Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:5]([O:7][C@@H:8]1[CH:13]2[CH2:14][CH2:15][N:10]([CH2:11][CH2:12]2)[CH2:9]1)=[O:6].C(N(CC)CC)C.[C:29](Cl)(=[O:37])[O:30][CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>C(Cl)Cl>[CH:31]1([O:30][C:29]([NH:3][CH:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:5]([O:7][C@@H:8]2[CH:13]3[CH2:12][CH2:11][N:10]([CH2:15][CH2:14]3)[CH2:9]2)=[O:6])=[O:37])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: O=C(Cl)OC1CCCCC1
Reactant: NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1)OC1CCCCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 60.4 %

Procedure:
To a suspension of (R)-quinuclidin-3-yl 2-amino-2-phenylacetate dihydrochloride (I25) (150 mg, 0.45 mmol) in DCM (5 ml), were added triethylamine (188 μl, 1.35 mmol) and cyclohexyl carbonochloridate (78 μl, 0.54 mmol). The reaction was stirred at RT for 4 hours, and then the solvent was evaporated. The residue was taken up with EtOAc and washed with water and brine, dried over Na2SO4 and evaporated to dryness to obtain (R)-quinuclidin-3-yl 2-(cyclohexyloxycarbonylamino)-2-phenylacetate (105 mg; 60% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:25]([F:28])([F:27])[F:26])[O:13][N:12]=[C:11]([C:14]3[CH:23]=[CH:22][C:17]([C:18]([NH:20][CH3:21])=[O:19])=[C:16]([CH3:24])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(N(CC)CC)C.[S:36]1(=O)[CH2:40][CH2:39][CH2:38][CH2:37]1>C1(C)C=CC=CC=1.[I-].[Zn+2].[I-]>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:25]([F:27])([F:26])[F:28])[O:13][N:12]=[C:11]([C:14]3[CH:23]=[CH:22][C:17]([C:18]([N:20]([CH3:21])[CH:37]4[CH2:38][CH2:39][CH2:40][S:36]4)=[O:19])=[C:16]([CH3:24])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CNC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C
Reactant: O=S1CCCC1
Agent: [I-]
Agent: [Zn+2]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)N(C)C1CCCS1
Temperature: 0 °C
Yield: 18.1 %

Procedure:
In a solution of 0.43 g of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-methyl-N-methyl benzoic acid amide synthesized similarly to Synthetic Example 29 and 0.20 g of triethylamine in 5 ml of toluene, 0.45 g of trimethyl silyl trifurate was added and stirred vigorously. 10 minutes after the stirring, the reaction mixture was cooled to 0° C., 0.10 g of tetrahydrothiophen-1-oxide and 0.06 g of zinc iodide were added with stirring, and continued to stir at room temperature further for 4 days. After the completion of the reaction, 10 ml of ice water was added in the reaction mixture, and extracted with ethyl acetate (20 ml×2), the organic phase was dehydrated and dried with saturated sodium chloride aqueous solution and anhydrous sodium sulfate in that order, and the solvent was distilled under reduced pressure. The residue was purified with silica gel column chromatography that was eluated with ethyl acetate-hexane (1:2) to obtain 0.09 g of the aimed product as white crystal.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8](Cl)(=[O:15])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]>>[C:2]1([NH:1][C:8](=[O:15])[CH:9]=[CH:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCCCC(=O)Cl
Reactant: Nc1ccccc1
Product: CCCCC=CC(=O)Nc1ccccc1
Yield: 94 %

Procedure:
The procedure described in Example 1 is repeated, but in section a) aniline is used in place of n-pentylamine and n-heptanoyl chloride is used in place of caproyl chloride. N-Phenyl-n-heptenamide (m.p. 50° C.) is obtained in 94% yield. This is reacted with PCl5 as in Example 1, section b), and gives in quantitative yield N-phenyl-heptaneiminoyl chloride as a yellowish oil which is converted according to section c) into the desired product and purified by chromatography on silica gel in hexane/ether=1:1. M.p. 83°-84° C. UV (EtOH): 320 nm (ε=19502).
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1.Cl.Cl.[NH2:24][C:25]1[N:26]=[N:27][N:28]([CH:30]2[CH2:34][CH2:33][NH:32][CH2:31]2)[CH:29]=1.N1(C2CCCCCCCCCC2)CCCCCCCCCN1>N1C=CC=CC=1>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:32]2[CH2:33][CH2:34][CH:30]([N:28]3[CH:29]=[C:25]([NH2:24])[N:26]=[N:27]3)[CH2:31]2)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Reactant: Nc1cn(C2CCNC2)nn1
Agent: C1CCCCCC(N2CCCCCCCCCN2)CCCC1
Agent: Cl
Solvent: c1ccncc1
Product: Nc1cn(C2CCN(c3c(F)c(N)c4c(=O)c(C(=O)O)cn(C5CC5)c4c3F)C2)nn1
Temperature: 110 °C

Procedure:
A mixture of 5-amino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (100 mg, 0.67 mmol), 3-(4-amino-1,2,3-triazol-1-yl)pyrrolidine dihydrochloride (185 mg, 0.83 mmol) and diazabicycloundecane (127 mg, 0.83 mmol) in pyridine (3 ml) was heated at 110° C. for 24 hrs. Reaction mixture was concentrated to dryness under vacuum and residue was dissolved in water, extracted with methylene chloride, dried over sodium sulfate and concentrated to dryness. The solid residue thus obtained was crystallized from chloroform to brown solid. Yield 15 mg (10.4%), m.p. 210°-213° C. 1H NMR (TFA) δ: 1.22-1.58 (m, 4H), 2.70-2.90 (m, 2H), 4.06-4.54 (m, 5H), 5.48-5.60 (m, 1H), 7.79 (s, 1H), 9.14 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:6][C:5](=[O:7])[C:4]([C:8]2[N:12]([CH3:13])[N:11]=[CH:10][CH:9]=2)=[CH:3]1>C(O)C.[C].[Pd]>[CH3:1][C:2]1([CH3:14])[CH2:6][C:5](=[O:7])[CH:4]([C:8]2[N:12]([CH3:13])[N:11]=[CH:10][CH:9]=2)[CH2:3]1
Reactant: Cn1nccc1C1=CC(C)(C)CC1=O
Agent: [Pd]
Solvent: CCO
Product: Cn1nccc1C1CC(C)(C)CC1=O
Yield: 95.1 %

Procedure:
A solution of the 4,4-dimethyl-2-(1-methyl-1H-pyrazol-5-yl)cyclopent-2-en-1-one (780 mg, 4.10 mmol) prepared in Example 93c and palladium carbon (5%; 700 mg) in ethanol (8.0 mL) was stirred for 6 hours under a hydrogen atmosphere. The reaction solution was filtered through celite to yield the title compound (750 mg, 95%) in a crude form as a yellow oil.
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5]C[CH2:3][CH2:2]1.[CH:8](OC)([O:11][CH3:12])[O:9][CH3:10].C(O)C(C)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH3:10][O:9][C:8]1([O:11][CH3:12])[CH2:5][CH2:6][CH2:1][CH2:2][CH2:3]1
Reactant: O=C1CCCCC1
Reactant: COC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)CO
Product: COC1(OC)CCCCC1

Procedure:
Cyclohexanone dimethyl ketal (CHMK) was prepared as described in Example 1 from 1 mol of cyclohexanone and trimethyl orthoformate. 370.6 g of isobutanol (2-methyl-1-propanol, 5.0 mols) were added, and the transketalization was then carried out under reflux while the sump temperature was gradually increased from 110° to 160° C. After a running time of 2 hours, another 0.4 g of p-toluenesulfonic acid was added. The low-boiling-point components, i.e. methyl formate, methanol and a small amount of isobutyl formate, were removed by distillation under reflux (ratio 1:5 to 1:2) over the course of 4 hours.
Reaction SMILES: C([O:8][C:9](=[O:42])[CH2:10][C@@H:11]([NH:27][C:28](=[O:41])/[CH:29]=[CH:30]/[C:31]1[CH:36]=[C:35]([C:37]#[N:38])[CH:34]=[CH:33][C:32]=1[O:39][CH3:40])[CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([O:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[CH2:15][CH2:14]1)C1C=CC=CC=1.[OH-].[Na+]>CO>[C:37]([C:35]1[CH:34]=[CH:33][C:32]([O:39][CH3:40])=[C:31](/[CH:30]=[CH:29]/[C:28]([NH:27][C@@H:11]([CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([O:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH2:15][CH2:14]2)[CH2:10][C:9]([OH:42])=[O:8])=[O:41])[CH:36]=1)#[N:38]
Reactant: COc1ccc(C#N)cc1/C=C/C(=O)N[C@H](CC(=O)OCc1ccccc1)CN1CCC(Oc2ccc(F)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(C#N)cc1/C=C/C(=O)N[C@H](CC(=O)O)CN1CCC(Oc2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of (R)-3-[(E)-3-(5-cyano-2-methoxy-phenyl)-acryloylamino]-4-[4-(4-fluoro-phenoxy)-piperidin-1-yl]-butyric acid benzyl ester (1.43 g, 2.52 mmol) in methanol (15 ml) is treated with NaOH solution, (2.5 ml, 4M). The reaction mixture is stirred at ambient temperature for 1 hour. The methanol is evaporated and the resulting aqueous solution diluted with water and washed with diethyl ether. The aqueous phase is neutralised with 1N HCl solution and extracted into isopropanol/chloroform (1:3). The organic phase is evaporated and dried under high vacuum to afford (R)-3-[(E)-3-(5-cyano-2-methoxy-phenyl)-acryloylamino]-4-[4-(4-fluoro-phenoxy)-piperidin-1-yl]-butyric acid. [MH]+ 482.1.
Reaction SMILES: [CH2:1]([N:5]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[C@H:6]([C:12]([OH:14])=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][NH2:11])[CH:2]([CH3:4])[CH3:3].[C:25]([O:29][C:30]([NH:32][C@H:33]([C:44](O)=[O:45])[CH2:34][S:35][CH2:36][C:37]1[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=1)=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[CH3:43][C:40]1[CH:39]=[CH:38][C:37]([CH2:36][S:35][CH2:34][C@H:33]([NH:32][C:30]([O:29][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:31])[C:44]([NH:11][CH2:10][CH2:9][CH2:8][CH2:7][C@H:6]([N:5]([S:15]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH2:1][CH:2]([CH3:3])[CH3:4])[C:12]([OH:14])=[O:13])=[O:45])=[CH:42][CH:41]=1
Reactant: Cc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCN)C(=O)O)cc1
Reactant: Cc1ccc(CSC[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Product: Cc1ccc(CSC[C@H](NC(=O)OC(C)(C)C)C(=O)NCCCC[C@@H](C(=O)O)N(CC(C)C)S(=O)(=O)c2ccc(C)cc2)cc1

Procedure:
The title compound was prepared from Nα-isobutyl-Nα-(4-methylbenzenesulfonyl)-L-lysine (100 mg, 0.29 mmol, example 1, step E) as described in general procedure Bc using commercially available Nα-tert-butoxycarbonyl-S-(4-methylbenzyl)-L-cysteine (67 mg, 0.3 mmol). The final product was triturated with ether to yield 130 mg (65%) of the desired material.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([CH2:25][O:24][C:23]3[CH:26]=[C:27]4[C:31](=[CH:32][C:22]1=3)[CH2:30][CH2:29][O:28]4)[C:5](=[O:21])[N:6]2[CH2:11][C:12]1[O:13][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:16]=1.BrC1C=CC=C2C=1[C:36]1([C:52]3=CC4OCOC=4C=[C:51]3[O:50][CH2:49]1)C(=O)N2CCCCC.O1C=CC(B(O)O)=C1.CN(C)C1N=CC(B(O)O)=CC=1>>[O:50]1[CH:51]=[CH:52][C:36]([C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[C:4]2([CH2:25][O:24][C:23]4[CH:26]=[C:27]5[C:31](=[CH:32][C:22]2=4)[CH2:30][CH2:29][O:28]5)[C:5](=[O:21])[N:6]3[CH2:11][C:12]2[O:13][C:14]([C:17]([F:18])([F:20])[F:19])=[CH:15][CH:16]=2)=[CH:49]1
Reactant: O=C1N(Cc2ccc(C(F)(F)F)o2)c2cccc(Br)c2C12COc1cc3c(cc12)CCO3
Reactant: CCCCCN1C(=O)C2(COc3cc4c(cc32)OCO4)c2c(Br)cccc21
Agent: CN(C)c1ccc(B(O)O)cn1
Agent: OB(O)c1ccoc1
Product: O=C1N(Cc2ccc(C(F)(F)F)o2)c2cccc(-c3ccoc3)c2C12COc1cc3c(cc12)CCO3

Procedure:
Following the procedure as described in EXAMPLE 4, and making non-critical variations using 4′-bromo-1′-{[5-(trifluoromethyl)-2-furyl]methyl}-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one to replace 4′-bromo-1′-pentylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, and 3-furylboronic acid to replace [6-(dimethylamino)pyridin-3-yl]boronic acid, the title compound was obtained (27%) as a colorless solid: mp 167-169° C.; 1H NMR (300 MHz, CDCl3) δ 7.34-7.29 (m, 2H), 7.01 (dd, 1H), 6.95 (dd, 1H), 6.77 (dd, 1H), 6.74 (dd, 1H), 6.51 (s, 1H), 6.41 (d, 1H), 6.34 (s, 1H), 6.00 (dd, 1H), 4.97 (ABq, 2H), 4.67 (ABq, 2H), 4.56 (t, 2H), 3.01 (t, 2H); MS (ES+) m/z 494.4 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N:9]2[N:32]=[C:31]([CH3:33])/[C:12](=[N:13]/[NH:14][C:15]3[CH:16]=[CH:17][CH:18]=[C:19]([C:22]4[CH:23]=[CH:24][CH:25]=[C:26]([C:28]([OH:30])=[O:29])[CH:27]=4)[C:20]=3[OH:21])/[C:10]2=[O:11])=[CH:6][C:7]=1[CH3:8]>C(O)(=O)C>[CH3:8][C:7]1[CH:6]=[C:5]([N:9]2[C:10](=[O:11])[C:12](=[N:13][NH:14][C:15]3[C:20]([OH:21])=[C:19]([C:22]4[CH:23]=[CH:24][CH:25]=[C:26]([C:28]([OH:30])=[O:29])[CH:27]=4)[CH:18]=[CH:17][CH:16]=3)[C:31]([CH3:33])=[N:32]2)[CH:4]=[CH:3][C:2]=1[CH3:1]
Reactant: CC1=NN(c2ccc(C)c(C)c2)C(=O)/C1=N\Nc1cccc(-c2cccc(C(=O)O)c2)c1O
Solvent: CC(=O)O
Product: CC1=NN(c2ccc(C)c(C)c2)C(=O)C1=NNc1cccc(-c2cccc(C(=O)O)c2)c1O
Temperature: 40 °C
Reaction time: 5 h
Yield: 88 %

Procedure:
Crude Eltrombopag (151 g, HPLC purity: 98.5%) was suspended in 2.9 L of glacial acetic acid in 3 L reactor. The suspension was stirred for five hours under reflux and cooled to 40° C. Crystals formed and were filtrated off, washed with 200 mL of methanol:water (1:1) and dried at 60° C./0 mbar overnight yielding 133 g orange solid of pure 3′-{N′-[1-(3,4-Dimethylphenyl)-3-methyl-5-oxo-1,5-dihydro-pyrazol-4-ylidene]hydrazino}-2′-hydroxybiphenyl-3-carboxylic acid (HPLC: 99.8%; XRPD: form I) (Yield=88%). PXRD analysis provided the diffractogram as shown in FIG. 1. DSC analysis provided the thermogram as shown in FIG. 2
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[OH:7][CH:8]1[CH:22]([N:23]2[CH2:28][CH2:27][CH:26]([CH3:29])[CH2:25][CH2:24]2)[C:21]2=[CH:30][CH:18]([O:19][C:20]2=[O:31])[CH:17]2[CH:13]([O:14][C:15](=[O:33])[CH:16]2[CH3:32])[CH2:12][C:11]2([CH3:34])[CH:9]1[O:10]2.C(OC1C(N2CCC(C)CC2)C2=CC(OC2=O)C2C(OC(=O)C2C)CC2(C)C1O2)(=O)C>N1C=CC=CC=1>[C:2](=[O:3])([O:7][CH:8]1[CH:22]([N:23]2[CH2:28][CH2:27][CH:26]([CH3:29])[CH2:25][CH2:24]2)[C:21]2=[CH:30][CH:18]([O:19][C:20]2=[O:31])[CH:17]2[CH:13]([O:14][C:15](=[O:33])[CH:16]2[CH3:32])[CH2:12][C:11]2([CH3:34])[CH:9]1[O:10]2)[O:4][CH2:5][CH3:6]
Reactant: CCOC(=O)Cl
Reactant: CC1CCN(C2C3=CC(OC3=O)C3C(CC4(C)OC4C2O)OC(=O)C3C)CC1
Agent: CC(=O)OC1C(N2CCC(C)CC2)C2=CC(OC2=O)C2C(CC3(C)OC13)OC(=O)C2C
Solvent: c1ccncc1
Product: CCOC(=O)OC1C(N2CCC(C)CC2)C2=CC(OC2=O)C2C(CC3(C)OC13)OC(=O)C2C
Reaction time: 2 h
Yield: 43.1 %

Procedure:
Ethyl chloroformate (300 μmol; 28 μl) is added to a solution of the compound of Example 9 (100 μmol; 40 mg) in pyridine (0.5 ml). The reaction mass is stirred for 2 hours then treated in the same manner as for the preparation of the compound of Example 17. 20 mg of product is obtained in the form of a white powder.
Reaction SMILES: [C:1]1([C:7]2[N:11]([S:12]([C:15]3[S:16][CH:17]=[CH:18][CH:19]=3)(=[O:14])=[O:13])[CH:10]=[C:9]([C:20](OCC)=[O:21])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].C([Al+]CC(C)C)C(C)C.Cl>O1CCCC1.C1(C)C=CC=CC=1>[C:1]1([C:7]2[N:11]([S:12]([C:15]3[S:16][CH:17]=[CH:18][CH:19]=3)(=[O:14])=[O:13])[CH:10]=[C:9]([CH2:20][OH:21])[CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1cc(-c2ccccc2)n(S(=O)(=O)c2cccs2)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=S(=O)(c1cccs1)n1cc(CO)cc1-c1ccccc1
Temperature: -70 °C
Reaction time: 1 h
Yield: 83.6 %

Procedure:
A solution (20 mL) of ethyl 5-phenyl-1-(2-thienylsulfonyl)-1H-pyrrole-3-carboxylate (650 mg) in tetrahydrofuran was cooled to −70° C., and a 1.5 mol/L solution (5 mL) of diisobutylaluminum hydride in toluene was added dropwise by small portions. The mixture was further stirred at −70° C. for 1 hr, 1 mol/L hydrochloric acid (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=7:3→1:1) to give the title compound as a pale-red oil (yield 480 mg, 84%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]2>CO.O=[Pt]=O>[CH3:12][CH:9]1[CH2:8][CH2:7][C:6]2[C:11](=[C:2]([OH:1])[CH:3]=[CH:4][CH:5]=2)[NH:10]1
Reactant: Cc1ccc2cccc(O)c2n1
Agent: O=[Pt]=O
Solvent: CO
Product: CC1CCc2cccc(O)c2N1
Reaction time: 24 h

Procedure:
7.50 g (47.0 mmol) of 8-hydroxy-2-methylquinoline were hydrogenated in an autoclave in the presence of 0.75 g of PtO2 in 60 ml of methanol at 4 bar of H2 and a temperature of 50° C. for 24 h. The reaction solution was filtered, and the filtrate was concentrated to dryness. The residue of 2-methyl-8-hydroxy-1,2,3,4-tetrahydroquinoline obtained was dissolved in 60 ml of ethanol, 3.85 ml of 37% strength formaldehyde solution and 1.1 g of Pd/C (10% strength) were added, and the reaction mixture obtained was hydrogenated in an autoclave at 4 bar of H2 and a temperature of 50° C. again for 24 h. It was filtered, the filtrate was concentrated, and the residue was purified by chromatography on SiO2 (EA/n-heptane 1:4). 1.56 g of the title compound were obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:8])[CH2:4][C:5]([CH3:7])=O.[CH3:9][O:10][C:11]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[C:12]=1[CH:13]=O.[NH2:34][C:35]([NH2:37])=[O:36].Cl>O1CCCC1>[CH3:1][O:2][C:3]([C:4]1[CH:13]([C:12]2[C:15]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[CH:16][CH:17]=[CH:18][C:11]=2[O:10][CH3:9])[NH:34][C:35](=[O:36])[NH:37][C:5]=1[CH3:7])=[O:8]
Reactant: CCCCCCCCCCCCCCCc1cccc(OC)c1C=O
Reactant: COC(=O)CC(C)=O
Reactant: NC(N)=O
Agent: Cl
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCc1cccc(OC)c1C1NC(=O)NC(C)=C1C(=O)OC
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of methylacetoacetate (1.2 g, 8.5 mmol), 2-methoxy-6-pentadecyl benzaldehyde (3.1 g, 8.5 mmol) and urea (1.00 g, 17 mmol) in tetrahydrofuran (20 mL) was heated to reflux (65-70° C.) in the presence of hydrochloric acid (30%) for 7 h. The reaction mixture after being cooled to room temperature was poured into crushed ice (20 g) and stirred for 5 min. The viscous liquid was extracted with ethylacetate (40 mL) and was washed with 1N hydrochloric acid, water, sodium bicarbonate and brine. After drying over anhydrous sodium sulfate, the solvent was evaporated to yield light yellow oil. This crude product was purified by flash column chromatography and recrystallized from hexane to get white crystalline solid of title compound.
Reaction SMILES: [NH2:1][CH2:2][CH:3]=[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH3:15])[CH:12]=2)[CH2:7][CH2:6][CH2:5]1.C(N(CC)CC)C.[C:23](Cl)(=[O:25])[CH3:24].O>C1COCC1>[C:23]([NH:1][CH2:2]/[CH:3]=[C:4]1\[CH2:5][CH2:6][CH2:7][C:8]2[C:13]\1=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)(=[O:25])[CH3:24]
Reactant: CC(=O)Cl
Reactant: COc1ccc2c(c1)C(=CCN)CCC2
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1)/C(=C/CNC(C)=O)CCC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40.2 %

Procedure:
To a solution of 1-(2-aminoethylidene)-7-methoxy-1,2,3,4-tetrahydronaphthalene (2.0 g, 9.74 mmol) and triethylamine (1.5 g, 14,6 mmol) in THF (20 ml) was gradually added dropwise, under ice-cooling, acetyl chloride (0.76 g, 9.74 mmol). The mixture was stirred for 30 minutes at room temperature. The reaction mixture was poured into water, and the organic layer was subjected to extraction with chloroform. The extract solution was washed with brine and water, which was dried over anhydrous magnesium sulfate. The solvent was then distilled off under reduced pressure. The residue was purified by means of a silica gel column chromatography (ethyl acetate), followed by recrystallization from ethyl acetate/hexane to give the above-titled compound (yield 0.96 g, 40%).
Reaction SMILES: [ClH:1].[NH:2]([C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]3[N:21]=[CH:20][NH:19][C:17]3=2)[N:12]=[C:11]([CH3:22])[CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:23][CH2:24][O:25]C1C=CC(N)=CC=1>C(O)C>[ClH:1].[CH3:23][CH2:24][O:25][C:6]1[CH:7]=[CH:8][C:3]([NH:2][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]4[N:21]=[CH:20][NH:19][C:17]4=3)[N:12]=[C:11]([CH3:22])[CH:10]=2)=[CH:4][CH:5]=1
Reactant: CCOc1ccc(N)cc1
Reactant: Cc1cc(Nc2ccccc2)c2c(ccc3nc[nH]c32)n1
Agent: Cl
Solvent: CCO
Product: CCOc1ccc(Nc2cc(C)nc3ccc4nc[nH]c4c23)cc1

Procedure:
A mixture of 33 g. (0.15 mole) of the compound of Example I, C. and 23 g. (0.15 mole) of p-phenetidine in 1800 ml. of ethanol was refluxed for 6 hr. The solvent was removed by evaporation in vacuo and the residue was slurried with ether. The crude solid was collected by filtration and was recrystallized from ethanol. The product was collected as yellow needles melting at 229°-230° in a yield of 19 g. (36%). Recrystallization from ethanol raised the melting point to 330°-331°.
Reaction SMILES: [C:1]1([CH3:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O[CH:11]=[CH:12][C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])C>ClCCl.[Cl-].[Zn+2].[Cl-]>[F:17][C:14]([F:15])([F:16])[C:13](=[O:18])[CH:12]=[CH:11][C:4]1[CH:5]=[CH:6][C:1]([CH3:7])=[CH:2][CH:3]=1
Reactant: CCOC=CC(=O)C(F)(F)F
Reactant: Cc1ccccc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClCCl
Product: Cc1ccc(C=CC(=O)C(F)(F)F)cc1
Temperature: 22 °C
Reaction time: 3 h

Procedure:
To a solution of toluene (8, R1=p-CH3, R3=R4=H, 10 mmol) and 4-ethoxy-1,1,1-trifluoro-3-buten-2-one (10 mmol) in dichloromethane (10 mL) is added zinc chloride (0.015 g, 1.5 mol %). The reaction mixture is stirred for 3 h at 22° C. The resulting precipitate is filtered, washed with dichloromethane (2×15 mL) and dried.
Reaction SMILES: [N:1]([Si](C)(C)C)=[N+:2]=[N-:3].[CH3:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[N:24]2[C:19]([CH:20]=[N:21][C:22]([C:25]#[N:26])=[N:23]2)=[CH:18][CH:17]=1.C1(C)C=CC=CC=1.C([Sn](CCCC)=O)CCC>>[CH3:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[N:24]2[C:19]([CH:20]=[N:21][C:22]([C:25]3[NH:26][N:3]=[N:2][N:1]=3)=[N:23]2)=[CH:18][CH:17]=1
Reactant: COc1ccccc1-c1ccc2cnc(C#N)nn12
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: COc1ccccc1-c1ccc2cnc(-c3nnn[nH]3)nn12
Temperature: 90 °C

Procedure:
Azidotrimethylsilane (0.250 mL, 1.88 mmol) was added to 7-(2-Methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazine-2-carbonitrile (48.0 mg, 0.192 mmol) in Toluene (4.0 mL, 38 mmol) and Dibutyloxostannane (50.0 mg, 0.201 mmol) and heat at 90° C. for 4 h. Cool and conc. in vacuo, then purify by prep HPLC. The lyophilate was dissolved in MeOH, loaded onto a Phenomenex sulfonic acid resin, which was washed with MeOH and then the product eluted as the free base with 2M NH3 in MeOH. Conc. and reconc. from DCM afforded 7-(2-Methoxy-phenyl)-2-(1H-tetrazol-5-yl)-pyrrolo[2,1-f][1,2,4]triazine as a yellow film. LCMS (HPLC): 294 (M+H); 1H-NMR (DMSO-d6): 9.25 (s, 1H), 7.83 (m, 1H), 7.47 (m, 1H), 7.23 (m, 2H), 7.11 (m, 3H), 3.83 (s, 3H).
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Li].Cl[Si:16]([C:19]1[CH2:20][C:21]2[C:26]([CH:27]=1)=[CH:25][CH:24]=[CH:23][CH:22]=2)([CH3:18])[CH3:17]>C(OCC)C>[C:1]1([Si:16]([C:19]2[CH2:20][C:21]3[C:26]([CH:27]=2)=[CH:25][CH:24]=[CH:23][CH:22]=3)([CH3:17])[CH3:18])[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Reactant: C[Si](C)(Cl)C1=Cc2ccccc2C1
Agent: [Li]
Solvent: CCOCC
Product: C[Si](C)(C1=Cc2ccccc2C1)c1cccc2c1Cc1ccccc1-2
Temperature: 25 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
A solution of lithium fluorene from Example 4 was slowly added dropwise at 0° C., by means of a septum and a syringe, to a solution of chloro-2-indenyl-dimethylsilane (2.85 g, 0.0136 mol.) according to Example 1 in 20 ml of diethyl ether. After 2 hours' stirring at 25° C., the resulting LiCl was filtered off. The solvent was removed from the filtrate and the beige-colored residue was dissolved in hot ether/petroleum ether and crystallized at −30° C. 3.45 g (75%) of fluorenyl-2-indenyldimethylsilane were obtained in the form of a colorless solid. M.p.: 125° C.