Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[CH:15]1([C:18]2[CH:23]=[CH:22][C:21]([CH2:24]O)=[CH:20][CH:19]=2)[CH2:17][CH2:16]1>>[CH:15]1([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][O:1][C:2]3[N:6]([C:7]4[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=4)[N:5]=[CH:4][CH:3]=3)=[CH:20][CH:19]=2)[CH2:17][CH2:16]1
Reactant: OCc1ccc(C2CC2)cc1
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Product: N#Cc1ccnc(-n2nccc2OCc2ccc(C3CC3)cc2)c1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and (4-cyclopropylphenyl)methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 0.61-0.65 (2H, m), 0.89-0.94 (2H, m), 1.91-1.84 (1H, m), 5.12 (2H, s), 5.67 (1H, d, J=1.6 Hz), 7.01-7.24 (4H, m), 7.32-7.33 (1H, m), 7.50 (1H, d, J=1.2 Hz), 7.95 (1H, s), 8.63 (1H, d, J=4.8 Hz). [M+H] Calc'd for C19H16N4O, 317. Found, 317.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:14])([CH3:13])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])(O)=O.[Na+].[CH2:20](Cl)[Cl:21]>O>[C:1]([O:5][C:6]([NH:8][C:9]([CH3:14])([CH3:13])[C:10]([O:12][CH2:20][Cl:21])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CC(C)(C)OC(=O)NC(C)(C)C(=O)OCCl

Procedure:
The title compound was prepared according to the procedure as described in Example 17 Step 1 using 2-((tert-butoxycarbonyl)amino)-2-methylpropanoic acid (1.07 g, 5.29 mmol) in DCM (25 mL) and H2O (25 mL), NaHCO3 (1.78 g, 21.2 mmol), TBAHSO4 (0.18 g, 0.53 mmol) and a solution of chloromethyl sulfochloridate (638 μL, 6.35 mmol) in DCM (5 mL). The title compound was obtained as a white solid (1.16 g, 87.7%). The title compound was characterized by 1H NMR as shown below:
Reaction SMILES: [F:1][C:2]1[CH:35]=[CH:34][C:5]([CH2:6][C:7]2[N:11]([CH2:12][C:13]([O:15]C(C)(C)C)=[O:14])[N:10]=[C:9]([C:20]3[N:21]=[N:22][N:23]([CH2:25][C:26]4[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=4)[CH:24]=3)[CH:8]=2)=[CH:4][CH:3]=1.CO.C1COCC1.[OH-].[Na+]>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[N:11]([CH2:12][C:13]([OH:15])=[O:14])[N:10]=[C:9]([C:20]3[N:21]=[N:22][N:23]([CH2:25][C:26]4[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=4)[CH:24]=3)[CH:8]=2)=[CH:34][CH:35]=1
Reactant: COc1ccc(Cn2cc(-c3cc(Cc4ccc(F)cc4)n(CC(=O)OC(C)(C)C)n3)nn2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(Cn2cc(-c3cc(Cc4ccc(F)cc4)n(CC(=O)O)n3)nn2)cc1
Temperature: 25 °C
Yield: 89.1 %

Procedure:
To a solution of tert-butyl {5-(4-fluorobenzyl)-3-[1-(4-methoxybenzyl)-1H-1,2,3-triazol-4-yl]-1H-pyrazol-1-yl}acetate (14.0 g, 29.3 mmol) in mixed solvent of MeOH/THF (60 mL/20 mL) was added a solution of NaOH (3.5 g, 88 mmol) in H2O (20 mL) and the reaction mixture was stirred at room temperature for an hour. The mixture was evaporated and the residue was diluted with water (100 mL) and washed with EtOAc (2×100 mL). The aqueous layer was adjusted to pH=3-4 with conc. HCl. The precipitate was filtered and dried in vacuo to afford the title compound (11.0 g, 90.0%) as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:3]=1[O:4][Si:5]([C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:7])[CH3:6].[Br-].[CH:18]1([Zn+])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.C1COCC1>[C:8]([Si:5]([O:4][C:3]1[C:12]([F:16])=[CH:13][CH:14]=[CH:15][C:2]=1[CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)([CH3:7])[CH3:6])([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)[Si](C)(C)Oc1c(F)cccc1Br
Reactant: [Zn+]C1CCCCC1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)Oc1c(F)cccc1C1CCCCC1
Temperature: 25 °C

Procedure:
A solution consisting of (2-bromo-6-fluorophenoxy)(tert-butyl)dimethylsilane (0.832 g, 2.73 mmol) and bis(tri-tert-butylphosphine)palladium(0) (0.070 g, 0.14 mmol) and dry THF (5 mL) was treated with cyclohexylzinc(II) bromide (7.0 mL, 3.5 mmol, 0.5 M in THF). The resultant mixture was heated for 45 minutes at 50° C., cooled to rt, and concentrated to dryness. The resultant residue was subjected to FCC purification to the title compound (0.841 g, 89%) which was used without purification.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:3]=1[NH2:4].[CH3:10][C:11]1[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1.Cl>N1C=CC=CC=1>[CH3:10][C:11]1[CH:16]=[CH:15][C:14]([S:17]([NH:4][C:3]2[CH:5]=[C:6]([F:9])[CH:7]=[CH:8][C:2]=2[F:1])(=[O:19])=[O:18])=[CH:13][CH:12]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1cc(F)ccc1F
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2cc(F)ccc2F)cc1
Reaction time: 48 h
Yield: 76.1 %

Procedure:
A stirred mixture of 15.0 g (0.116 mole) of 2,5-difluoroaniline and 24.4 g (0.128 mole) of 4-methylphenylsulfonyl chloride in 50 ml of pyridine was heated at reflux for approximately 18 hours. The reaction mixture was cooled and poured into 500 ml of 6N hydrochloric acid. This acidic mixture was allowed to stand at room temperature for two days. A precipitate formed and was collected by filtration. The filter cake was washed with dilute hydrochloric acid and was dried under reduced pressure to yield 25.0 g of N-(4-methylphenylsulfonyl)-2,5-difluoroaniline. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[OH-].[Na+].Cl[C:13]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:14]=1[C:15]#[N:16].O>CS(C)=O>[CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][C:13]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:14]=2[C:15]#[N:16])=[CH:5][CH:4]=1
Reactant: CSc1ccc(O)cc1
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CSc1ccc(Oc2ccc([N+](=O)[O-])cc2C#N)cc1
Temperature: 60 °C
Yield: 97.1 %

Procedure:
To a solution of 11.55 g (0.0824 moles) of 4-(methylthio)phenol dissolved in 150 ml of DMSO was added 3.3 g (0.0824 moles) of NaOH. The slurry was heated to 60° C. and 13.7 g (0.0730 moles) of 2-chloro-5-nitrobenzonitrile was added and the mixture heated at 75° C. for 21/2 hrs. The mixture was cooled and poured into a solution of 200 ml of 5 N aqueous NaOH and 500 ml of water. The product was collected by filtration, washed well with water and dried, to obtain 20.3 g of product (94.6% yield). Recrystallization from methanol afforded purified 2-(4-(methylthio)phenoxy)-5-nitrobenzonitrile, mp 124°-126° C.
Reaction SMILES: B.C1COCC1.C(OC([NH:14][N:15]=[C:16]1[CH2:21][CH2:20][N:19]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:18][CH2:17]1)=O)(C)(C)C>Cl>[C:22]([N:19]1[CH2:18][CH2:17][CH:16]([NH:15][NH2:14])[CH2:21][CH2:20]1)([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)NN=C1CCN(C(C)(C)C)CC1
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)(C)N1CCC(NN)CC1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
A 1M solution borane in THF (28.7 mL, 28.7 mmol) was added to N′-(1-tert-Butyl-piperidin-4-ylidene)-hydrazinecarboxylic acid tert-butyl ester. The mixture was stirred for 16 h, and then 40 mL of 6M HCl was added. The mixture was heated to 60° C. for 30 min. The mixture was concentrated and 200 mL of petroleum ether was added, followed by powdered NaOH (5 g). The slurry was stirred manually for 30 min, and then the mixture was dried with MgSO4, filtered, and concentrated to give 1.21 g of (1-tert-butyl-piperidin-4-yl)-hydrazine (1.21 g).
Reaction SMILES: [CH2:1](Cl)/[CH:2]=[CH:3]/[CH2:4]Cl.[C:7]([O:15][CH2:16][CH3:17])(=[O:14])[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].[OH-].[K+]>C(Cl)Cl>[CH:2]([CH:3]1[CH2:4][C:8]1([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:7]([O:15][CH2:16][CH3:17])=[O:14])=[CH2:1]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: ClC/C=C/CCl
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Product: C=CC1CC1(C(=O)OCC)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 59.6 %

Procedure:
The following experiment demonstrates the in situ preparation of the onium compound in the process. In a reaction flask were added 137.5 g (1.1 mol) trans 1,4-dichlorobutene-2, 160.0 g (1.0 mol) diethyl malonate, 600 cc methylene chloride and 6.8 g (5 mol % based on diethyl malonate) N,N-dimethylbenzylamine. The mixture was stirred at ambient temperature for 20 minutes and 124.8 g (2.0 mol) flaked 90% potassium hydroxide then added in small portions over a one-hour period while maintaining the reaction temperature at 25° C. with external cooling. The reaction was then stirred at ambient temperature for four hours. Diethyl 2-vinylcyclopropane-1,1-dicarboxylate (126.6 g; 59.8% yield) was obtained. In a similar manner, 5 mol % tri-n-butylphosphine was employed in the reaction and 69.6% yield diethyl 2-vinylcyclopropane-1,1-dicarboxylate obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:15]=1[C:14](=[O:16])[C:13]1[CH:12]=[CH:11][C:10]([OH:17])=[C:9]([CH3:18])[C:8]=1[O:7]2.C(=O)([O-])[O-].[K+].[K+].Br[CH2:26][C:27]([O:29]CC)=[O:28].[OH-].[Na+].Cl>O.CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:15]=1[C:14](=[O:16])[C:13]1[CH:12]=[CH:11][C:10]([O:17][CH2:26][C:27]([OH:29])=[O:28])=[C:9]([CH3:18])[C:8]=1[O:7]2
Reactant: CCOC(=O)CBr
Reactant: Cc1c(O)ccc2c(=O)c3c(F)cccc3oc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(OCC(=O)O)ccc2c(=O)c3c(F)cccc3oc12
Reaction time: 2 h
Yield: 75.4 %

Procedure:
A mixture of 1.5 g of 8-fluoro-3-hydroxy-4-methyl9-oxo-9H-xanthene, 3.0 g of potassium carbonate, 3.6 g of ethyl bromoacetate and 40 ml of DMF was stirred at 60°-70° C. for 2 hours. After cooling the mixture, sodium hydroxide (3 g) and water (40 ml) were added and the resulting mixture was stirred at 90°-100° C. for 30 minutes. After cooling, the mixture was rendered acidic with hydrochloric acid and the solid crystal was recovered by filtration, washed with water and dried. Recrystallization from DMF gave 1.4 g of 8-fluoro-4-methyl-9-oxo-9H-xanthene-3-yloxyacetic acid. m.p. 259°-261° C. This compound showed a mass spectrum having a molecular ion peak at m/e 302.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[N:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][N:10]=2)[CH:5]=[CH:4][C:3]=1[C@H:19]1[O:24][CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20]1.FC(F)(F)C(O)=O.[OH-].[Na+]>C(#N)C.O>[F:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[N:10]=[CH:11][C:12]([C:15]([F:18])([F:16])[F:17])=[CH:13][N:14]=2)[CH:5]=[CH:4][C:3]=1[C@H:19]1[O:24][CH2:23][CH2:22][NH:21][CH2:20]1
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](c2ccc(Nc3ncc(C(F)(F)F)cn3)cc2F)C1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CC#N
Product: Fc1cc(Nc2ncc(C(F)(F)F)cn2)ccc1[C@@H]1CNCCO1
Temperature: 80 °C
Reaction time: 16 h
Yield: 73.7 %

Procedure:
To a stirred solution of (R)-tert-butyl 2-(2-fluoro-4-(5-(trifluoromethyl)pyrimidin-2-ylamino)phenyl)morpholine-4-carboxylate (300 mg) in acetonitrile (2 ml) and water (6 ml) was added trifluoroacetic acid (522 μl). The reaction mixture was then capped and the mixture was shaken at 80° C. for 16 h. The reaction mixture was then cooled to room temperature and poured into 4 M aq. NaOH and extracted twice with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash column chromatography (silica gel, CH2Cl2/MeOH/aq. NH3) to afford (R)—N-(3-fluoro-4-(morpholin-2-yl)phenyl)-5-(trifluoromethyl)pyrimidin-2-amine (171 mg, 74%) as an off-white solid. MS (ISP): 343.1 ([M+H]+).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)[CH:5]=[CH:4][CH:3]=1.[Cl:17][C:18]1[C:19](B(O)O)=[CH:20][C:21]([F:24])=[N:22][CH:23]=1.C(Cl)Cl.COCCOC>CCOC(C)=O.CO.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:17][C:18]1[C:19]([C:2]2[CH:3]=[CH:4][CH:5]=[C:6]([NH:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=3)[N:7]=2)=[CH:20][C:21]([F:24])=[N:22][CH:23]=1
Reactant: OB(O)c1cc(F)ncc1Cl
Reactant: Fc1cccc(CNc2cccc(Br)n2)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CO
Solvent: COCCOC
Solvent: ClCCl
Product: Fc1cccc(CNc2cccc(-c3cc(F)ncc3Cl)n2)c1
Temperature: 25 °C

Procedure:
A mixture of 6-bromo-N-(3-fluorobenzyl)pyridin-2-amine (A, 2.0 g, 7.11 mmol), 5-chloro-2-fluoropyridin-4-ylboronic acid (2.0 g, 11.4 mmol), PdCl2(dppf).CH2Cl2 adduct (0.465 g, 0.569 mmol), DME (27 mL) and 2M aqueous Na2CO2 (9.25 mL, 18.50 mmol) was stirred at about 100° C. for 3 hr. After cooling to ambient temperature, the mixture was diluted with EtOAc (25 mL) and MeOH (20 mL), filtered, and concentrated in vacuo to yield a crude material. The crude material was purified by column chromatography [silica gel, 120 g, EtOAc/hexane=0/100 to 20/80] providing 5′-chloro-2′-fluoro-N-(3-fluorobenzyl)-2,4′-bipyridin-6-amine (1.26 g) as an off-white solid. LCMS (m/z): 332.2 [M+H]+; Retention time=0.92 min.
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][N:6]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]([C:17]3[C:25]([OH:26])=[CH:24][C:20]4[O:21][CH2:22][O:23][C:19]=4[CH:18]=3)([CH2:15]O)[C:7]2=[O:27])[CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH:1]1([CH2:4][CH2:5][N:6]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]3([C:17]4=[CH:18][C:19]5[O:23][CH2:22][O:21][C:20]=5[CH:24]=[C:25]4[O:26][CH2:15]3)[C:7]2=[O:27])[CH2:3][CH2:2]1
Reactant: O=C1N(CCC2CC2)c2ccccc2C1(CO)c1cc2c(cc1O)OCO2
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1N(CCC2CC2)c2ccccc2C12COc1cc3c(cc12)OCO3
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.8 %

Procedure:
To a solution of 1-(2-cyclopropylethyl)-3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1,3-dihydro-2H-indol-2-one (0.92 g, 2.51 mmol) in anhydrous THF (20.0 mL) was added triphenylphosphine (0.82 g, 3.13 mmol) and diethyl azodicarboxylate (0.55, 3.13 mmol) at −78° C. The brown reaction solution was stirred at ambient temperature for 16 h, and quenched with saturated ammonium chloride (50.0 mL). The organic solvent was removed under reduced pressure and the aqueous mixture was extracted with ethyl acetate (3×50.0 mL). The combined organic layers were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The brown residue was subjected to column chromatography eluting with ethyl acetate/hexane (5% to 20%, gradient) to give the title compound (0.63 g, 72%) which was crystallized from ether to afford a colorless solid: mp 125-127° C.; 1H NMR (300 MHz, CDCl3) δ 7.30-7.25 (m, 1H), 7.14 (d, 1H), 7.02 (t, 1H), 6.89 (d, 1H), 6.49 (s, 1H), 6.11 (s, 1H), 5.84 (m, 2H), 4.76 (m, 2H), 3.93-3.74 (m, 2H), 1.65-1.57 (m, 2H), 0.76-0.56 (m, 1H), 0.48-0.41 (m, 2H), 0.08-0.03 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 177.4, 155.9, 148.8, 142.6, 142.3, 132.4, 128.8, 124.0, 123.1, 119.5, 108.6, 103.1, 101.5, 93.6, 80.6, 58.2, 40.5, 32.5, 30.8, 8.7, 4.4; MS (ES+) m/z 350.3 (M+1).
Reaction SMILES: CS[C:3]1[S:4][C:5](=[CH:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][N:14]=[CH:13]3)[C:6](=[O:8])[N:7]=1.[CH3:20][O:21][C:22]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:23]=1[NH2:30].CCN(C(C)C)C(C)C>>[CH3:20][O:21][C:22]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:23]=1[NH:30][C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][N:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1
Reactant: CSC1=NC(=O)C(=Cc2ccc3ncncc3c2)S1
Reactant: COc1ccc(N)c(OC)c1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(NC2=NC(=O)/C(=C/c3ccc4ncncc4c3)S2)c(OC)c1

Procedure:
Similar procedure as described in example 1d was used, starting from 2-methylsulfanyl-5-quinazolin-6-ylmethylene-thiazol-4-one, 2,4-dimethoxy-phenylamine and DIEA to give 2-(2,4-dimethoxy-phenylamino)-5-[1-quinazolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one: LC-MS m/e observed. LC-MS m/e 393 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=O)[NH:9][C:8]([C@@H:13]([NH:15][C:16](=[O:32])[O:17][CH2:18][CH:19]1[C:31]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:25]3[C:20]1=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH3:14])=[CH:7]2.CN(C=O)C.S(Cl)([Cl:40])=O>C1(C)C=CC=CC=1>[Cl:40][C:10]1[C:11]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2[Cl:1])[CH:7]=[C:8]([C@@H:13]([NH:15][C:16](=[O:32])[O:17][CH2:18][CH:19]2[C:31]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:25]3[C:20]2=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH3:14])[N:9]=1
Reactant: O=S(Cl)Cl
Reactant: C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)c1cc2cccc(Cl)c2c(=O)[nH]1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)c1cc2cccc(Cl)c2c(Cl)n1
Temperature: 25 °C

Procedure:
To a solution of (S)-(9H-fluoren-9-yl)methyl 1-(8-chloro-1-oxo-1,2-dihydroisoquinolin-3-yl)ethylcarbamate (345) (58 g, 130 mmol, 1.0 eq) and DMF (0.5 mL) in toluene (300 mL), sulfurous dichloride (78 g, 0.65 mol, 5.0 eq) was added slowly, and the resulting mixture was stirred at reflux for 2.5 h. The mixture was allowed to cool to RT and then concentrated in vacuo. The residue was poured into water (200 mL) and extracted with ethyl acetate (3×100 mL). The organic layer was washed with water (2×100 mL) and brine (100 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (5-20% ethyl acetate-petroleum ether) to afford (S)-(9H-fluoren-9-yl)methyl 1-(1,8-dichloroisoquinolin-3-yl)ethylcarbamate (346).
Reaction SMILES: C[Si](C)(C)[N:3]([C@H:8]([B:13]1[O:17][C@@H:16]2[CH2:18][C@@H:19]3[CH2:22][C@H:21]([C@:15]2([CH3:25])[O:14]1)[C:20]3([CH3:24])[CH3:23])[CH2:9][CH:10]([CH3:12])[CH3:11])[Si](C)(C)C.[ClH:28]>O1CCOCC1.C(OCC)C>[ClH:28].[CH3:25][C@:15]12[C@H:21]3[CH2:22][C@H:19]([C:20]3([CH3:23])[CH3:24])[CH2:18][C@H:16]1[O:17][B:13]([C@@H:8]([NH2:3])[CH2:9][CH:10]([CH3:12])[CH3:11])[O:14]2
Reactant: CC(C)C[C@@H](B1O[C@@H]2C[C@@H]3C[C@@H](C3(C)C)[C@]2(C)O1)N([Si](C)(C)C)[Si](C)(C)C
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: CC(C)C[C@H](N)B1O[C@@H]2C[C@@H]3C[C@@H](C3(C)C)[C@]2(C)O1
Temperature: 0 °C
Reaction time: 4 h
Yield: 66 %

Procedure:
To a solution of crude N,N-Bis(trimethylsilyl)-(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutylamine of Step 3 (79 g, 0.193 mol) in a mixture of dioxane (100 ml) and diethyl ether (200 ml), a 4 N solution of hydrogen chloride in dioxane (193 ml, 0.772 mol) was added, while cooling at 0° C. The mixture was then stirred at room temperature for 4 hours and concentrated. The residue was taken up with anhydrous hexane (500 ml) and a 2 M solution of hydrogen chloride in diethyl ether (48 ml, 0.096 mol) was added. The mixture was stirred at 0° C. for 1 hour, then concentrated. The residue was taken up with anhydrous hexane and the resulting suspension was stirred at room temperature overnight. The solid was collected by filtration and dried under vacuum affording 38.1 g of product (66% yield). A second crop (4.13 g, 7% yield) was obtained from the mother liquors.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[C:13]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[C:20](=[O:21])[C:12]=2[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]1=[O:22].[NH2:23][CH2:24][CH2:25][OH:26].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[OH:26][CH2:25][CH2:24][NH:23][CH2:2][CH2:3][N:4]1[C:13]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[C:20](=[O:21])[C:12]=2[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]1=[O:22]
Reactant: O=C1c2ccccc2-c2c1c1ccccc1c(=O)n2CCCl
Reactant: NCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2-c2c1c1ccccc1c(=O)n2CCNCCO
Temperature: 110 °C
Reaction time: 2 h

Procedure:
A mixture of 1 g of 6-(2-chloroethyl)-5,11-dioxo-5,6-dihydro-11H-indeno[1,2-c]isoquinoline (IV, X=2, m.p. 214°-215° C.), 1 g of dry 2-aminoethanol and 1 g of anhydrous potassium carbonate in 30 ml of anhydrous dimethylformamide is treated by warming to 100°14 110° C. and kept at this temperature for two hours. The hot mixture is filtered and the product collected on filter washed with 10 ml of ethanol. After twelve hours of standing in refrigerator (5° C. the eliminated crystallic substance is separated by suction, washed with ethanol and dried at temperature of 60° C. The yield 0.7 g (65% of theory), m. p. of the product is 184° C. It is possible to purify the substance as in Example 1.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.CC1(C)C(C)(C)OB([C:17]2[CH:21]=[CH:20][O:19][C:18]=2[CH3:22])O1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.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>[Cl:1][C:2]1[N:7]=[C:6]([C:17]2[CH:21]=[CH:20][O:19][C:18]=2[CH3:22])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1occc1B1OC(C)(C)C(C)(C)O1
Reactant: Clc1ccnc(Cl)n1
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: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1occc1-c1ccnc(Cl)n1
Temperature: 25 °C
Yield: 52.5 %

Procedure:
2,4-Dichloropyrimidine (1.0 g, 6.71 mmol), 4,4,5,5-tetramethyl-2-(2-methyl-3-furanyl)-1,3,2-dioxaborolane (1.397 g, 6.71 mmol), sodium carbonate (1.067 g, 10.07 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.388 g, 0.336 mmol) were added together in 1,4-dioxane (42 mL) and water (7.00 mL) and the resulting mixture was heated at 85° C. under argon for 4 hours. The reaction mixture was allowed to cool to room temperature, diluted with water and extracted with ethyl acetate (×3). The ethyl acetate layers were combined, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by Biotage SP4 column chromatography eluting with a gradient of 0-30% ethyl acetate and iso-hexane. Product containing fractions were combined and evaporated under reduced pressure to give the title compound (686 mg, 3.52 mmol, 52.5 yield) as a white solid. LC/MS [M+H]+=195/197.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][N:8](C(OCC)=O)[CH2:7][CH2:6]1.O.CCOC(C)=O.[OH-].[Na+]>Cl>[Cl:1][C:2]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:3]=1[CH2:4][N:5]1[CH2:6][CH2:7][NH:8][CH2:9][CH2:10]1
Reactant: CCOC(=O)N1CCN(Cc2cc(Cl)ccc2Cl)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: Clc1ccc(Cl)c(CN2CCNCC2)c1
Reaction time: 40 h
Yield: 44.4 %

Procedure:
A solution containing 13 g of 1-(2,5-dichlorobenzyl)-4-ethoxycarbonylpiperazine in 35 mL of 37% HCl was stirred for 40 h at reflux. Subsequently, 30 mL of water and 30 mL of EtOAc were added at room temperature, adjusting the pH to 11 via addition of 35% NaOH. The organic phase, which was dried on anhydrous sodium sulphate, was evaporated to dryness under vacuum. The crude was purified via flash chromatography (CHCl3-MeOH 7:3) giving 4.46 g (50%) of the title compound.
Reaction SMILES: [C:1]1(C)[CH:6]=CC(S(O)(=O)=O)=C[CH:2]=1.[OH:12][CH2:13][C:14]([CH2:19][OH:20])([CH2:17][CH3:18])[CH2:15][OH:16].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:2][C:1]1([CH3:6])[O:16][CH2:15][C:14]([CH2:17][CH3:18])([CH2:19][OH:20])[CH2:13][O:12]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CCC(CO)(CO)CO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCC1(CO)COC(C)(C)OC1
Reaction time: 4 h
Yield: 8050.3 %

Procedure:
2.75 g of p-toluenesulfonic acid are added to 275 g (2.05 mol) of 2,2-bis(hydroxymethyl)-1-butanol in 1.4 1 of acetone, and the mixture is heated to reflux. After 4 hours, the solution is neutralized while still hot by adding 8.25 g of potassium carbonate, and the mixture is stirred for a further 30 minutes and subsequently allowed to stand overnight at room temperature. The turbid mixture is filtered through kieselguhr, and the solvent is removed by distillation in vacuo, leaving 400 ml of a turbid, oily residue, which is purified by distillation in a high vacuum, giving 224 g of the alcohol 1 as a colorless oil.