Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:24])[C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([C:16]3[CH:17]=[N:18][C:19]([F:23])=[CH:20][C:21]=3[CH3:22])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH:33]1(B(O)O)[CH2:35][CH2:34]1>O1CCCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>[CH:33]1([C:2]2[CH:3]=[C:4]([CH3:24])[C:5]([N:8]3[CH2:13][CH2:12][N:11]([C:14]([C:16]4[CH:17]=[N:18][C:19]([F:23])=[CH:20][C:21]=4[CH3:22])=[O:15])[CH2:10][CH2:9]3)=[N:6][CH:7]=2)[CH2:35][CH2:34]1
Reactant: Cc1cc(F)ncc1C(=O)N1CCN(c2ncc(Br)cc2C)CC1
Reactant: OB(O)C1CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1CCOC1
Product: Cc1cc(F)ncc1C(=O)N1CCN(c2ncc(C3CC3)cc2C)CC1
Yield: 120.5 %

Procedure:
To a solution of [4-(5-bromo-3-methylpyridin-2-yl)piperazin-1-yl](6-fluoro-4-methylpyridin-3-yl)methanone (2.2 g) described in Preparation Example 113 in tetrahydrofuran (15 mL) were added 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (229 mg), palladium acetate (125 mg), tripotassium phosphate (3.12 g) and cyclopropylboronic acid (721 mg), and the mixture was refluxed for 7 hr. After cooling, the mixture was extracted with ethyl acetate, washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography to give the title compound (2.39 g).
Reaction SMILES: CS(O[CH:6]([CH:18]1[CH2:20][CH2:19]1)[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=O)=O.[OH-].[K+]>CN(C)C=O>[N+:15]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[CH:8]1[CH2:7][CH:6]1[CH:18]1[CH2:20][CH2:19]1)([O-:17])=[O:16]
Reactant: CS(=O)(=O)OC(CCc1ccccc1[N+](=O)[O-])C1CC1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccccc1C1CC1C1CC1
Temperature: 0 °C
Reaction time: 6 h
Yield: 61 %

Procedure:
The 1-cyclopropyl-3-(2-nitrophenyl)-propyl methanesulfonate is dissolved in 15 ml of dimethylformamide and 0.21 g of potassium hydroxide (3.2 mmol) is added, and stirring is carried out for 6 hours at ambient temperature. The reaction mixture is added to ice-water. Extraction is carried out with ethyl acetate, and the organic phase is dried over sodium sulfate and concentrated by evaporation. Chromatography on silica gel is carried out in order to remove by-products (eluant: ethyl acetate/hexane 1:15). After removal of the eluant, 0.28 g of 2-(2-nitrophenyl)-bicyclopropane (61% of theory) is obtained in the form of a brownish liquid (trans:cis ratio: 4.4:1).
Reaction SMILES: C[O-].[Na+].[NH:4]1[CH:8]=[CH:7][N:6]=[CH:5]1.[C:9]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:14]=[CH:13][C:12]([C:15]2([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[CH2:17][O:16]2)=[CH:11][CH:10]=1>CO.CN(C)C=O>[C:9]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:14]=[CH:13][C:12]([C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])([OH:16])[CH2:17][N:4]2[CH:8]=[CH:7][N:6]=[CH:5]2)=[CH:11][CH:10]=1
Reactant: c1c[nH]cn1
Reactant: Clc1ccccc1C1(c2ccc(-c3ccccc3)cc2)CO1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: OC(Cn1ccnc1)(c1ccc(-c2ccccc2)cc1)c1ccccc1Cl
Temperature: 80 °C
Yield: 78.4 %

Procedure:
3.5 g (0.065 mol) of sodium methylate are dissolved in 20 ml of methanol, and 7.5 g (0.11 mole) of imidazole are added. A solution of 15 g (0.05 mol) of 2-(4-biphenylyl)-2-(2-chlorophenyl)-oxirane in 75 ml of dimethylformamide is added dropwise to this mixture and the reaction mixture is heated to 80° C. for 1.5 hours. Thereafter, it is poured onto water and the crystals which form are filtered off and dried. 14.7 g (79% of theory) of 1-(4-biphenylyl)-1-(2-chlorophenyl)-2-imidazol-1-yl-ethanol of melting point 222° C. are obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3[CH:12]=[CH:13][C:14]([CH3:16])=[CH:15][C:9]=3[CH2:8][C@@H:7](N3CCN(CCN4CCOC4=O)CC3)[C:6]=2[CH:31]=1.C(Cl)(Cl)Cl.CS(O)(=O)=[O:38]>C1C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3[CH:12]=[CH:13][C:14]([CH3:16])=[CH:15][C:9]=3[CH2:8][CH:7]([OH:38])[C:6]=2[CH:31]=1
Reactant: Cc1ccc2c(c1)C[C@@H](N1CCN(CCN3CCOC3=O)CC1)c1cc(F)ccc1S2
Reactant: CS(=O)(=O)O
Solvent: c1ccccc1
Solvent: ClC(Cl)Cl
Product: Cc1ccc2c(c1)CC(O)c1cc(F)ccc1S2
Yield: 97 %

Procedure:
5.0 G. of enriched (-)-(R)-3-{2-[4-(8-fluoro-10,11-dihydro-2-methyl-dibenzo[b,f]thiepin-10-yl)-1-piperazinyl]ethyl}-2-oxazolidinone αD20 = -9.5°; α365 = +125.0° (chloroform; c = 2.50%)] are heated under reflux for 18 hours with stirring in 81 ml. of 0.5-M methanesulfonic acid and the mixture is subsequently treated with benzene. The organic phase is washed with water, dried over sodium sulfate and evaporated. The residue is crystallized from n-hexane, and there is obtained racemic 8-fluoro-10,11-dihydro-2-methyl-dibenzo[b,f]thiepin-10-ol having a melting point of 89.5°-90° C. The yield is 97%. This compound can be converted in accordance with the procedure described in Example 1 into the 10-chloro compound which can subsequently be used in Example 1 or 11.
Reaction SMILES: Br[C:2]1[CH:35]=[CH:34][C:5]([CH2:6][C:7]2[N:8]([C:20]3[CH:25]=[CH:24][C:23]([N:26]4[S:30](=[O:32])(=[O:31])[NH:29][C:28](=[O:33])[CH2:27]4)=[CH:22][CH:21]=3)[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[N:11]=2)=[CH:4][CH:3]=1.[NH2:36][C:37]1[CH:42]=[CH:41][C:40](B(O)O)=[CH:39][CH:38]=1>>[NH2:36][C:37]1[CH:42]=[CH:41][C:40]([C:2]2[CH:35]=[CH:34][C:5]([CH2:6][C:7]3[N:8]([C:20]4[CH:25]=[CH:24][C:23]([N:26]5[S:30](=[O:31])(=[O:32])[NH:29][C:28](=[O:33])[CH2:27]5)=[CH:22][CH:21]=4)[CH:9]=[C:10]([C:12]4[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=4[Cl:19])[N:11]=3)=[CH:4][CH:3]=2)=[CH:39][CH:38]=1
Reactant: Nc1ccc(B(O)O)cc1
Reactant: O=C1CN(c2ccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(Br)cc3)cc2)S(=O)(=O)N1
Product: Nc1ccc(-c2ccc(Cc3nc(-c4ccc(Cl)cc4Cl)cn3-c3ccc(N4CC(=O)NS4(=O)=O)cc3)cc2)cc1

Procedure:
5-{4-[2-(4-Bromo-benzyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide (592 mg, 1 mmol) was treated as described in general procedure G using 4-aminophenylboronic acid (274 mg, 2 mmol) to give 5-{4-[2-(4′-amino-biphenyl-4-ylmethyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:18][CH:17]=3)=[C:11]([CH2:30][CH2:31][CH3:32])[N:10]3[N:33]=[C:34]([CH3:36])[N:35]=[C:9]23)[CH2:4][CH2:3]1.[CH3:37][S:38]([CH3:40])=O.C(OC(=O)C)(=O)C>O>[CH3:36][C:34]1[N:35]=[C:9]2[N:8]([C@H:5]3[CH2:6][CH2:7][C@H:2]([O:1][CH2:37][S:38][CH3:40])[CH2:3][CH2:4]3)[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:18][CH:17]=3)=[C:11]([CH2:30][CH2:31][CH3:32])[N:10]2[N:33]=1
Reactant: CS(C)=O
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](O)CC2)c2nc(C)nn12
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCSC)CC2)c2nc(C)nn12
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A mixture of 4′-{[4-(trans-4-hydroxycyclohexyl)-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (1.5 g), dimethyl sulfoxide (45 mL) and acetic anhydride (15 mL) was stirred at room temperature for 17 hr. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.83 g, 49%).
Reaction SMILES: N(=[C:3]1[C:7]2=[C:8]3[C:13](=[CH:14][CH:15]=[C:6]2[NH:5][C:4]1=[O:16])[N:12]=[CH:11][CH:10]=[CH:9]3)N.[O-]CC.[Na+].C(O)(=O)C>O>[CH2:3]1[C:7]2=[C:8]3[C:13](=[CH:14][CH:15]=[C:6]2[NH:5][C:4]1=[O:16])[N:12]=[CH:11][CH:10]=[CH:9]3
Reactant: NN=C1C(=O)Nc2ccc3ncccc3c21
Agent: CC[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=C1Cc2c(ccc3ncccc23)N1
Yield: 33.2 %

Procedure:
A solution of 2.3 g (12 mmol) of 3-H-pyrrolo[3,2-f]quinoline-1,2-dione (prepared from 6-aminoquinoline according to Procedure A) and 2.0 ml (0.06 mol) of hydrazine in 50 ml of DMF and 50 ml of ethanol was stirred at reflux for 2 h. The resulting suspension was allowed to cool to ambient temperature and was then chilled in an ice bath and filtered. The solid was washed with a small volume of ethanol and allowed to air dry to give 1-hydrazono-1,3-dihydropyrrolo[3,2-f]quinolin-2-one as an orange solid (1.8 g, 73%): 1H NMR (DMSO-d6): δ 7.37 (d, J=8.8 Hz, 1H), 7.47 (dd, J=8.4, 4.2 Hz, 1H), 7.81 (d, J=8.8 Hz, 1H), 8.71 (dd, J=4.2, 1.6 Hz, 1H), 8.80 (d, J=8.4 Hz, 1H), 9.90 (br d, J=14.7 Hz, 1H), 10.89 (br d, J=14.7 Hz, 1H), 10.95 (br s, 1H); ESI-MS m/z 213 (M+H)+. A solution 1.8 g (8.5 mmol) of 1-hydrazono-1,3-dihydropyrrolo[3,2-f]quinolin-2-one in 50 ml of freshly prepared 0.5 M sodium ethoxide solution was stirred at reflux for 3 h. The solution was diluted with 50 ml of water, neutralized with acetic acid, and concentrated on a rotary evaporator until cloudy. The solution was stored in a refrigerator overnight. The solid was filtered off, and the filtrate was extracted with three 80-ml portions of EtOAc. A solution of the solid in MeOH/EtOAc was combined with the extracts and passed through a short pad of silica gel, eluting with EtOAc. The solution was then concentrated to a small volume on a rotary evaporator, and the resulting suspension was diluted with an equal volume of ethanol, sonicated, and filtered to give 3-H-pyrrolo[3,2-f]quinoline-2-one as a light green solid (0.52 g, 33%); 1H NMR (DMSO6): δ 3.80 (s, 2H), 7.35 (d, J=8.8 Hz, 1H), 7.44 (dd, J=8.4, 4.2 Hz, 1H), 7.88 (d, J=8.8 Hz, 1H), 8.08 (d, J=8.4 Hz, 1H), 8.70 (dd, J=4.2, 1.6 Hz, 1H), 10.57 (br s, 1H); APCI-MS m/z 183 (M−H)−.
Reaction SMILES: [OH:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+].[CH3:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH2:20]Br>C(O)C>[CH3:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH2:20][O:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: Cc1ccccc1CBr
Reactant: O=C(CO)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Cc1ccccc1COCC(=O)c1ccccc1
Yield: 58.8 %

Procedure:
102 g (0.75 mol) of 2-hydroxyacetophenone and 102 g (0.75 mol) of potassium carbonate in 500 ml of absolute ethanol are initially taken. 139 g (0.75 mol) of 2-methylbenzyl bromide are added dropwise and the mixture is refluxed for 10 h. The mixture is cooled and filtered under suction, after which the filtrate is evaporated down. The crude product is recrystallized from diethyl ether. 106 g (59%) of product are obtained as crystals (mp.=53°-55° C.).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([S:21][CH3:22])[C:10]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([I:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])=[C:6]2[N:5]=[C:4]([CH3:23])[CH:3]=1.[NH3:24]>CO>[I:20][C:17]1[CH:18]=[CH:19][C:14]([S:11]([C:10]2[C:9]([S:21][CH3:22])=[N:8][N:7]3[C:2]([NH2:24])=[CH:3][C:4]([CH3:23])=[N:5][C:6]=23)(=[O:13])=[O:12])=[CH:15][CH:16]=1
Reactant: N
Reactant: CSc1nn2c(Cl)cc(C)nc2c1S(=O)(=O)c1ccc(I)cc1
Solvent: CO
Product: CSc1nn2c(N)cc(C)nc2c1S(=O)(=O)c1ccc(I)cc1

Procedure:
In an analogous manner to that described in Example 4), from 7-chloro-3-(4-iodo-benzenesulphonyl)-5-methyl-2-methylsulphanyl-pyrazolo[1,5-a]pyrimidine and NH3 in MeOH there was obtained 3-(4-iodo-benzenesulphonyl)-5-methyl-2-methylsulphanyl-pyrazolo[1,5-a]pyrimidine-7-ylamine as colorless crystals, m.p.>230°.
Reaction SMILES: [OH:1][N:2]=[C:3]([CH2:18][CH:19]([CH3:21])[CH3:20])[C:4]([NH:6][CH:7]([C:13]([O:15]CC)=[O:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:5].[OH-].[Na+].O.Cl>C(O)C>[CH2:11]([O:10][C:8](=[O:9])[CH:7]([NH:6][C:4](=[O:5])[C:3](=[N:2][OH:1])[CH2:18][CH:19]([CH3:20])[CH3:21])[C:13]([OH:15])=[O:14])[CH3:12]
Reactant: CCOC(=O)C(NC(=O)C(CC(C)C)=NO)C(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(NC(=O)C(CC(C)C)=NO)C(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
In to a solution of 29.19 g of diethyl N-(2-hydroxyimino-4-methylpentanoyl)aminomalonate in 200 ml of ethanol was added 2.8 g of sodium hydroxide and 200 ml of water, then the mixture was stirred at room temperature for 4 hours. The reaction mixture was neutralized with 10% hydrochloric acid, then concentrated. To the residue thus obtained was added 10% hydrochloric acid to make it acidified, then it was extracted with ethyl acetate, and the ethyl acetate layer was washed with water, an aqueous solution saturated with sodium chloride in this order, then dried with magnesium sulfate. The solvent was removed by distillation to obtain 23.0 of N-(2-hydroxyimino-4-methylpentanoyl)aminomalonic acid monoethyl ester.
Reaction SMILES: [NH2-].[Na+].[Cl:3][C:4]1[CH:17]=[CH:16][C:15]2[S:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH:5]=1.N.[I-].[K+].Cl[CH2:22][CH:23]1[CH:28]2[CH2:29][CH2:30][N:25]([CH2:26][CH2:27]2)[CH2:24]1>C1(C)C(C)=CC=CC=1.CN(C)C=O>[Cl:3][C:4]1[CH:17]=[CH:16][C:15]2[S:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([CH2:22][CH:23]3[CH:28]4[CH2:29][CH2:30][N:25]([CH2:26][CH2:27]4)[CH2:24]3)[C:6]=2[CH:5]=1
Reactant: ClCC1CN2CCC1CC2
Reactant: Clc1ccc2c(c1)Nc1ccccc1S2
Agent: N
Agent: [I-]
Agent: [K+]
Solvent: Cc1ccccc1C
Solvent: CN(C)C=O
Product: Clc1ccc2c(c1)N(CC1CN3CCC1CC3)c1ccccc1S2
Reaction time: 32 h

Procedure:
3 ml of a 35% suspension of sodium amide in xylene were added to a suspension of 7 g of 2-chloro-phenothiazine in 100 ml of anhydrous xylene. The mixture was agitated and heated to reflux. When evolution of ammonia ceased (20 hours), a solution of 0.35 g of potassium iodide in 2.3 ml of dimethylformamide was added to the reaction mixture all at once and 34 ml of a 7% solution of 3-chloromethyl-quinuclidine in xylene were then added over a period of an hour. Refluxing of the reaction mixture was continued for 32 hours. After cooling, the reaction mixture was worked up as in Example 2. After recrystallisation of the crude product in in isopropyl oxide, 2-chloro-10-(3-quinuclidinyl-methyl)-phenothiazine, m.p. 122° C, was obtained.
Reaction SMILES: [C:1]1([CH3:36])[CH:6]=[CH:5][C:4]([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=3)=[CH:10][C:9]([CH2:19][CH:20]([C:29]3[CH:30]=[C:31]([CH3:35])[CH:32]=[CH:33][CH:34]=3)[CH2:21][S:22]([C:24]3[NH:28][N:27]=[CH:26][N:25]=3)=[O:23])=[N:8]2)=[CH:3][CH:2]=1.OO.C(O)(=[O:41])C.CO>CN(C)C=O>[C:1]1([CH3:36])[CH:2]=[CH:3][C:4]([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=3)=[CH:10][C:9]([CH2:19][CH:20]([C:29]3[CH:30]=[C:31]([CH3:35])[CH:32]=[CH:33][CH:34]=3)[CH2:21][S:22]([C:24]3[NH:28][N:27]=[CH:26][N:25]=3)(=[O:41])=[O:23])=[N:8]2)=[CH:5][CH:6]=1
Reactant: Cc1ccc(-c2cc(CC(CS(=O)c3ncn[nH]3)c3cccc(C)c3)nn2-c2ccc(C)cc2)cc1
Reactant: CC(=O)O
Agent: OO
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1ccc(-c2cc(CC(CS(=O)(=O)c3ncn[nH]3)c3cccc(C)c3)nn2-c2ccc(C)cc2)cc1
Temperature: 50 °C
Yield: 95 %

Procedure:
To a flask was added 5-[3-(1,5-di-p-tolyl-1H-pyrazol-3-yl)-2-m-tolyl-propane-1-sulfinyl]-1H-[1,2,4]triazole (Example 136; 25 mg, 0.05 mmol), hydrogen peroxide (0.15 mL, 30% solution in water) and acetic acid (0.1 ml). The mixture was heated at 50° C. for 24 h and then cooled. Methanol (0.5 mL) and N,N-dimethylformamide (0.5 mL) were added to dissolve the resulting precipitate. This solution was then purified directly by reversed-phase chromatography yielding the title compound (24 mg, 95%). HPLC: Rt=2.97 (Method B). MS (ESI): mass calculated for C29H29N5O2S, 511.20; m/z found, 512.2 [M+H]+. 1H NMR (500 MHz, DMSO-d6): 14.87 (br s, 1H), 8.72 (s, 1H), 7.18 (d, J=8.2 Hz, 2H), 7.13 (d, J=8.0 Hz, 2H), 7.08 (d, J=7.0 Hz, 1H), 7.07-7.04 (m, 3H), 7.01-6.99 (m, 3H), 6.95 (d, J=7.4 Hz, 1H), 6.15 (s, 1H), 3.91 (d, J=6.6 Hz, 2H), 3.52-3.49 (m, 1H), 3.08 (dd, J=14.7, 7.6 Hz, 1H) 2.91 (dd, J=14.5, 7.4 Hz, 1H), 2.31 (s, 3H), 2.27 (s, 3H), 2.23 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[OH-].[K+].Cl[C:14]1[CH:19]=[N:18][CH:17]=[CH:16][N:15]=1.O>CS(C)=O>[N:15]1[CH:16]=[CH:17][N:18]=[CH:19][C:14]=1[O:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2
Reactant: Clc1cnccn1
Reactant: Oc1cccc2[nH]ccc12
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: c1cc(Oc2cnccn2)c2cc[nH]c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.9 %

Procedure:
A solution of 2.66 g of 4-hydroxyindole in 60 ml of DMSO is combined with 1.4 g of potassium hydroxide (pulverized) and stirred under an N2 atmosphere for one hour at room temperature. After adding 2.5 g of 2-chloropyrazine, the mixture is heated for 2 hours to 100° C., poured into water, and extracted with ethyl acetate. The residue from the organic phase is purified over silica gel, thus obtaining 2.95 g (70%) of 4-(2-pyrazinyloxy)indole, mp 192°- 193° C.
Reaction SMILES: CCN(C(C)C)C(C)C.OC(C(F)(F)F)=O.[NH2:17][CH2:18][C:19]([N:21]1[CH2:26][CH2:25][N:24]([C:27](=[O:38])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:34]([F:37])([F:36])[F:35])[CH2:23][CH2:22]1)=[O:20].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[C:61]1([C:67]2[CH:68]=[CH:69][C:70]([C:73](O)=[O:74])=[N:71][CH:72]=2)[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1>CN(C=O)C.O>[O:20]=[C:19]([N:21]1[CH2:22][CH2:23][N:24]([C:27](=[O:38])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:34]([F:37])([F:35])[F:36])[CH2:25][CH2:26]1)[CH2:18][NH:17][C:73]([C:70]1[CH:69]=[CH:68][C:67]([C:61]2[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=2)=[CH:72][N:71]=1)=[O:74]
Reactant: O=C(O)c1ccc(-c2ccccc2)cn1
Reactant: NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1)c1ccc(-c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 73.3 %

Procedure:
DIPEA (59 mg, 0.45 mmol) was added to a stirred solution of 2-amino-1-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone TFA salt. (78 mg, 0.18 mmol) in DMF (1 mL). HOBT (24 mg, 0.18 mmol) and EDCI.HCl (29 mg, 0.15 mmol) were then added at room temperature. After 2 minutes, 5-phenyl-pyridine-2-carboxylic acid (30 mg, 0.15 mmol) was added and the resulting mixture was stirred at room temperature for 4 hrs. Cold water was then added and the product was extracted with EtOAc and the organic layer was washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to afford 55 mg (73.3% yield) of 5-phenyl-pyridine-2-carboxylic acid {2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-amide LCMS Purity %: 90.8%, 1H NMR (DMSO-d6): δ 9.0 (d, 1H), 8.9-8.8 (t, 1H), 8.3 (dd, 1H), 8.1 (m, 1H), 7.9-7.6 (m, 5H), 7.6-7.4 (m, 4H), 4.4-4.3 (d, 1H), 4.2 (d, 1H), 3.8-3.4 (m, 6H), 3.2-3.1 (m, 2H).
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([N:11]3[C:16](=[O:17])[C:15]([CH2:18][C:19]4[CH:24]=[CH:23][C:22]([C:25]5[C:26]([C:31]#[N:32])=[CH:27][CH:28]=[CH:29][CH:30]=5)=[CH:21][CH:20]=4)=[C:14]([CH2:33][CH2:34][CH3:35])[N:13]4[N:36]=[C:37]([CH3:39])[N:38]=[C:12]34)[CH2:7][CH2:6]2)[O:4]CC1.Cl.O1CCCC1>C(OCC)(=O)C>[CH3:39][C:37]1[N:38]=[C:12]2[N:11]([CH:8]3[CH2:7][CH2:6][C:5](=[O:4])[CH2:10][CH2:9]3)[C:16](=[O:17])[C:15]([CH2:18][C:19]3[CH:20]=[CH:21][C:22]([C:25]4[C:26]([C:31]#[N:32])=[CH:27][CH:28]=[CH:29][CH:30]=4)=[CH:23][CH:24]=3)=[C:14]([CH2:33][CH2:34][CH3:35])[N:13]2[N:36]=1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC3(CC2)OCCO3)c2nc(C)nn12
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC(=O)CC2)c2nc(C)nn12
Temperature: 70 °C
Reaction time: 16 h
Yield: 80.9 %

Procedure:
A mixture of 4′-{[4-(1,4-dioxaspiro[4.5]dec-8-yl)-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (27 g), 6N hydrochloric acid (80 mL) and tetrahydrofuran (160 mL) was stirred at 70° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (20 g, 80%).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:5](=[CH:7][C:8]3[N:9]=[C:10]([NH2:14])[S:11][C:12]=3[CH:13]=2)[N:6]=1.[Cl:15][CH2:16][C:17]([O:19]C1C=CC([N+]([O-])=O)=CC=1)=O>O1CCOCC1>[Cl:15][CH2:16][C:17]([NH:14][C:10]1[S:11][C:12]2[C:8](=[CH:7][C:5]3[N:6]=[C:2]([NH:1][C:17](=[O:19])[CH2:16][Cl:15])[S:3][C:4]=3[CH:13]=2)[N:9]=1)=[O:19]
Reactant: O=C(CCl)Oc1ccc([N+](=O)[O-])cc1
Reactant: Nc1nc2cc3nc(N)sc3cc2s1
Solvent: C1COCCO1
Product: O=C(CCl)Nc1nc2cc3nc(NC(=O)CCl)sc3cc2s1
Yield: 93 %

Procedure:
A mixture consisting of 222 mgm of 2,6-diamino-benzo[1,2-d:5,4-d']bisthiazole, 500 mgm of p-nitro-phenyl chloroacetate and 5 ml of dioxane were refluxed for 15 minutes. The reaction mixture was allowed to cool, and the crystalline substance which had separated out was filtered off, washed and dried. 350 mgm (93% of theory) of 2,6-bis-(chloroacetyl-amino)-benzo[1,2-d:5,4-d']bisthiazole, M.P. 330° C., were obtained.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=2)[C:6](=[C:16]([C:18]2[CH:23]=[N:22][CH:21]=[CH:20][N:19]=2)O)[C:5]1=[O:24])(=[O:3])[CH3:2].C(Cl)(Cl)(Cl)[Cl:26].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCOCC1>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=2)[C:6](=[C:16]([Cl:26])[C:18]2[CH:23]=[N:22][CH:21]=[CH:20][N:19]=2)[C:5]1=[O:24])(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc2c(c1)C(=C(O)c1cnccn1)C(=O)N2C(C)=O
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CC(=O)c1ccc2c(c1)C(=C(Cl)c1cnccn1)C(=O)N2C(C)=O

Procedure:
1.2 g (3.7 mmol) 1,5-diacetyl-3-[pyrazin-2-yl-hydroxy-methylidene]-2-indolinone (Ex. V.23) are dissolved in 50 ml dioxane and refluxed with 2 ml carbon tetrachloride and 2 g triphenylphosphine for 5 h. Then the mixture is left to cool and evaporated down. The residue is chromatographed through a silica gel column with methylene chloride/methanol 25:1, the corresponding fractions are combined and concentrated by rotary evaporation.
Reaction SMILES: [C:1]1([O:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9](Cl)(=[O:13])/[CH:10]=[CH:11]/[CH3:12].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[CH3:8][O:7][C:1]1[CH:6]=[CH:5][C:4]([C:9](=[O:13])/[CH:10]=[CH:11]/[CH3:12])=[CH:3][CH:2]=1
Reactant: COc1ccccc1
Reactant: C/C=C/C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: C/C=C/C(=O)c1ccc(OC)cc1

Procedure:
Anisole (0.3 mL), crotonoyl chloride (24 mg), and aluminium chloride (160 mg) were reacted in dichloromethane (1.5 mL) at from −50° C. to room temperature for 4 hours. The resultant was treated in the same manner as described in Example 1 to obtain the title compound (75 mg).
Reaction SMILES: [Si:1]([O:8][C:9]([CH3:31])([CH3:30])[CH2:10][N:11]1[C:19]2[C:14](=[CH:15][C:16]([O:20][C:21]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:22]=3[C:23]#[N:24])=[CH:17][CH:18]=2)[CH:13]=[N:12]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[Si:1]([O:8][C:9]([CH3:31])([CH3:30])[CH2:10][N:11]1[C:19]2[C:14](=[CH:15][C:16]([O:20][C:21]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:22]=3[CH2:23][NH2:24])=[CH:17][CH:18]=2)[CH:13]=[N:12]1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(C)(Cn1ncc2cc(Oc3ccc(F)cc3C#N)ccc21)O[Si](C)(C)C(C)(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(Cn1ncc2cc(Oc3ccc(F)cc3CN)ccc21)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a cooled (0° C.) solution of 2-{1-[2-(tert-butyldimethylsilanyloxy)-2-methyl-propyl]-1H-indazol-5-yloxy}-5-fluorobenzonitrile (0.071 g, 0.162 mmol) in THF (2 mL) was added LAH (0.32 mL of 1M in THF). The solution was warmed to room temperature and stirred for 1 hour. The reaction mixture was cooled to 0° C. and quenched with water (12 μL), 3N NaOH (12 μL) and water (36 μL). The salts were removed by filtration and the filtrate was concentrated under reduced pressure and used in the next reaction without further purification.