Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([S:14][CH3:15])[N:11]3[N:16]=[CH:17][CH:18]=[C:10]3[CH:9]=2)=[CH:4][CH:3]=1.[Br:19]N1C(=O)CCC1=O.ClC1C=CC=CC=1>>[Br:19][C:18]1[CH:17]=[N:16][N:11]2[C:10]=1[CH:9]=[C:8]([C:5]1[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=1)[N:13]=[C:12]2[S:14][CH3:15]
Reactant: O=C1CCC(=O)N1Br
Reactant: CSc1nc(-c2ccc(I)cc2)cc2ccnn12
Solvent: Clc1ccccc1
Product: CSc1nc(-c2ccc(I)cc2)cc2c(Br)cnn12
Reaction time: 1 h

Procedure:
To a solution of 5-(4-iodo-phenyl)-7-methylsulfanyl-pyrazolo[1,5-c]pyrimidin (1000 mg) in chlorobenzene N-bromosuccinimide (730 mg) is added. The mixture is stirred for 1 hour then the chlorobenzene is evaporated. The residue is partitioned between ethylacetate and sodium-hydrogencarbonate (5%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][C:12]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([CH3:21])[CH:16]=3)(O)[CH3:13])[C:6]3[CH2:22][CH2:23][N:24]([CH3:26])[CH2:25][C:5]=3[C:4]=2[CH:3]=1.S(Cl)(Cl)=O.[OH-].[K+]>C(Cl)Cl.CN(C=O)C.CN1C(=O)CCC1.O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7](/[CH:11]=[C:12](/[C:15]3[CH:20]=[CH:19][N:18]=[C:17]([CH3:21])[CH:16]=3)\[CH3:13])[C:6]3[CH2:22][CH2:23][N:24]([CH3:26])[CH2:25][C:5]=3[C:4]=2[CH:3]=1
Reactant: Cc1cc(C(C)(O)Cn2c3c(c4cc(Cl)ccc42)CN(C)CC3)ccn1
Agent: [K+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C/C(=C\n1c2c(c3cc(Cl)ccc31)CN(C)CC2)c1ccnc(C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 14.2 %

Procedure:
1-(8-Chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-2-(2-methylpyridin-4-yl)propan-2-ol (150 mg, 0.4 mmol) in DCM (12 mL) and DMF (2 drops) was stirred at 0-10° C. Thionyl chloride (145 mg, 1.2 mmol) diluted in DCM (8 mL) was added dropwise and the RM stirred at RT for 2 h. The solvent was removed and the residue dried to obtain foamy solid. The solid was dissolved in NMP (2 mL), stirred for 5 min. Powdered KOH (141 mg, 2.52 mmol) was added to the reaction mixture, which was heated at 80° C. for 1 h. After completion of reaction, the reaction mixture was poured in water and the compound extracted with DCM (3×50 mL). The organic layer was washed with water, dried over sodium sulfate and concentrated under vacuum to obtain the crude product which was purified by reverse phase HPLC to obtain 20 mg of 8-chloro-2,3,4,5-tetrahydro-2-methyl-5-((E)-2-(2-methylpyridin-4-yl)prop-1-enyl)-1H-pyrido[4,5-b]indole as the free base. The free base was converted to HCl salt by treating with ethanolic HCl. 1H NMR (CD3OD, Di-HCl salt) δ (ppm): 8.70 (d, 1H), 8.20 (s, 1H), 8.15 (d, 1H), 7.72 (s, 1H), 7.60 (s, 1H), 7.25 (m, 2H), 4.70 (m, 1H), 4.40 (m, 1H), 3.80 (m, 1H), 3.60 (m, 1H), 3.20 (m, 2H), 3.10 (s, 3H), 2.82 (s, 3H), 2.10 (s, 3H).
Reaction SMILES: [Si:1]([O:18][CH2:19][C@H:20]1[S:25][CH:23]([OH:24])[CH2:22][CH2:21]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26]([OH:29])(=S)[CH3:27].C1(C)C(S(O)(=O)=O)=CC=CC=1>C(Cl)Cl>[C:26]([SH:25]1[CH:23]([OH:24])[CH2:22][CH2:21][C@H:20]1[CH2:19][O:18][Si:1]([C:14]([CH3:17])([CH3:15])[CH3:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:29])[CH3:27]
Reactant: CC(C)(C)[Si](OC[C@@H]1CCC(O)S1)(c1ccccc1)c1ccccc1
Reactant: CC(O)=S
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: ClCCl
Product: CC(=O)[SH]1C(O)CC[C@H]1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Yield: 67.1 %

Procedure:
Two grams of 5-O-(tert-butyldiphenylsilyl)-2,3-dideoxy-4-thioribofuranose (prepared according to J. A. Secrist et al., J. Med. Chem., 1992,35,533) is stirred with 0.456 g of thioacetic acid in 25 ml of methylene chloride and 0.0.025 g of toluenesulfonic acid for 68 hours. On workup the reactiion is adsorbed onto magnesium silicate and then flash chromatographed on silica gel to give 1.5 g of the desired product.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][PH3+].CC(C)([O-])C.[K+].[CH:12]([CH:14]1[CH2:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15]1)=O>C1COCC1>[CH3:2][O:3][CH:4]=[CH:12][CH:14]1[CH2:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21])[CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CCCC(C=O)C1
Reactant: COC[PH3+]
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC=CC1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 48.1 %

Procedure:
To a suspension of methoxymethylphosphonium chloride (5.14 g, 15 mmol) in THF (18 mL) was added potassium tert-butoxide (1.98 g, 15 mmol) at 0° C., and the mixture was stirred at 0° C. for 0.5 hr. A solution of tert-butyl 3-formyl-1-piperidinecarboxylate (2.13 g, 10 mmol) in THF (8 mL) was added dropwise at −20° C., and the resulting mixture was stirred at 0° C. to room temperature overnight. The mixture was partitioned between toluene and water. The separated organic phase was washed with brine, dried over Na2SO4, filtered, and evaporated. Purification by column chromatography on silica gel (hexane/ethyl acetate=5/1) gave tert-butyl 3-(2-methoxyethenyl)-1-piperidinecarboxylate as a colorless oil (1.16 g, yield; 48%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[CH2:6][CH2:7][NH2:8].[C:14]1([CH3:25])[CH:19]=[CH:18][C:17]([NH:20][CH2:21][C:22](O)=[O:23])=[CH:16][CH:15]=1>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:6][CH2:7][NH:8][C:22](=[O:23])[CH2:21][NH:20][C:17]2[CH:18]=[CH:19][C:14]([CH3:25])=[CH:15][CH:16]=2)[CH:9]=[CH:10][C:11]=1[O:12][CH3:13]
Reactant: COc1ccc(CCN)cc1OC
Reactant: Cc1ccc(NCC(=O)O)cc1
Solvent: CCOC(C)=O
Product: COc1ccc(CCNC(=O)CNc2ccc(C)cc2)cc1OC
Yield: 71.4 %

Procedure:
3,4-Dimethoxyphenethylamine (14.4 g) and p-toluidinoacetic acid (13.1 g) were heated for 1.5 hours at 190° C. in a stream of nitrogen. After cooling, the reaction mixture was dissolved in ethyl acetate and the solution was washed with a cooled 1 N sodium hydroxide solution and water and then dried. The solvent was distilled off and the oily residue was crystallized by adding ether to give N-[2-(3,4-dimethoxyphenyl)ethyl]-2-(p-toluidino)acetamide (18.6 g), mp 87° to 88.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](OS(C(F)(F)F)(=O)=O)[CH:5]=[C:6]([Cl:31])[C:7]=1[CH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([CH:14]2[C:22]3[N:21](S(C(F)(F)F)(=O)=O)[N:20]=[CH:19][C:18]=3[CH2:17][CH2:16][CH2:15]2)[C:10]1=[O:30].ClC1C=C(OS(C(F)(F)F)(=O)=O)C=C(Cl)C=1C[C@@H]1CCN(C2C3C(=CN(S(C(F)(F)F)(=O)=O)N=3)CCC2)C1=O.[F:79][C:80]1[CH:85]=[CH:84][C:83](B(O)O)=[CH:82][CH:81]=1.C(=O)([O-])[O-].[Na+].[Na+].[Li+].[OH-]>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:83]2[CH:84]=[CH:85][C:80]([F:79])=[CH:81][CH:82]=2)[CH:5]=[C:6]([Cl:31])[C:7]=1[CH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([CH:14]2[C:22]3[NH:21][N:20]=[CH:19][C:18]=3[CH2:17][CH2:16][CH2:15]2)[C:10]1=[O:30]
Reactant: OB(O)c1ccc(F)cc1
Reactant: O=C1[C@H](Cc2c(Cl)cc(OS(=O)(=O)C(F)(F)F)cc2Cl)CCN1C1CCCc2cnn(S(=O)(=O)C(F)(F)F)c21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: O=C1[C@H](Cc2c(Cl)cc(OS(=O)(=O)C(F)(F)F)cc2Cl)CCN1C1CCCc2cn(S(=O)(=O)C(F)(F)F)nc21
Solvent: O
Solvent: C1CCOC1
Product: O=C1[C@H](Cc2c(Cl)cc(-c3ccc(F)cc3)cc2Cl)CCN1C1CCCc2cn[nH]c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
Purge a solution of trifluoro-methanesulfonic acid 3,5-dichloro-4-[(R)-2-oxo-1-(1-trifluoromethanesulfonyl-4,5,6,7-tetrahydro-1H-indazol-7-yl)-pyrrolidin-3-ylmethyl]-phenyl ester and trifluoro-methanesulfonic acid 3,5-dichloro-4-[(R)-2-oxo-1-(2-trifluoromethanesulfonyl-4,5,6,7-tetrahydro-2H-indazol-7-yl)-pyrrolidin-3-ylmethyl]-phenyl ester (Preparation 79) (1.64 g, 2.54 mmol), 4-fluorophenylboronic acid (0.427 g, 3.05 mmol), and 2M sodium carbonate (3.8 mL) in THF (63 mL) with nitrogen. Treat the reaction with tetrakis(triphenylphosphine)palladium(0) (0.147 g, 0.127 mmol) and heat the reaction to 80° C. and stir for 1 hr. Cool to room temperature and treat the reaction with 2N LiOH (12.7 mL) and stir for 1 hr. Dilute the reaction with water and extract with ethyl acetate. The organic layer is dried (Na2SO4) and the solvent is removed to afford crude product that is purified first with 0 to 10% methanol in CH2Cl2 and then with a Varian 10 g SCX column with 9/1 CH2Cl2/MeOH and then 2:1 CH2Cl2/2M NH3 in MeOH to afford 0.735 g (63%) of the titled product. MS (m/z): 458 (M+1).
Reaction SMILES: [CH2:1]([O:5][C:6](=[O:12])[CH2:7][C:8]([CH2:10][OH:11])=[CH2:9])[CH2:2][CH2:3][CH3:4].[CH3:13][C:14]1[CH:23]=[C:22]([CH2:24][O:25][C:26]2[CH:34]=[CH:33][C:29]([CH:30]=[N:31][OH:32])=[CH:28][CH:27]=2)[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=1>>[CH2:1]([O:5][C:6](=[O:12])[CH2:7][C:8]1([CH:10]=[O:11])[O:32][N:31]=[C:30]([C:29]2[CH:28]=[CH:27][C:26]([O:25][CH2:24][C:22]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[N:15]=[C:14]([CH3:13])[CH:23]=3)=[CH:34][CH:33]=2)[CH2:9]1)[CH2:2][CH2:3][CH3:4]
Reactant: Cc1cc(COc2ccc(C=NO)cc2)c2ccccc2n1
Reactant: C=C(CO)CC(=O)OCCCC
Product: CCCCOC(=O)CC1(C=O)CC(c2ccc(OCc3cc(C)nc4ccccc34)cc2)=NO1
Yield: 36 %

Procedure:
Following a procedure analogous to that used in step 1c, but using 3-hydroxymethyl-but-3-enoic acid butyl ester from step 3a and 4-(2-methyl-quinolin-4-ylmethoxy)-benzaldehyde oxime from step 1b, the crude product was prepared. The product was purified by FCC on silica gel to give {5-formyl-3-[4-(2-methyl-quinolin-4-ylmethoxy)-phenyl]-4,5-dihydro-isoxazol-5-yl}-acetic acid butyl ester (0.13 g, 36%) as an oil. MS found: (M+H)+=461.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:15]=[CH:14][C:13]([CH:16]([CH3:19])[C:17]#[N:18])=[C:12]([O:20][CH3:21])[CH:11]=1.O1C2C=CC=CC=2N=[C:23]1[C:31]1C=CC(C#N)=C(OC)C=1.ICCC>>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:15]=[CH:14][C:13]([CH:16]([CH2:19][CH2:23][CH3:31])[C:17]#[N:18])=[C:12]([O:20][CH3:21])[CH:11]=1
Reactant: COc1cc(-c2nc3ccccc3o2)ccc1C(C)C#N
Reactant: COc1cc(-c2nc3ccccc3o2)ccc1C#N
Solvent: CCCI
Product: CCCC(C#N)c1ccc(-c2nc3ccccc3o2)cc1OC

Procedure:
Utilizing the general procedure outlined in the synthesis of 2-[4-(1,3-benzoxazol-2-yl)-2-methoxyphenyl]propanenitrile, 4-(1,3-benzoxazol-2-yl)-2-methoxybenzonitrile (200 mg, 0.75 mmol) was reacted with 1-iodopropane (73 μL, 0.75 mmol) to afford the desired 2-[4-(1,3-benzoxazol-2-yl)-2-methoxyphenyl]pentanenitrile as a yellow solid: 1H NMR (CDCl3, 300 MHz) δ 7.87–7.84 (d, 1H), 7.79–7.75 (m, 2H), 7.60–7.54 (m, 2H), 7.38–7.35 (m, 2H), 4.27–4.23 (t, 1H), 3.98 (s, 3H), 1.89–1.82 (M, 2H), 1.57–1.53 (m, 2H), 1.00–0.95 (t, 3H). MS (ESI) 307 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][CH2:10]Cl)=[CH:4][CH:3]=1.[CH2:12]([NH2:15])[CH:13]=[CH2:14]>C1(C)C=CC=CC=1>[CH2:12]([NH:15][CH2:10][CH:9]=[CH:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[CH:13]=[CH2:14]
Reactant: Fc1ccc(C=CCCl)cc1
Reactant: C=CCN
Solvent: Cc1ccccc1
Product: C=CCNCC=Cc1ccc(F)cc1

Procedure:
231.8 g (1.359 mol) of 3-(4-fluorophenyl)allyl chloride were added over the course of 25 min to a refluxing solution of 795.0 g (13.92 mol) of allylamine in 360 ml of toluene, and the mixture was then refluxed for 1 h. 1,000 ml were then distilled out through a 10 cm distillation column (5 mm glass rings) at a bath temperature up to 125° C. 1,000 ml of water were added to the distillation residue, and the pH was adjusted to 0.7 with 38% strength hydrochloric acid. The organic phase was separated off and discarded. The aqueous phase was adjusted to pH 12.7 with 50% strength sodium hydroxide solution and was extracted with toluene. The toluene extracts were dried with sodium sulfate and concentrated.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][C:3]=1[O:13][CH3:14].[F:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Br)=[CH:18][CH:17]=1>>[F:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][O:1][C:2]2[CH:12]=[CH:11][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=2[O:13][CH3:14])=[CH:18][CH:17]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: CCOC(=O)c1ccc(O)c(OC)c1
Product: COc1cc(C(=O)O)ccc1OCc1ccc(F)cc1
Yield: 96.5 %

Procedure:
In a manner identical to Reference Example 4, ethyl 4-hydroxy-3-methoxybenzoate (4.10 g) was benzylated with 4-fluorobenzyl bromide (4.35 g) and then hydrolyzed to yield 5.57 g of 4-(4-fluorobenzyloxy)-3-methoxybenzoic acid. In a manner similar to Example 8, this material (1.38 g) were subjected to a condensation reaction with 1-isobutylpiperazine dihydrochloride (1.08 g), thereby yielding 2.24 g of 1-[4-(4-fluorobenzyloxy)-3-methoxybenzoyl]-4-isobutyl piperazine. This material was dissolved in diethyl ether (50 ml) and then 1N hydrogen chloride ether solution (10 ml) was added thereto. The mixture was stirred at room temperature for 10 minutes and then the resulting crystals were collected by filtration and recrystallized (from n-hexane/ethanol), thereby yielding 1.60 g of the aimed compound.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[Br:8][C:9]1[CH:10]=[N:11][CH:12]=[C:13]([N+:16]([O-])=O)[C:14]=1Cl.CCN(C(C)C)C(C)C.C(Cl)Cl.CCOC(C)=O>C(Cl)Cl.C(O)(=O)C.[Fe]>[Br:8][C:9]1[C:14]([N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)=[C:13]([NH2:16])[CH:12]=[N:11][CH:10]=1
Reactant: O=[N+]([O-])c1cncc(Br)c1Cl
Reactant: CN1CCNCC1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CN1CCN(c2c(N)cncc2Br)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-methylpiperazine (2.109 g, 21.06 mmol) in DCM (62.50 mL) was added to a stirred solution of 3-bromo-4-chloro-5-nitro-pyridine (5000 mg, 21.06 mmol) and DIPEA (3.266 g, 4.402 mL, 25.27 mmol) in DCM (62.50 mL) at RT. The reaction was allowed to stir at ambient temperature for 2 h, then was concentrated in vacuo. The residue was partitioned between a saturated aqueous solution of NaHCO3 and DCM. Combined organic extract was dried and concentrated in vacuo. The orange solid was suspended in Acetic acid (60.00 mL) before iron (7.059 g, 126.4 mmol) was added. The mixture was warmed at 50° C. and stirred for 15 min. The mixture was allowed to cool to RT and DCM:EtOAc (4:1) (400 mL) was added to the reaction. The resulting brown suspension was filtered using a prewetted Celite cartridge (25 g), washing with more DCM:MeOH (4:1) (200 mL). Combined filtrate was concentrated in vacuo to afford a red/brown gum which was purified by chromatography on silica (Rf companion, 80 g cartridge), eluting with DCM-DCM:MeOH:NE3(90:10:1) a gradient of 100-0 to 20:80. Fractions containing clean product were collected and concentrated in vacuo to afford 5-bromo-4-(4-methylpiperazin-1-yl)pyridin-3-amine as a viscous, clear light yellow oil that solidifies on standing. MS (ES+) 273.1.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[CH:16]=O)([CH3:7])[CH3:6])[CH3:2].[Cl:19][C:20]1[CH:28]=[C:27]2[C:23]([CH2:24][C:25](=[O:29])[NH:26]2)=[CH:22][CH:21]=1.N1CCCC1>CO>[CH2:1]([O:3][C:4](=[O:18])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[CH:16]=[C:24]1[C:23]2[C:27](=[CH:28][C:20]([Cl:19])=[CH:21][CH:22]=2)[NH:26][C:25]1=[O:29])([CH3:7])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(Cl)cc1C=O
Reactant: O=C1Cc2ccc(Cl)cc2N1
Solvent: C1CCNC1
Solvent: CO
Product: CCOC(=O)C(C)(C)Oc1ccc(Cl)cc1C=C1C(=O)Nc2cc(Cl)ccc21
Yield: 77.9 %

Procedure:
In a manner similar to the method described in Example 227b, 2-(4-chloro-2-formyl-phenoxy)-2-methyl-propionic acid ethyl ester (7 g, 26 mmol) was reacted with 6-chlorooxindole (3.6 g, 22 mmol) and pyrrolidine (1.85 g, 26 mmol) in methanol to give E/Z 2-[4-chloro-2-(6-chloro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-phenoxy]-2-methyl-propionic acid ethyl ester as a yellow solid (7.2 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.C(N(CC)CC)C.O>C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: C1COCCN1
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O
Product: O=[N+]([O-])c1ccc(N2CCOCC2)c(F)c1
Temperature: 27.5 °C
Reaction time: 1 h
Yield: 94.2 %

Procedure:
3,4-difluoro nitrobenzene (100 gr) is slowly added to a mixture of morpholine (76.6 gr), triethylamine (23 ml) and in presence of acetonitrile solvent (115 ml) at 40-50° C. Reaction mass is heated for 6 hrs at reflux temperature, cooled to 25-30° C. Then water (600 ml) is added slowly to the reaction mass and then cooled to 0-5° C. The reaction mixture is stirred for 1 hr. The solid is filtered to give 134 gr of 3-fluoro-4-morpholinyl nitrobenzene.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH2:9][N:8]([CH2:14][CH2:15][N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)[C:7]2=[O:21].[CH3:22]C(N(C)C)=O.CI>O>[Cl:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH3:22])[CH2:9][N:8]([CH2:14][CH2:15][N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)[C:7]2=[O:21]
Reactant: CC(=O)N(C)C
Reactant: O=C1c2cc(Cl)ccc2NCN1CCN1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: CN1CN(CCN2CCCC2)C(=O)c2cc(Cl)ccc21
Reaction time: 0.5 h
Yield: 14 %

Procedure:
543 Milligrammes (22.5 mmoles) of 60% sodium hydride are added to 3.50 grammes (12.5 mmoles) of 6-chloro-2,3-dihydro-3-[2-(pyrrolidino)ethyl]-4(1H)-quinazolinone in 25 mlof anhydrous dimethylacetamide and the solution is left at room temperature, in agitation and in an inert gas atmosphere, for 30 minutes. 0.86 Ml (13.8 mmoles) of methyl iodide are slowly dripped and the reactionmixture is kept for 6 hours at room temperature. The reaction mixture is then diluted with water and ice and the product is extracted with ethyl ether and recovered through evaporation of the organic solvent, obtaining an oily substance, with a yield of 14%, presenting the following chemical-physical characteristics:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH:4]=[C:5]1[CH2:10][CH2:9][CH:8]([CH2:11][O:12][CH3:13])[CH2:7][CH2:6]1>C(OC(=O)C)C.[Pd]>[CH3:1][O:2][C:3](=[O:14])[CH2:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][O:12][CH3:13])[CH2:7][CH2:6]1
Reactant: COCC1CCC(=CC(=O)OC)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC[C@H]1CC[C@H](CC(=O)OC)CC1

Procedure:
Prepared from (4-Methoxymethyl-cyclohexylidene)-acetic acid methyl ester (0.550 g, 3 mmol) by hydrogenation using Pd/C (10%) (0.295 g, 0.3 mmol) in ethylacetate (15 ml). 1/3 cis/trans mixture.
Reaction SMILES: OS(O)(=O)=O.[F:6][C:7]([F:23])([F:22])[C:8](=[O:21])[C:9](=[N:19][OH:20])[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18]>C1(C)C=CC=CC=1>[OH:21][C:8]1([C:7]([F:22])([F:23])[F:6])[C:17]2[C:12](=[C:13]([CH3:18])[CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10][C:9]1=[N:19][OH:20]
Reactant: Cc1ccccc1CCC(=NO)C(=O)C(F)(F)F
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: Cc1cccc2c1CCC(=NO)C2(O)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.4 %

Procedure:
Cold concentrated H2SO4 (12 ml, 98% w/v H2SO4 in water) was added to a stirred suspension of 1,1,1-trifluoro-5-(2-methylphenyl)-2,3-pentanedione 3-oxime (11.9 g, 45.9 mmol) in toluene (16 mL) at 0° C. The reaction mixture and allowed to warm to room temperature (25° C.) and then stirred for 30 min. Ice was added to the reaction mixture. The resulting mixture was extracted with diethyl ether (2×). The ether extract was washed successively with water and a saturated aqueous solution of NaHCO3, dried (MgSO4) and concentrated under reduced pressure to give the title compound (10.4 g, 87% yield). This product was used for the reaction described in the following example. A small sample was triturated with hexane to give off-white crystals; mp 154°-156° C.; nmr (CDCl3) δ 2.3 (s, 3H), 2.9 (m, 4H), 7.2 (m, 2 H), 7.6 (m, 1H); ir (CHCl3) 3570, 3480, 1170 cm-1 ; uvλmax (MeOH) 273 nm (ε 570), 266 (590).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:19])=[C:6]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([NH2:18])[N:14]=[CH:15]3)=[CH:10][CH:9]=2)[CH:7]=1.[F:20][CH:21]([F:25])[C:22](O)=[O:23].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.O>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[F:20][CH:21]([F:25])[C:22]([NH:18][C:13]1[N:14]=[CH:15][C:16]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[C:8]([C:6]1[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[CH3:19])[CH:17]=2)=[O:23]
Reactant: O=C(O)C(F)F
Reactant: Cc1ccc(F)cc1-c1ccc2cc(N)ncc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(F)cc1-c1ccc2cc(NC(=O)C(F)F)ncc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.3 %

Procedure:
7-(5-Fluoro-2-methylphenyl)isoquinolin-3-amine (150 mg, 0.595 mmol), 2,2-difluoroacetic acid (171 mg, 1.78 mmol), 4-(Dimethylamino)pyridine (18 mg, 0.15 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (676 mg, 1.78 mmol) were dissolved in pyridine (20 mL). After the reaction mixture was stirred at room temperature overnight, water (1 mL) was added and it was extracted with ethyl acetate. It was concentrated and purified by prep-HPLC to give the desired product (59.6 mg). LCMS (ESI): RT (Min)=1.161, M+H+=330.9, method=A; 1H NMR (400 MHz, DMSO-d6) δ 11.48 (s, 1H), 9.22 (s, 1H), 8.50 (s, 1H), 8.08 (s, 1H), 8.03 (d, J=8.4 Hz, 1H), 7.75 (d, J=8.4 Hz, 1H), 7.38-7.34 (m, 1H), 7.16 (d, J=8.8 Hz, 2H), 6.44 (t, J=54.0 Hz, 1H), 2.22 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH2:7])=[CH:4][CH:3]=1.[F:10][C:11]([F:26])([F:25])[C:12]1[CH:13]=[C:14]([N:22]=[C:23]=[S:24])[CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:17]=1>C1COCC1>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([NH:1][C:23]([NH:22][C:14]2[CH:15]=[C:16]([C:18]([F:19])([F:20])[F:21])[CH:17]=[C:12]([C:11]([F:10])([F:25])[F:26])[CH:13]=2)=[S:24])=[CH:3][CH:4]=1)=[CH2:7]
Reactant: FC(F)(F)c1cc(N=C=S)cc(C(F)(F)F)c1
Reactant: C=Cc1ccc(N)cc1
Solvent: C1CCOC1
Product: C=Cc1ccc(NC(=S)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1
Yield: 60 %

Procedure:
To a stirred solution of 4-aminostyrene (3.5 mmol) in dry THF (20 mL) under nitrogen was added 3,5-bis-(trifluoromethyl)phenyl isothiocyanate (3.5 mmol). The solution was refluxed overnight and then the solvent was evaporated under reduced pressure. The resulting solid residue was purified by column chromatography to yield the desired product in 60% yield.
Reaction SMILES: [F:1][C:2]1[S:6][C:5]([N:7]([CH3:20])[CH:8]2[CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9]2)=[N:4][CH:3]=1.[C:21]([OH:27])([C:23]([F:26])([F:25])[F:24])=[O:22]>C(Cl)Cl>[F:24][C:23]([F:26])([F:25])[C:21]([OH:27])=[O:22].[F:1][C:2]1[S:6][C:5]([N:7]([CH3:20])[CH:8]2[CH2:12][CH2:11][NH:10][CH2:9]2)=[N:4][CH:3]=1
Reactant: CN(c1ncc(F)s1)C1CCN(C(=O)OC(C)(C)C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(c1ncc(F)s1)C1CCNC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
A solution of 590 mg (1.96 mmol) tert.-butyl 3-((5-fluorothiazol-2-yl)(methyl)amino)-pyrrolidine-1-carboxylate in DCM (10 ml) was combined with 5 ml of TFA and stirred for 1 h at RT. The mixture was then evaporated under a vacuum, redissolved with MeOH and again evaporated, 611 mg (1.94 mmol, 99%) of 5-fluoro-N-methyl-N-(pyrrolidin-3-yl)thiazol-2-amine trifluoroacetate being obtained which were further reacted without being purified.