Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:15](=[O:16])[CH2:14][C:12](=[O:13])[N:11]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:9]1=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[S:30]1[CH:34]=[CH:33][CH:32]=[C:31]1[CH2:35][C:36](Cl)=[O:37].CCOCC>ClCCl>[CH2:1]([N:8]1[C:15](=[O:16])[CH:14]([C:36](=[O:37])[CH2:35][C:31]2[S:30][CH:34]=[CH:33][CH:32]=2)[C:12](=[O:13])[N:11]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:9]1=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)Cc1cccs1
Reactant: O=C1CC(=O)N(Cc2ccccc2)C(=O)N1Cc1ccccc1
Solvent: CCOCC
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Cc1cccs1)C1C(=O)N(Cc2ccccc2)C(=O)N(Cc2ccccc2)C1=O
Temperature: 0 °C
Yield: 70.8 %

Procedure:
To a solution of 1,3-dibenzylbarbituric acid 154 mg (0.500 mmol) in dry dichloromethane 2.0 mL under a nitrogen atmosphere, added was pyridine 1.0 mL (12 mmol) and stirred at 0° C. Added was 2-thienylacetyl chloride 80 mg (0.50 mmol, 1.00 equivalent) in dichloromethane 1.0 mL to the solution slowly during a period of 20 minutes, then stirred at room temperature for 3 hours. Added was ether 50 mL and washed the organic layer with 2 M hydrochloric acid and saturated brine, and dried over sodium sulfate. Purified was the crude product 216 mg after removal of the solvent under the reduced pressure, by column chromatography (silica gel, eluted with dichloromethane). It obtained 1,3-dibenzyl-5-(2-thienylacetyl)barbituric acid 153 mg as yellow viscous oil (56.9% yield).
Reaction SMILES: [CH:1](N(CC)C(C)C)(C)C.C[Si](C=[N+]=[N-])(C)C.CCCCCC.[CH:23]([C:26]1[C:31]([OH:32])=[CH:30][CH:29]=[C:28]([CH:33]([CH3:35])[CH3:34])[C:27]=1[NH:36][C:37](=[O:49])[CH2:38][N:39]1[CH2:44][CH2:43][N:42]([CH2:45][CH2:46][CH2:47][OH:48])[CH2:41][CH2:40]1)([CH3:25])[CH3:24]>C(#N)C.CO>[CH:23]([C:26]1[C:31]([O:32][CH3:1])=[CH:30][CH:29]=[C:28]([CH:33]([CH3:35])[CH3:34])[C:27]=1[NH:36][C:37](=[O:49])[CH2:38][N:39]1[CH2:44][CH2:43][N:42]([CH2:45][CH2:46][CH2:47][OH:48])[CH2:41][CH2:40]1)([CH3:24])[CH3:25]
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)c1ccc(O)c(C(C)C)c1NC(=O)CN1CCN(CCCO)CC1
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CC#N
Solvent: CCCCCC
Solvent: CO
Product: COc1ccc(C(C)C)c(NC(=O)CN2CCN(CCCO)CC2)c1C(C)C
Reaction time: 96 h
Yield: 86.9 %

Procedure:
N,N-Diisopropylethylamine (513 mg, 3.97 mmol) and a solution of trimethylsilyl diazomethane in hexane (2.0 M, 2.0 ml, 3.97 mmol) were added to a solution of N-(2,6-diisopropyl-3-hydroxyphenyl)-2-[4-(3-hydroxypropyl) piperazin-1-yl]acetamide (500 mg, 1.32 mmol) in a mixed solvent of methanol (8 ml) and acetonitrile (12 ml) and the mixture was stirred for four days. After the reaction, the solvent was evaporated. The residue was made basic by adding an aqueous solution of sodium bicarbonate and extracted with chloroform. The organic layer was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate and the solvent was evaporated therefrom. The residue was purified by a silica gel column chromatography (developing solvent, chloroform methanol=10:1) to provide 449 mg (yield 87%) of N-(2,6-diisopropyl-3-methoxyphenyl)-2-[4-(3-hydroxypropyl) piperazin-1-yl]acetamide.
Reaction SMILES: O=[C:2]1[CH:9]2[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:11][C:3]1([C:12](OCC)=[O:13])[CH2:4]3)[CH2:8]2.Cl.[Cl:18][C:19]1[CH:20]=[C:21]([NH:25][NH2:26])[CH:22]=[CH:23][CH:24]=1.C(N(CC)CC)C>C(O)C>[Cl:18][C:19]1[CH:20]=[C:21]([N:25]2[N:26]=[C:2]3[CH:9]4[CH2:10][CH:5]5[CH2:4][C:3]3([CH2:11][CH:7]([CH2:6]5)[CH2:8]4)[C:12]2=[O:13])[CH:22]=[CH:23][CH:24]=1
Reactant: NNc1cccc(Cl)c1
Reactant: CCOC(=O)C12CC3CC(CC(C3)C1=O)C2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C1N(c2cccc(Cl)c2)N=C2C3CC4CC(C3)CC12C4
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of ethyl 2-oxoadamantane-1-carboxylate (5) (1.0 g, 4.5 mmol) and 3-chlorophenylhydrazine hydrochloride (3.6 g, 20 mmol) in 40 ml of ethanol is added triethylamine (2.0 g, 20 mmol). The reaction mixture is stirred at room temperature under a nitrogen atmosphere for 20 hours, then heated to reflux for 2 hours. After cooling to ambient temperature, the solvent is removed under reduced pressure and the crude residue solid is dissolved in 30 ml of methylene chloride. The organic extract is washed with 25 ml of diluted hydrochloric acid to remove the excess of 3-chlorophenylhydrazine, then dried over anhydrous magnesium sulfate. The solvent is evaporated to leave the title compound (6) as a dark-colored, viscous oil which is flash-chromatographed on silica gel using ether-pentane (2:8) as the eluent. Subsequent recrystallization from methanol provides the pure product as pale yellow needles melting at 119.5°-120.5° C. Anal. Calcd for C17H17ClN2O: C, 67.88; H, 5.70; N, 9:31; Cl, 11.79. Found: C, 67.54; H, 5.75; N, 9.12; Cl, 11.86.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:19][C:20]3[N:21]=[C:22]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[O:23][C:24]=3[CH3:25])[CH:13]=2)[CH:7]=[CH:6][C:5]=1[CH2:32][CH2:33][C:34]([O:36]CC)=[O:35])[CH3:2].O1CCCC1.[OH-].[Na+].Cl>O.C(O)C>[CH2:1]([O:3][C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:19][C:20]3[N:21]=[C:22]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[O:23][C:24]=3[CH3:25])[CH:13]=2)[CH:7]=[CH:6][C:5]=1[CH2:32][CH2:33][C:34]([OH:36])=[O:35])[CH3:2]
Reactant: CCOC(=O)CCc1ccc(OCc2cccc(OCc3nc(-c4ccccc4)oc3C)c2)cc1OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: CCOc1cc(OCc2cccc(OCc3nc(-c4ccccc4)oc3C)c2)ccc1CCC(=O)O
Temperature: 50 °C
Reaction time: 2 h
Yield: 84.4 %

Procedure:
To a mixture of ethyl 3-[2-ethoxy-4-[3-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]propionate (0.94 g), tetrahydrofuran (4 mL) and ethanol (4 mL) was added a 1N aqueous sodium hydroxide solution (3.6 mL) and the mixture was stirred at 50° C. for 2 hrs. 1N Hydrochloric acid and water were added to acidify the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give crystals (0.75 g, 85%) of 3-[2-ethoxy-4-[3-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]propionic acid. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 122-123° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])[CH2:12][CH:11]2[OH:26])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].Cl[CH2:28][C:29]1[CH:30]=[CH:31][C:32]2[O:37][CH2:36][C:35](=[O:38])[N:34]([CH2:39][CH2:40][CH2:41][O:42][CH3:43])[C:33]=2[CH:44]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[O:17])[CH2:12][CH:11]2[O:26][CH2:28][C:29]2[CH:30]=[CH:31][C:32]3[O:37][CH2:36][C:35](=[O:38])[N:34]([CH2:39][CH2:40][CH2:41][O:42][CH3:43])[C:33]=3[CH:44]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COCCCN1C(=O)COc2ccc(CCl)cc21
Reactant: COc1ccc(C2CCN(C(=O)OCc3ccccc3)CC2O)cc1F
Product: COCCCN1C(=O)COc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(OC)c(F)c3)cc21

Procedure:
Analogously to Method D, 0.050 g of benzyl 4-(3-fluoro-4-methoxyphenyl)-3-hydroxypiperidine-1-carboxylate and 0.042 g of 6-chloromethyl-4-(3-methoxypropyl)-4H-benzo[1,4]oxazin-3-one are reacted. The title compound is obtained as a colourless resin. Rf=0.26 (2:1 EtOAc-heptane); Rt=5.10.
Reaction SMILES: O=CCCCNC(=O)C1C=CC=CC=1.[OH:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21]([C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=1)=[O:22]>>[O:15]=[CH:16][CH2:17][CH2:18][CH2:19][NH:20][C:21]([C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=1)=[O:22]
Reactant: O=C(NCCCCO)c1ccc2ccccc2c1
Agent: O=CCCCNC(=O)c1ccccc1
Product: O=CCCCNC(=O)c1ccc2ccccc2c1

Procedure:
Naphthalene-2-carboxylic acid (4-oxo-butyl)-amide (2E) is prepared analogously to 1E starting with 2D.
Reaction SMILES: [C:1]([N+:4]1([O-])[CH2:9][CH2:8][C:7](=[C:10]2[C:16]3=[N:17][C:18]([CH3:21])=[CH:19][CH:20]=[C:15]3[CH2:14][CH2:13][C:12]3[CH:22]=[C:23]([Cl:26])[CH:24]=[CH:25][C:11]2=3)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].N1C=CC=CC=1CC(N1CCC(=C2C3=NC=CC=C3CCC3C=C(Cl)C=CC2=3)CC1)=O>>[C:1]([N:4]1[CH2:9][CH2:8][C:7](=[C:10]2[C:16]3=[N:17][C:18]([CH3:21])=[CH:19][CH:20]=[C:15]3[CH2:14][CH2:13][C:12]3[CH:22]=[C:23]([Cl:26])[CH:24]=[CH:25][C:11]2=3)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)[N+]1([O-])CCC(=C2c3ccc(Cl)cc3CCc3ccc(C)nc32)CC1
Agent: O=C(Cc1ccccn1)N1CCC(=C2c3ccc(Cl)cc3CCc3cccnc32)CC1
Product: CC(=O)N1CCC(=C2c3ccc(Cl)cc3CCc3ccc(C)nc32)CC1

Procedure:
1-acetyl-4-(8-chloro-5,6-dihydro-2-methyl-11 H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidine N-oxide ie., ##STR10## 1-(2-pyridylacetyl)-4-(8-chloro-5,6-dihydro-11 H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidine;
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:19])[C:11]([NH:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:12][CH:13]=2)=[CH:4][N:3]=1.[Br:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH:23]=O.OOS([O-])=O.[K+].S([O-])([O-])(=O)=S.[Na+].[Na+]>CN(C=O)C.O>[Br:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[C:23]1[N:14]([C:15]([CH3:16])([CH3:18])[CH3:17])[C:11]2[CH:12]=[CH:13][C:8]([C:5]3[CH:4]=[N:3][C:2]([NH2:1])=[N:7][CH:6]=3)=[CH:9][C:10]=2[N:19]=1
Reactant: O=Cc1ccccc1Br
Reactant: CC(C)(C)Nc1ccc(-c2cnc(N)nc2)cc1N
Agent: O=S([O-])([O-])=S
Agent: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)n1c(-c2ccccc2Br)nc2cc(-c3cnc(N)nc3)ccc21
Reaction time: 1 h
Yield: 48.7 %

Procedure:
To a solution of 4-(2-amino-pyrimidin-5-yl)-N1-tert-butyl-benzene-1,2-diamine (1 g, 3.89 mmol) in DMF (30 mL) is added 2-bromobenzaldehyde (0.7 mL, 5.83 mmol) at room temperature. Oxone (2.4 g, 3.89 mmol) in H2O (5 mL) is added and the solution is stirred for 1 hour. Saturated sodium thiosulfate solution (10 mL) is added and the mixture is extracted with EtOAc (3×15 mL) and H2O (20 mL). The combined organic layer is dried (MgSO4), filtered and concentrated. The residue is purified by silica gel flash column chromatography eluting with 10% MeOH in CH2Cl2 to afford 5-[2-(2-bromo-phenyl)-1-tert-butyl-1H-benzimidazol-5-yl]-pyrimidin-2-ylamine (800 mg, 48%) as a white solid.
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1)[CH2:6][O:7][C@H:8]1[O:13][CH2:12][CH2:11][N:10]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21]C)=[O:20])[C@@H:9]1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[OH-].[Na+]>CO>[F:37][C:2]([F:1])([F:36])[C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([C:32]([F:33])([F:34])[F:35])[CH:31]=1)[CH2:6][O:7][C@H:8]1[O:13][CH2:12][CH2:11][N:10]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])[C@@H:9]1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COC(=O)CCCCCN1CCO[C@H](OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H]1c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCCCCN1CCO[C@H](OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H]1c1ccccc1
Yield: 89.4 %

Procedure:
A solution of 0.15 g (0.28 mmol) of 2-(S)-(3,5-Bis(trifluoromethyl)benzyloxy)-4-(methoxycarbonylpentyl)-3-(R)-phenylmorpholine (from Example 64) in 3 mL of MeOH was saponified by treating with 0.5 mL of 5N NaOH for 40 min at 65° C. The solution was cooled, concentrated and the residue was diluted with water. The aqueous solution was adjusted to pH 6 by adding 2N HCl and it was extracted with EtOAc. The organic layer was washed with brine, dried and concentrated. The residue upon chromatography on a flash column with 50% EtOAc/hexane furnished 0.13 g (89%) of the product
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([N:8]2[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:21]2[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[N:23]=[C:22]2[NH:30][CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[CH:16][CH:15]=1.CN(C)C=O>C1C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][CH2:10][CH2:9][N:34]2[CH2:35][CH2:36][CH:31]([NH:30][C:22]3[N:21]([CH2:20][C:17]4[CH:18]=[CH:19][C:14]([F:13])=[CH:15][CH:16]=4)[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[N:23]=3)[CH2:32][CH2:33]2)=[O:7])=[CH:11][CH:12]=1
Reactant: O=C(c1ccc(F)cc1)N1CC1
Reactant: Fc1ccc(Cn2c(NC3CCNCC3)nc3ccccc32)cc1
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: O=C(NCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1)c1ccc(F)cc1
Yield: 19 %

Procedure:
To 3.96 parts of 1-(4-fluorobenzoyl)aziridine, dissolved in 16 parts of benzene, are added 3.25 parts of 1-[(4-fluorophenyl)methyl]-N-(4-piperidinyl)-1H-benzimidazol-2-amine, 90 parts of benzene and 45 parts of N,N-dimethylformamide. The whole is stirred and refluxed for 5 hours. The reaction mixture is cooled and poured onto water. The layers are separated and the aqueous phase is extracted with methylbenzene. The combined organic phases are dried, filtered and evaporated. The residue is crystallized from a mixture of 2-propanone and 2,2'-oxybispropane, yielding 1part (19%) of 4-fluoro-N-[2-{4-[1-(4-fluorophenylmethyl)-1H-benzimidazol-2-ylamino]-1-piperidinyl}ethyl]benzamide; mp. 193.7° C.
Reaction SMILES: [O:1]=[C:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C:4](=[CH:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:21]([OH:23])=O)[NH:3]1.[S:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[C:29]([NH2:32])([CH3:31])[CH3:30]>>[S:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[C:29]([NH:32][C:21]([C@H:11]1[CH2:10][CH2:9][C@H:8]2[C@H:7]3[C@H:16]([CH2:15][CH2:14][C@:12]12[CH3:13])[C@:17]1([CH3:20])[C:4]([NH:3][C:2](=[O:1])[CH2:19][CH2:18]1)=[CH:5][CH2:6]3)=[O:23])([CH3:31])[CH3:30]
Reactant: CC(C)(N)c1cccs1
Reactant: C[C@]12CC[C@H]3[C@@H](CC=C4NC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)O
Product: CC(C)(NC(=O)[C@H]1CC[C@H]2[C@@H]3CC=C4NC(=O)CC[C@]4(C)[C@H]3CC[C@]12C)c1cccs1
Yield: 27 %

Procedure:
The title compound was prepared in a yield of 27% in a similar manner to that described in Example 2 by reacting 3-oxo-4-azaandrost-5-ene-17β-carboxylic acid and 1-(2-thienyl)-1-methylethylamine.
Reaction SMILES: [I:1][C:2]1[O:3][C:4]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[C:5]([C:7]([O:9]CC)=[O:8])[N:6]=1.[OH-].C[Sn+](C)C>ClCCCl>[I:1][C:2]1[O:3][C:4]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[C:5]([C:7]([OH:9])=[O:8])[N:6]=1
Reactant: CCOC(=O)c1nc(I)oc1-c1ccc(OC)cc1
Agent: C[Sn+](C)C
Agent: [OH-]
Solvent: ClCCCl
Product: COc1ccc(-c2oc(I)nc2C(=O)O)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of ethyl 2-iodo-5-(4-methoxyphenyl)oxazole-4-carboxylate (1.00 g, 2.7 mmol) in DCE (25 mL) was added trimethyl tin hydroxide (1.70 g, 9.4 mmol) and the resultant mixture stirred at 80° C. for 3 hours. Trimethyl tin hydroxide (0.24 g, 1.3 mmol) was then added and the reaction stirred at 80° C. overnight. The reaction was cooled to room temperature and extracted with DCM. The organic phase was washed with 1M aqueous HCl and brine, dried over MgSO4 and the solvent removed in vacuo to give 2-iodo-5-(4-methoxyphenyl)oxazole-4-carboxylic acid (0.92 g, 2.7 mmol, 99%) as a white solid which was used without further purification. 1H NMR (CDCl3) 3.88 (3H, s), 6.99 (2H, d), 8.13 (2H, d). LCMS (1) Rt: 1.03 min; m/z (ES+) 346.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=[CH:6][C:3]=1[NH:4][CH3:5].[C:16]([C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25](O)=O)=[CH:20][CH:19]=1)#[N:17]>O1CCCC1.C(O)(=O)C>[C:10]1([C:8]2[CH:7]=[CH:6][C:3]3[N:4]([CH3:5])[C:25]([CH2:24][C:21]4[CH:22]=[CH:23][C:18]([C:16]#[N:17])=[CH:19][CH:20]=4)=[N:1][C:2]=3[CH:9]=2)[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CNc1ccc(-c2ccccc2)cc1N
Reactant: N#Cc1ccc(CC(=O)O)cc1
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Cn1c(Cc2ccc(C#N)cc2)nc2cc(-c3ccccc3)ccc21

Procedure:
Prepared analogously to Example 24f from 2-amino-4-phenyl-N-methyl-aniline, 4-cyanophenylacetic acid and N,N'-carbonyldiimidazole in tetrahydrofuran and glacial acetic acid.
Reaction SMILES: [C:1]1([CH3:12])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][NH:8][C:9]([NH2:11])=[S:10].Br.Br[CH2:15][CH2:16]N>C(O)(C)C>[C:1]1([CH3:12])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][NH:8][C:9]1[S:10][CH2:15][CH2:16][N:11]=1
Reactant: Cc1ccccc1NNC(N)=S
Reactant: NCCBr
Agent: Br
Solvent: CC(C)O
Product: Cc1ccccc1NNC1=NCCS1
Temperature: 25 °C

Procedure:
A mixture of 27.2 g. (0.15 moles) of 1-(o-tolyl)-3-thiosemicarbazide, 31 g. (0.15 moles) of 2-bromoethylamine hydrobromide, and 800 ml. of isopropanol are heated at reflux temperature for 16 hours. The reaction mixture is cooled to room temperature and filtered. The solid material is washed with hot water and the aqueous solution is treated with saturated sodium bicarbonate solution. The solid material which separates is filtered, washed with water, and recrystallized with methanol affording 13 g. of 2-(o-tolylhydrazino)-2-thiazoline, m.p. 126°-127° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=[C:5]([C:13]([O:15]C)=[O:14])[C:4]=1[C:17]1[C:22]([C:23]([O:25]C)=[O:24])=[CH:21][C:20]2[O:27][CH2:28][O:29][C:19]=2[C:18]=1[O:30][CH3:31].[OH-].[Na+]>CO>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=[C:5]([C:13]([OH:15])=[O:14])[C:4]=1[C:17]1[C:22]([C:23]([OH:25])=[O:24])=[CH:21][C:20]2[O:27][CH2:28][O:29][C:19]=2[C:18]=1[O:30][CH3:31]
Reactant: COC(=O)c1cc(OC)c(OC)c(OC)c1-c1c(C(=O)OC)cc2c(c1OC)OCO2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(C(=O)O)c(-c2c(C(=O)O)cc3c(c2OC)OCO3)c(OC)c1OC
Yield: 79.4 %

Procedure:
In 20 ml of methanol was dissolved 1.75 g of dimethyl 2,2',3,4-tetramethoxy-3',4'-methylenedioxy-1,1'-biphenyl-6,6'-dicarboxylate obtained in Example 2, and 10 ml of a 10% aqueous solution of sodium hydroxide was added to the solution and the mixture was heated and refluxed for 16 hours. After termination of the reaction, the reaction mixture was cooled and the precipitated crystals were recovered by filtration and recrystallized from methanol to obtain 1.3 g of 2,2',3,4- tetramethoxy-3',4'-methylenedioxy-1,1'-biphenyl-6,6'-dicarboxylic acid (the yield was 81%)
Reaction SMILES: [NH:1]1[C:11]2[C:12]3[CH:3]([CH2:4][C:5](=[O:13])[NH:6][C:7]=3[CH:8]=[CH:9][CH:10]=2)[C:2]1=[O:14]>C1(C)C=CC=CC=1.[O-2].[Mn+4].[O-2]>[NH:1]1[C:11]2[C:12]3[C:3](=[CH:4][C:5](=[O:13])[NH:6][C:7]=3[CH:8]=[CH:9][CH:10]=2)[C:2]1=[O:14]
Reactant: O=C1CC2C(=O)Nc3cccc(c32)N1
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: O=C1Nc2cccc3[nH]c(=O)cc1c23

Procedure:
A mixture of (±)-2a,5-dihydropyrrolo[4,3,2-de]quinoline-2,4(1H,3H)-dione from Step C (200 mg, 1.06 mmol), and manganese (IV) oxide (185 mg, 2.13 mmol) was heated in toluene (3 mL) at 110° C. for 1 h. The mixture was filtered through a pad of Celite, washing with CH2Cl2:MeOH, and the filtrate was concentrated in vacuo to give the title compound. MS: m/z=187 (M+1).
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:7][CH:6]=1.[CH3:21][CH:22]1[CH2:27][NH:26][CH2:25][CH2:24][NH:23]1.C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:8]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:9]=[CH:10][C:5]([O:4][C:3]2[CH:17]=[CH:18][CH:19]=[CH:20][C:2]=2[N:26]2[CH2:25][CH2:24][NH:23][CH:22]([CH3:21])[CH2:27]2)=[CH:6][CH:7]=1
Reactant: Brc1ccccc1Oc1ccc(-c2ccccc2)cc1
Reactant: CC1CNCCN1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: CC1CN(c2ccccc2Oc2ccc(-c3ccccc3)cc2)CCN1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
A mixture of 4-(2-bromo-phenoxy)-biphenyl (0.73 g, 2.25 mmol), rac-2-methylpiperazine (0.285 g, 0.285 mmol), Pd2 dba3 (0.022 g, 1 mol %), rac-binap (0.043 g, 3 mol %) and NaOBut (0.300 g, 3.12 mmol) in dry toluene (15 mL) under argon and stirred at 90° C. overnight. After cooling to room temperature the mixture is filtered and evaporated onto silica gel and and purified by column chromatography eluting with ethyl acetate/heptane 1:2. Yield: 0.264 g (34%). 1H NMR (CDCl3, 500 MHz) 7.55 (m, 2H), 7.49 (m, 2H), 7.38 (m, 2H), 7.27 (m, 1H), 7.10 (m, 1H), 6.90–7.00 (m, 5H), 3.30–3.35 (m, 2H), 2.88 (m, 1H), 2.62–2.80 (m, 3H), 2.30–2.40 (m, 1H) 1.60–2.00 (br, 1H), 0.99 (d, 3H); MS(m/z): 345.1.
Reaction SMILES: C([N:8]1[CH2:15][CH2:14][N:13]([C:16]2[C:17]3[CH:24]=[CH:23][NH:22][C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:12][C:9]21[CH2:11][CH2:10]2)C1C=CC=CC=1.C([O-])=O.[NH4+]>CO.[Pd]>[CH2:11]1[C:9]2([CH2:12][N:13]([C:16]3[C:17]4[CH:24]=[CH:23][NH:22][C:18]=4[N:19]=[CH:20][N:21]=3)[CH2:14][CH2:15][NH:8]2)[CH2:10]1
Reactant: c1ccc(CN2CCN(c3ncnc4[nH]ccc34)CC23CC3)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: c1nc(N2CCNC3(CC3)C2)c2cc[nH]c2n1
Reaction time: 0.25 h
Yield: 165.8 %

Procedure:
To 4-(4-benzyl-4,7-diaza-spiro[2.5]oct-7-yl)-7H-pyrrolo[2,3-d]pyrimidine (intermediate 20) (50 g, 78.36 mmol) in MeOH, was added 10% Pd/C (20 g) and HCOONH4 (98 g, 783.69 mmol) and the reaction mixture was heated to reflux for 30 min. The reaction mixture was filtered through celite bed and washed with MeOH and concentrated under reduced pressure. The crude compound was treated with 50% NaOH solution (200 ml) and stirred for 15 min and solid was obtained by filtration. And the solid was wash with 50 ml of water and dried under vacuum. The crude compound (33 g) in acetone (10 times) was heated to reflux for 30 min. The reaction mixture was cooled and filtered and the solid was washed with acetone to afford the title compound as a solid (29.78 g, 83%).
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O[CH2:32][CH2:33][N:34]1[C:39](=[O:40])[CH:38]=[CH:37][C:36]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[N:35]1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1.CCCCCC>[O:40]=[C:39]1[N:34]([CH2:33][CH2:32][N:5]2[C:1](=[O:11])[C:2]3[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:4]2=[O:6])[N:35]=[C:36]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:37]=[CH:38]1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: O=c1ccc(-c2ccccc2)nn1CCO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1CCn1nc(-c2ccccc2)ccc1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of phthalimide (1.0 g, 6.8 mmol), Ph3P (1.9 g, 7.2 mmol), 2-(2-hydroxyethyl)-6-phenylpyridazin-3(2H)-one (1.2 g, 5.5 mmol) in THF (20 mL) was added diisopropyl azodicarboxylate (1.4 mL, 7.2 mmol) dropwise. The resulting hot, clear solution was stirred at room temperature. After 3 h, hexane (40 mL) was added. The slurry was filtered and the solid was washed with ether (6×15 mL) to give the product as a white (2.1 g). MS (ESI pos. ion) calc'd for C20H15N3O3: 345.1; found: 346.4 (MH+). 1H NMR (400 MHz, DMSO-d6) δ ppm 4.03 (dd, 2 H) 4.39 (t, 2 H) 6.99 (d, J=9.78 Hz, 1 H) 7.26 (t, J=7.43 Hz, 2 H) 7.34 (t, J=7.34 Hz, 1 H) 7.50 (d, J=7.24 Hz, 2 H) 7.72-7.82 (m, 4 H) 7.97 (d, J=9.78 Hz, 1 H)
Reaction SMILES: [CH3:1][N:2]1[C:15]([C:16]([O:18]C)=O)=[C:14]([OH:20])[C:5]2[N:6]([CH3:13])[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:4]=2[S:3]1(=[O:22])=[O:21].[NH2:23][C:24]1[S:25][C:26]([CH3:29])=[CH:27][N:28]=1>>[CH3:1][N:2]1[C:15]([C:16]([NH:23][C:24]2[S:25][C:26]([CH3:29])=[CH:27][N:28]=2)=[O:18])=[C:14]([OH:20])[C:5]2[N:6]([CH3:13])[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:4]=2[S:3]1(=[O:22])=[O:21]
Reactant: Cc1cnc(N)s1
Reactant: COC(=O)C1=C(O)c2c(c3ccccc3n2C)S(=O)(=O)N1C
Product: Cc1cnc(NC(=O)C2=C(O)c3c(c4ccccc4n3C)S(=O)(=O)N2C)s1
Yield: 90 %

Procedure:
2,5-Dihydro-2,5-dimethyl-4-hydroxy-N-(5-methyl-2-thiazolyl)-1,2-thiazino[5,6-b]indole-3-carboxamide-1,1-dioxide was prepared analogous to Example 1 from methyl 2,5-Dihydro-2, 5-dimethyl-4-hydroxy-1,2-thiazino[5,6-b]indole-3-carboxylate 1,1-dioxide and 2-amino-5-methyl-thiazole with a yield of 90% of theory; M.p.: 250° C. (decomposition).