Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:11]=2[Cl:17])=[CH:8][NH:7][CH:6]=1)([O:3]C)=[O:2].Cl>CO>[Cl:17][C:11]1[C:12]([Cl:16])=[CH:13][CH:14]=[CH:15][C:10]=1[C:9]1[C:5]([C:1]([OH:3])=[O:2])=[CH:6][NH:7][CH:8]=1
Reactant: COC(=O)c1c[nH]cc1-c1cccc(Cl)c1Cl
Agent: Cl
Solvent: CO
Product: O=C(O)c1c[nH]cc1-c1cccc(Cl)c1Cl
Temperature: 70 °C

Procedure:
3.2 g of the 3-carboxethoxy-4-(2,3-dichlorophenyl)pyrrole obtained in (a) and 40 ml of a 1:1 mixture of methanol and 5N HCl are stirred for hours at 70° C. After it has cooled to room temperature, the reaction mixture is poured onto ice and extracted with ethyl acetate. The ester phase is in turn extracted with 10% sodium hydroxide solution. The aqueous extract is washed twice with ethyl acetate, acidified with hydrochloric acid and extracted with ethyl acetate. The organic phase is washed with water, dried over magnesium sulfate and filtered. The filtrate is concentrated by evaporation and the resultant 4-(2,3-dichlorphenyl)pyrrole-3-carboxylic acid melts at 180°-182° C.
Reaction SMILES: [C:1]1([C:7]2[C:8]([C:12]#[N:13])=[CH:9][NH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:14]N1C(=O)CCC1=O>O1CCCC1>[Cl:14][C:11]1[NH:10][CH:9]=[C:8]([C:12]#[N:13])[C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: N#Cc1c[nH]cc1-c1ccccc1
Solvent: C1CCOC1
Product: N#Cc1c[nH]c(Cl)c1-c1ccccc1
Reaction time: 48 h
Yield: 97 %

Procedure:
To a solution of 44.3 g (263 mmol) of 4-phenyl-1H-pyrrole-3-carbonitrile (CAS 40167-37-1) in 600 ml of tetrahydrofuran are added portionwise 35.8 g (268 mmol) of N-chlorosuccinimide (CAS 128-09-6) and the mixture is then stirred for 48 hours at reflux. After cooling, the reaction medium is concentrated under reduced pressure and the residue is then taken up in water. The reaction product is extracted with ethyl acetate, the organic phase is dried over sodium sulfate and the solvent is evaporated off under reduced pressure to give a brown solid, which is triturated in diisopropyl ether and then isolated by filtration. The filtrate is concentrated under reduced pressure and the solid residue obtained is triturated in diisopropyl ether and then isolated by filtration. The two batches of solid are combined to give 51.7 g of 5-chloro-4-phenyl-1H-pyrrole-3-carbonitrile in the form of a beige-coloured powder after drying.
Reaction SMILES: C([Li])CCC.[CH2:6]([O:8][C:9]1[CH:22]=[CH:21][C:20]2[C:19]3[C:14](=[C:15]([F:23])[CH:16]=[CH:17][CH:18]=3)[C:13]([F:25])([F:24])[C:12]([F:27])([F:26])[C:11]=2[C:10]=1[F:28])[CH3:7].[I:29]I>C1COCC1>[CH2:6]([O:8][C:9]1[CH:22]=[CH:21][C:20]2[C:19]3[C:14](=[C:15]([F:23])[C:16]([I:29])=[CH:17][CH:18]=3)[C:13]([F:24])([F:25])[C:12]([F:27])([F:26])[C:11]=2[C:10]=1[F:28])[CH3:7]
Reactant: II
Reactant: CCOc1ccc2c(c1F)C(F)(F)C(F)(F)c1c(F)cccc1-2
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOc1ccc2c(c1F)C(F)(F)C(F)(F)c1c-2ccc(I)c1F
Temperature: -60 °C
Reaction time: 1 h
Yield: 75.5 %

Procedure:
Under a nitrogen atmosphere, n-butyllithium (1.65 M, 14.1 mL, 23.26 mmol) was slowly added dropwise, at −60° C. or lower, to a THF (50 mL) solution of compound (87) (6.44 g, 19.38 mmol). The reaction mixture was agitated at −60° C. or lower for 1 hour, and then a THF (30 mL) solution of iodine (5.9 g, 23.26 mmol) was added dropwise thereto. The reaction mixture was returned to room temperature, and then quenched with a saturated aqueous solution of ammonium chloride, and extracted with 50 mL of toluene three times. Combined organic layers were washed with a sodium thiosulfate aqueous solution, a saturated aqueous solution of sodium hydrogencarbonate, water and saturated brine, and then dried over magnesium sulfate, and a solvent was distilled off by an evaporator. The residue was purified by silica gel column chromatography, and thus 2-ethoxy-1,8,9,9,10,10-hexafluoro-7-iodo-9,10-dihydrophenanthrene (88) (6.7 g, yield 74.5%) was obtained.
Reaction SMILES: [CH:1]([NH:4][C:5]1[O:6][CH2:7][C:8](=[O:15])[C:9]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11])([CH3:3])[CH3:2].[NH:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][N:23]=2)[C:18]([CH:25]=O)=[CH:17]1.N1CCC[C@H]1C(O)=O>C(O)C>[NH:16]1[C:24]2=[N:23][CH:22]=[CH:21][CH:20]=[C:19]2[C:18]([CH:25]=[C:7]2[O:6][C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:8]2=[O:15])=[CH:17]1
Reactant: O=Cc1c[nH]c2ncccc12
Reactant: CCOC(=O)C1=C(NC(C)C)OCC1=O
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CCO
Product: CCOC(=O)C1=C(NC(C)C)OC(=Cc2c[nH]c3ncccc23)C1=O
Temperature: 25 °C
Yield: 57.3 %

Procedure:
To a solution of ethyl 2-(isopropylamino)-4-oxo-4,5-dihydrofuran-3-carboxylate (0.50 g, 2.3 mmol) which similarly prepared according to the procedure described in the Example 4, First step and 7-azaindole-3-carboxaldehyde (0.34 g, 2.3 mmol) in ethanol (15 mL), L-proline (0.027 g, 0.23 mmol) was added at ambient temperature. The mixture was refluxed for 16 h. Cooled to ambient temperature, the precipitate was collected by filtration, washed with ethanol then dried to afford the titled compound as solid (0.45 g, y. 56%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[C:7]([C:10]3([C:13]([OH:15])=[O:14])[CH2:12][CH2:11]3)[CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1>CO.O=[Pt]=O>[O:1]1[C:5]2[CH:6]=[C:7]([C:10]3([C:13]([OH:15])=[O:14])[CH2:12][CH2:11]3)[CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: O=C(O)C1(c2ccc3ccoc3c2)CC1
Agent: O=[Pt]=O
Solvent: CO
Product: O=C(O)C1(c2ccc3c(c2)OCC3)CC1
Temperature: 20 °C
Reaction time: 72 h
Yield: 42.2 %

Procedure:
To a solution of 1-(benzofuran-6-yl)cyclopropanecarboxylic acid (370 mg, 1.8 mmol) in MeOH (50 mL) was added PtO2 (75 mg, 20%) at room temperature. The reaction mixture was stirred under hydrogen atmosphere (1 atm) at 20° C. for 3 d. The reaction mixture was filtered and the solvent was evaporated in vacuo to afford the crude product, which was purified by prepared HPLC to give 1-(2,3-dihydrobenzofuran-6-yl)cyclopropanecarboxylic acid (155 mg, 42%). 1H NMR (300 MHz, MeOD) δ 7.13 (d, J=7.5. Hz, 1 H), 6.83 (d, J=7.8 Hz, 1 H), 6.74 (s, 1 H), 4.55 (t, J=8.7 Hz, 2 H), 3.18 (t, J=8.7 Hz, 2 H), 1.56-1.53 (m, 2 H), 1.19-1.15 (m, 2 H).
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=1)(=O)=O.[NH2:23][C:24]1[CH:34]=[CH:33][C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:26][CH:25]=1.CN(C)P(N(C)C)(N(C)C)=O>O>[CH:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:21]=[CH:22][C:13]=1[O:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][NH:23][C:24]1[CH:25]=[CH:26][C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:33][CH:34]=1
Reactant: CS(=O)(=O)OCCCCCCOc1ccc2ccccc2c1
Reactant: CCOC(=O)c1ccc(N)cc1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: CCOC(=O)c1ccc(NCCCCCCOc2ccc3ccccc3c2)cc1

Procedure:
A solution of 10.0 g. of 6-(2-naphthyloxy)-1-hexanol O-methanesulfonate and 9.7 g. of ethyl 4-aminobenzoate in 50 ml. of hexamethylphosphoramide is heated at 110° C. for 16 hours. The solution is cooled, diluted with water, filtered and the solid washed with ethanol and water to give 7.7 g. of product. Recrystallization from ethanol and once from acetone-hexane gives crystals, m.p. 109°-110° C.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:11]=[C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=2)[CH:9]=[CH:8][C:7]=1[Br:21])(=[O:3])[CH3:2].I[CH3:23].[H-].[Na+].O>CN(C)C=O>[C:1]([O:4][CH2:5][C:6]1[CH:11]=[C:10]([N:12]([C:13]2[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=2)[CH3:23])[CH:9]=[CH:8][C:7]=1[Br:21])(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1cc(Nc2ccc(C#N)cc2)ccc1Br
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)OCc1cc(N(C)c2ccc(C#N)cc2)ccc1Br
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 2-bromo-5-(4-cyanophenylamino)benzyl acetate (1.0 g, 2.9 mmol) in N,N-dimethylformamide (11 mL) under nitrogen atmosphere was added iodomethane (0.543 mL, 8.7 mmol), and the mixture was stirred in ice-water bath for five minutes. Then sodium hydride (0.174 g, 4.35 mmol) was added, and the reaction was stirred at room temperature for 24 hours. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried on anhydrous sodium sulfate. The solvent was removed under reduced pressure to give crude 2-bromo-5-[N-(4-cyanophenyl)-N-methylamino]benzyl acetate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15](OS(C(F)(F)F)(=O)=O)=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1.[CH2:25]([OH:29])[CH2:26][C:27]#[CH:28]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([C:28]#[C:27][CH2:26][CH2:25][OH:29])=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: O=S(=O)(Oc1ccc2c(-c3ccc(Cl)cc3)nsc2c1)C(F)(F)F
Reactant: C#CCCO
Product: OCCC#Cc1ccc2c(-c3ccc(Cl)cc3)nsc2c1

Procedure:
In analogy to example 14.1, Trifluoro-methanesulfonic acid 3-(4-chloro-phenyl)-benzo[d]isothiazol-6-yl ester and 3-butyn-1-ol were converted to yield 4-[3-(4-Chloro-phenyl)-benzo[d]isothiazol-6-yl]-but-3-yn-1-ol as yellow solid, mp: 128–129° C., MS: 313 (M, 1 Cl).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]=O)=[CH:9][C:4]=2[CH2:3][CH2:2]1.[S:12]1[CH2:16][C:15](=[O:17])[NH:14][C:13]1=[O:18]>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]=[C:16]3[S:12][C:13](=[O:18])[NH:14][C:15]3=[O:17])=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: O=C1CSC(=O)N1
Reactant: O=Cc1ccc2c(c1)CCO2
Product: O=C1NC(=O)C(=Cc2ccc3c(c2)CCO3)S1

Procedure:
Following the general method as outlined in Example 1, starting from 2,3-dihydro-1-benzofuran-5-carbaldehyde and 1,3-thiazolidine-2,4-dione, the title compound was obtained.
Reaction SMILES: [CH3:1][S:2]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[C:14]3[CH2:20][CH:19]([CH:21]4[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]4)[O:18][C:15]3=[CH:16][N:17]=2)=[CH:8][CH:7]=1)(=[O:4])=[O:3].Cl[C:28]1[N:33]=[CH:32][C:31]([CH2:34][CH3:35])=[CH:30][N:29]=1>>[CH2:34]([C:31]1[CH:30]=[N:29][C:28]([N:24]2[CH2:25][CH2:26][CH:21]([CH:19]3[O:18][C:15]4=[CH:16][N:17]=[C:12]([C:9]5[CH:10]=[CH:11][C:6]([CH2:5][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:7][CH:8]=5)[CH:13]=[C:14]4[CH2:20]3)[CH2:22][CH2:23]2)=[N:33][CH:32]=1)[CH3:35]
Reactant: CCc1cnc(Cl)nc1
Reactant: CS(=O)(=O)Cc1ccc(-c2cc3c(cn2)OC(C2CCNCC2)C3)cc1
Product: CCc1cnc(N2CCC(C3Cc4cc(-c5ccc(CS(C)(=O)=O)cc5)ncc4O3)CC2)nc1

Procedure:
The title compound is prepared from 5-(4-methanesulfonylmethyl-phenyl)-2-piperidin-4-yl-2,3-dihydro-furo[2,3-c]pyridine and 2-chloro-5-ethylpyrimidine following a procedure analogous to that described in Example 1. LC (method 6): tR=1.55 min; Mass spectrum (ESI+): m/z=479 [M+H]+.
Reaction SMILES: [NH:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[N:10][C:5]=2[C:4](=[O:11])[O:3][C:2]1=[O:12].N1C2N=C[CH:21]=[CH:22][C:17]=2[C:16](=O)OC1=O>>[CH2:16]([N:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[N:10][C:5]=2[C:4](=[O:11])[O:3][C:2]1=[O:12])[CH2:17][CH2:22][CH3:21]
Reactant: O=c1[nH]c2ncccc2c(=O)o1
Reactant: O=c1[nH]c2cccnc2c(=O)o1
Product: CCCCn1c(=O)oc(=O)c2ncccc21

Procedure:
The title compound was prepared according to the procedure of Example 1B substituting the product of Example 159A for the product of Example 1A (0.12 g, 35%). 1H NMR (300 MHz, DMSO-d6) δ 0.92 (t, J=7.35 Hz, 3 H) 1.40 (m, J=15.26, 7.17 Hz, 2 H) 1.60 (m, 2 H) 3.98 (m, 2 H) 7.81 (dd, J=8.82, 4.41 Hz, 1 H) 7.97 (dd, J=8.64, 1.29 Hz, 1 H) 8.55 (dd, J=4.23, 1.29 Hz, 1 H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([Br:11])[CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][C:20](=[N:26][OH:27])[C:21]([O:23][CH2:24][CH3:25])=[O:22]>C(Cl)Cl.C(OCC)(=O)C>[OH:27][N:26]=[C:20]([CH2:19][C:4]1[C:3]2[C:7](=[CH:8][C:9]([Br:11])=[CH:10][C:2]=2[Br:1])[NH:6][CH:5]=1)[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: Brc1cc(Br)c2cc[nH]c2c1
Reactant: CCOC(=O)C(CBr)=NO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)C(Cc1c[nH]c2cc(Br)cc(Br)c12)=NO

Procedure:
Mix 4,6-dibromoindole (2.09 g, 7.58 mmol), potassium carbonate (1.57 g, 11.4 mmol) and anhydrous methylene chloride (30 mL). Stir and add a solution of ethyl 3-bromo-2-hydroxyiminopropanoate (1.59 g, 7.58 mmol) in methylene chloride (20 mL). Stir under a nitrogen atmosphere for 48 hours. Take the solution up in ethyl acetate and wash with water (100 mL), saturated sodium hydrogen carbonate (100 mL) and brine (100 mL). Dry (MgSO4) and evaporate the solvent in in vacuo and purify by silica gel chromatography to give the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:25])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][NH:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:26]([O:33][C:34](=[O:37])CBr)[C:27]1C=CC=CC=1>CN(C=O)C>[CH2:1]([O:8][C:9](=[O:25])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]([CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:34]([O:33][CH2:26][CH3:27])=[O:37])=[CH:12][CH:11]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)c1ccc(CNCc2ccccc2)cc1
Reactant: O=C(CBr)OCc1ccccc1
Solvent: CN(C)C=O
Product: CCOC(=O)N(Cc1ccccc1)Cc1ccc(C(=O)OCc2ccccc2)cc1
Temperature: 0 °C

Procedure:
A solution of 4-(N-benzylaminomethyl)benzoic acid benzyl ester (5.21 g) and bromoacetic acid benzyl ester (1.7 ml) in DMF (10 ml) was stirred for two hours at 80° C. and ice water was added thereto. The reaction solution was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate, water and a saturated aqueous solution of sodium chloride, successively. The organic layer was dried over and evaporated. The residue was purified by silica gel column chromatography to obtain the title compound (2.26 g).
Reaction SMILES: [NH2:1][C:2](=[O:45])[CH2:3][N:4]([CH3:44])[C:5](=[O:43])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N:12]2[C:20]3[C:15](=[C:16]([NH:22][CH2:23][C:24]([OH:42])([C:38]([F:41])([F:40])[F:39])[CH2:25][C:26]([C:29]4[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=4[O:36]C)([CH3:28])[CH3:27])[CH:17]=[C:18]([CH3:21])[CH:19]=3)[CH:14]=[N:13]2)[CH:7]=1.C(=O)=O.CC(C)=O.B(Br)(Br)Br>ClCCl>[NH2:1][C:2](=[O:45])[CH2:3][N:4]([CH3:44])[C:5](=[O:43])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N:12]2[C:20]3[C:15](=[C:16]([NH:22][CH2:23][C:24]([OH:42])([C:38]([F:39])([F:40])[F:41])[CH2:25][C:26]([C:29]4[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=4[OH:36])([CH3:28])[CH3:27])[CH:17]=[C:18]([CH3:21])[CH:19]=3)[CH:14]=[N:13]2)[CH:7]=1
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(CNc1cc(C)cc2c1cnn2-c1cccc(C(=O)N(C)CC(N)=O)c1)C(F)(F)F
Agent: BrB(Br)Br
Agent: O=C=O
Solvent: ClCCl
Solvent: CC(C)=O
Product: Cc1cc(NCC(O)(CC(C)(C)c2cc(F)ccc2O)C(F)(F)F)c2cnn(-c3cccc(C(=O)N(C)CC(N)=O)c3)c2c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 31.9 %

Procedure:
N-(2-Amino-2-oxoethyl)-3-(4-{[4-[5-fluoro-2-(methyloxy)phenyl]-2-hydroxy-4-methyl-2-(trifluoromethyl)pentyl]amino}-6-methyl-1H-indazol-1-yl)-N-methylbenzamide (55.1 mg, 0.0875 mmol) was dissolved in anhydrous dichloromethane (0.2 mL) and cooled to −78° C. (cardice/acetone bath) under nitrogen. Boron tribromide (1.0M in dichloromethane) (0.435 mL, 0.435 mmol) was then added portionwise and after 5 minutes the mixture was allowed to warm to room temperature. The reaction was stirred at room temperature for 6 hours, re-cooled to −78° C. and quenched with methanol (1 mL). The reaction was warmed to room temperature when more dichloromethane (1 mL) and aqueous saturated sodium hydrogen carbonate solution (2 mL) were added and the mixture stirred vigorously and then poured onto a hydrophobic frit and the dichloromethane layer collected and evaporated in vacuo. This crude product was purified by mass-directed autopreparation (System B). Product containing fractions were combined and partitioned between dichloromethane and saturated aqueous sodium bicarbonate. The aqueous layer was re-extracted twice more with dichloromethane and the combined organic extracts were washed successively water and brine, dried through a hydrophobic frit and evaporated in vacuo to give the title compound (17.2 mg).
Reaction SMILES: [OH:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]CCCC)[C:3]([OH:5])=O.[Cl-].[CH2:21]([O:28][C:29](=[O:38])/[CH:30]=[CH:31]/[C@@H:32]([NH3+:37])[CH2:33][CH2:34][CH2:35][CH3:36])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl.CCN(CC)CC>[OH:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:3]([NH:37][C@@H:32]([CH2:33][CH2:34][CH2:35][CH3:36])/[CH:31]=[CH:30]/[C:29]([O:28][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:38])=[O:5]
Reactant: CCCC[C@H]([NH3+])/C=C/C(=O)OCc1ccccc1
Reactant: CCCCCCCCCCCCCCC(O)C(=O)O
Agent: On1nnc2ccccc21
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCC(O)C(=O)N[C@H](/C=C/C(=O)OCc1ccccc1)CCCC
Temperature: 0 °C
Reaction time: 24 h

Procedure:
To a stirred solution of 2-hydroxyhexadecanoic acid (0.54 g, 2.0 mmol) and (E,4S)-1-(benzyloxy)-1-oxooct-2-en-4-aminium chloride (0.28 g, 1.0 mmol) in CH2Cl2 (5 mL), Et3N (0.3 mL) and subsequently WSCI (0.57 g, 3.0 mmol) and HOBt (0.32 g, 2.0 mmol) were added at 0° C. The reaction mixture was stirred for 1 h at 0° C. and at room temperature for 1 day. The organic layer was washed with brine, dried over Na2SO4 and evaporated under reduced pressure. The residue was purified by column chromatography (CHCl3/MeOH 98/2). Yield 0.33 g (75%); [α]D−10.3 (c 0.5 CHCl3);
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[C:7]3[C:8](=[O:30])[C:9]4[CH:21]=[CH:20][C:19](OS(C(F)(F)F)(=O)=O)=[CH:18][C:10]=4[C:11]([CH3:17])([CH3:16])[C:12]=3[NH:13][C:14]=2[N:15]=1)#[N:2].[NH:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[CH3:16][C:11]1([CH3:17])[C:12]2[NH:13][C:14]3[N:15]=[C:3]([C:1]#[N:2])[CH:4]=[CH:5][C:6]=3[C:7]=2[C:8](=[O:30])[C:9]2[CH:21]=[CH:20][C:19]([N:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)=[CH:18][C:10]1=2
Reactant: CC1(C)c2cc(OS(=O)(=O)C(F)(F)F)ccc2C(=O)c2c1[nH]c1nc(C#N)ccc21
Reactant: C1CNCCN1
Product: CC1(C)c2cc(N3CCNCC3)ccc2C(=O)c2c1[nH]c1nc(C#N)ccc21

Procedure:
According to the method used for synthesizing Compound B2-1, trifluoromethanesulfonic acid 2-cyano-10,10-dimethyl-5-oxo-10,11-dihydro-5H-1,11-diaza-benzo[b]fluoren-8-yl ester was introduced with piperazine to obtain the title compound.
Reaction SMILES: [CH3:1][Mg]Br.[NH2:4][C:5]1[N:10]=[CH:9][C:8]([C:11]2[C:12]([CH:29]=[O:30])=[N:13][N:14]([CH:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]3)[CH:15]=2)=[CH:7][C:6]=1[C:31]1[O:32][C:33]2[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=2[N:35]=1>O1CCCC1>[NH2:4][C:5]1[N:10]=[CH:9][C:8]([C:11]2[C:12]([CH:29]([OH:30])[CH3:1])=[N:13][N:14]([CH:16]3[CH2:17][CH2:18][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:26])[CH3:27])=[O:23])[CH2:20][CH2:21]3)[CH:15]=2)=[CH:7][C:6]=1[C:31]1[O:32][C:33]2[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=2[N:35]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(N)c(-c4nc5ccccc5o4)c3)c(C=O)n2)CC1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(O)c1nn(C2CCN(C(=O)OC(C)(C)C)CC2)cc1-c1cnc(N)c(-c2nc3ccccc3o2)c1
Temperature: 25 °C
Reaction time: 0.02 h

Procedure:
Over a period of 1 minute at −10° C. under nitrogen, a solution of methylmagnesium bromide (1.287 ml, 1.4M in toluene) was added portionwise to a stirred solution of tert-butyl 4-[4-[6-amino-5-(1,3-benzoxazol-2-yl)-3-pyridyl]-3-formyl-pyrazol-1-yl]piperidine-1-carboxylate (0.44 g), dissolved in tetrahydrofuran (10 ml). The resulting solution was stirred at room temperature for 1 hour. The reaction mixture was allowed to warm to room temperature under stirring over a period of 1 hour, quenched with a saturated aqueous solution of ammonium chloride and extracted with dichloromethane (2×50 ml). The combined organic phases were washed with water (2×10 ml), dried over magnesium sulfate and concentrated to afford the crude product as a dark orange oil which solidified on standing. The product was purified by flash chromatography on silica gel eluting with 30 to 100% ethyl acetate in petroleum ether. The solvent was evaporated to dryness to afford tert-butyl 4-[4-[6-amino-5-(1,3-benzoxazol-2-yl)-3-pyridyl]-3-(1-hydroxyethyl)pyrazol-1-yl]piperidine-1-carboxylate (0.120 g) as a solid. NMR Spectrum: (DMSOd6) 1.42 (d, 3H), 1.43 (s, 9H), 1.79 (dd, 1H), 1.85 (dd, 1H), 2.01-2.08 (m, 2H), 2.93 (bs, 2H), 4.06 (bs, 2H), 4.28-4.38 (m, 1H), 4.77-4.87 (m, 1H), 5.22 (d, 1H), 7.40-7.48 (m, 2H), 7.64 (bs, 2H), 7.77 (dd, 1H), 7.84 (dd, 1H), 8.10 (s, 1H), 8.51 (d, 1H), 8.56 (d, 1H); Mass spectrum: M+H+ 505.
Reaction SMILES: [NH:1]([C:8]([C:11]1[N:12]([CH3:26])[C:13]([C:16]2[CH:25]=[CH:24][C:19]([C:20](OC)=[O:21])=[CH:18][CH:17]=2)=[N:14][N:15]=1)([CH3:10])[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[NH2:28]>CO>[NH:1]([C:8]([C:11]1[N:12]([CH3:26])[C:13]([C:16]2[CH:25]=[CH:24][C:19]([C:20]([NH2:28])=[O:21])=[CH:18][CH:17]=2)=[N:14][N:15]=1)([CH3:9])[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN
Reactant: COC(=O)c1ccc(-c2nnc(C(C)(C)Nc3ccccc3)n2C)cc1
Solvent: CO
Product: Cn1c(-c2ccc(C(N)=O)cc2)nnc1C(C)(C)Nc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 121.5 %

Procedure:
Methyl 4-[5-(1-anilino-1-methylethyl)-4-methyl-4H-1,2,4-triazol-3-yl}benzoate (300 mg) was dissolved in methanol (1 ml) and then methylamine (30% methanol solution, 886.3 mg) was added thereto, followed by stirring at room temperature overnight. The resulting precipitate was collected by filtration to obtain 349 mg of 4-[5-(1-anilino-1-methylethyl)-4-methyl-4H-1,2,4-triazol-3-yl}benzamide (white crystals).
Reaction SMILES: [C:1]1([S:7]([NH2:10])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].F[C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[N+:21]([O-:23])=[O:22].Cl>CN(C=O)C>[F:20][C:18]1[CH:17]=[CH:16][C:15]([N+:21]([O-:23])=[O:22])=[C:14]([NH:10][S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])[CH:19]=1
Reactant: NS(=O)(=O)c1ccccc1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(F)cc1NS(=O)(=O)c1ccccc1
Yield: 70.3 %

Procedure:
Benzenesulfonamide (3.14 g, 20 mmol) was dissolved in DMF (100 mL) and NaH (60% in oil, 40 mmol, 1.60 g) was added. The reaction was stirred until the gas evolution ceased. 2,4-Difluoronitrobenzene (18 mmol, 2.9 g, 2 mL) was added and the reaction mixture was stirred over night at 35° C. The reaction mixture was poured into HCl (1M aq, 100 mL) and extracted with toluene (25 mL×5). The organic phase was dried (MgSO4) and concentrated and re-crystallized from EtOH to give a first crop of 3.75 g of a yellow solid. A second crop of 0.20 g was collected from the EtOH remains. Yield 3.95 g, 13.3 mmol (74%). MS (posES-FIA) m/z=found: 296; Calc: 296.0.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:9]=[CH:10][CH:11]=1)[NH2:8])([CH3:4])([CH3:3])[CH3:2].Cl.[C:13](OCC)(=[O:15])C>>[C:1]([C:5]1[CH:6]=[C:7]([N:8]=[C:13]=[O:15])[CH:9]=[CH:10][CH:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(C)=O
Reactant: CC(C)(C)c1cccc(N)c1
Agent: Cl
Product: CC(C)(C)c1cccc(N=C=O)c1

Procedure:
3-(tert-Butyl)aniline (0.054 g, 0.36 mmol) was dissolved in ethyl acetate (2 mL) and added dry hydrogen chloride in ethyl acetate twice (3.5 M, 3 mL+2.5 mL). After 15 min the mixture was concentrated to dryness and co-evaporated three times from toluene (3×5 mL). The residue was added toluene (2.5 mL) and flushed with nitrogen for about 10 min. before diphosgene (0.43 mL) was added. Then the mixture was gently refluxed for 1 hour under a nitrogen atmosphere. The mixture was cooled and concentrated in vacuo. This was repeated twice to remove excess of diphosgene. The mixture was concentrated to dryness and co-evaporated three times from toluene (5 mL each time). The residue was concentrated to dryness and co-evaporated twice from toluene. Then it was redissolved in toluene 2.5 mL) and flushed with nitrogen for about 10 min, before diphosgene (0.43 mL) was added. The mixture was gently refluxed under nitrogen for 1 hour. After cooling, the mixture was concentrated and co-evaporated twice from toluene to remove excess diphosgene to afford 3-tert-butyl-phenyl isocyanate.