mmol) and triethylamine (0.06 mL, 0.3 mmol) were reacted to form the desired product which was purified by Gilson HPLC (CH3CN/Water, 0.1% TFA) (12.7 mg, 26%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[CH:13]=C)=[CH:5][CH:4]=1.I([O-])(=O)(=O)=[O:16].[Na+].C(=O)([O-])O.[Na+]>O1CCCC1.O.[Os](=O)(=O)(=O)=O>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[CH:13]=[O:16])=[CH:5][CH:4]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=Cc1cccc2ccc(OC)cc12
Agent: O=[Os](=O)(=O)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc2cccc(C=O)c2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The compound obtained in Step B (13.4 mmol) and osmium tetroxide (0.16 mmol) are dissolved in 70 ml of a mixture of tetrahydrofuran/water (1/1). Sodium periodate (26.9 mmol) is added in small portions and the reaction mixture is stirred for 2 hours at ambient temperature. The reaction mixture is poured into 50 ml of 5% sodium hydrogen carbonate solution, the insoluble material is filtered off and the aqueous phase is extracted twice with 75 ml of ether. The organic phase is washed with water, decolourised and evaporated. The precipitate obtained is recrystallised from cyclohexane and yields the title product in the form of a white solid.
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[CH3:5][CH2:6][O:7][C:8]([CH2:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:12])=[O:9]>O.C(O)(=O)C>[CH2:6]([O:7][C:8](=[O:9])[C:10](=[N:1][OH:3])[C:11](=[O:12])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH3:5]
Reactant: O=N[O-]
Reactant: CCOC(=O)CC(=O)c1ccccc1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)C(=NO)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.6 %

Procedure:
A solution of sodium nitrite (56.5 g, 0.815 mol) in water (400 mL) was added to a solution of ethyl benzoyl acetate (120 g, 0.625 mol) in glacial acetic acid (300 mL) at 0-10° C. over a period of 2 h. The product started precipitating during the course of addition and the reaction mixture was warmed to room temperature and stirred for 30 min. Water (2.5 L) was added and the mixture was stirred for a further 30 min and then filtered under suction. The solid was washed with water (20 mL), petroleum ether (200 mL) and then dissolved in chloroform (700 mL). The filtrate was extracted with chloroform (2×100 mL) and the combined organic phase was washed with water (2×200 mL), brine solution (2×250 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to afford ethyl-2-hydroxyimino-3-oxo-3-phenyl-propanoate (122.5 g, 88%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([NH:29][S:30]([CH2:33][C:34]([F:37])([F:36])[F:35])(=[O:32])=[O:31])=[CH:25][CH:24]=2)[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([CH2:15][C:16]1([CH3:21])OCC[O:17]1)=[CH:10][CH:9]=2)=[O:5])[CH3:2].S(=O)(=O)(O)O>CC(C)=O>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([NH:29][S:30]([CH2:33][C:34]([F:37])([F:36])[F:35])(=[O:32])=[O:31])=[CH:25][CH:24]=2)[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([CH2:15][C:16](=[O:17])[CH3:21])=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2cc(CC3(C)OCCO3)ccc2n1Cc1ccc(NS(=O)(=O)CC(F)(F)F)cc1
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: CCOC(=O)c1cc2cc(CC(C)=O)ccc2n1Cc1ccc(NS(=O)(=O)CC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 59.6 %

Procedure:
To a solution of crude 1-[4-(2,2,2-trifluoro-ethanesulfonylamino)-benzyl]-5-(2-methyl-[1,3]dioxolan-2-ylmethyl)-1H-indole-2-carboxylic acid ethyl ester (2.85 g, ≈5 mmol) in acetone (60 ml) was added concentrated sulfuric acid (0.6 ml). The solution was stirred at room temperature for about 45 minutes, and most of the solvent was removed under reduced pressure. The residue was taken up in ethyl acetate, washed with water and brine, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography (silica, 130 g) eluting with a gradient from 30% -ethyl acetate/hexane to 40% ethyl acetate/hexane, to give the title compound (1.48 g).
Reaction SMILES: N[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:13]([OH:16])(=[O:15])=[O:14])=[CH:9][C:10]=2[OH:12])[CH:5]=[C:4]([S:17]([OH:20])(=[O:19])=[O:18])[CH:3]=1.N([O-])=O.[Na+].[Cl-].[Na+].[BrH:27]>O.[Cu]Br>[Br:27][C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:13]([OH:16])(=[O:15])=[O:14])=[CH:9][C:10]=2[OH:12])[CH:5]=[C:4]([S:17]([OH:20])(=[O:19])=[O:18])[CH:3]=1
Reactant: Nc1cc(S(=O)(=O)O)cc2cc(S(=O)(=O)O)cc(O)c12
Reactant: Br
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Cl-]
Solvent: O
Product: O=S(=O)(O)c1cc(O)c2c(Br)cc(S(=O)(=O)O)cc2c1
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
1-Amino-8-hydroxynaphthalene-3,6-disulfonic acid (72% strength, 44.4 g, 0.1 mol) was stirred in a mixture of water (340 mls) and 48% hydrobromic acid (20 mls). The suspension was cooled to 0-5° C. and sodium nitrite (7.6 g, 0.11 mol) was added in small portions. The mixture was stirred for 2 hours at 0-5° C. and then the excess nitrous acid was destroyed by the addition of sulfamic acid solution. Further 48% hydrobromic acid (70 mls) was added and the mixture cooled to 5° C. A solution of copper (I) bromide (14.4 g, 0.1 mol) in 48% hydrobromic acid (30 mls) and water (20 mls) was then added dropwise at 0-5° C. The mixture was stirred for 10 minutes at 5° C. and then the temperature was slowly raised to and maintained at 90° C. for 1 hour. The reaction mixture was cooled to room temperature and sodium chloride added (30% w/v). The product was collected by filtration and washed with 20% sodium chloride solution. The dried product (56 g) contained 49% sodium chloride. Yield 74%.