Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1(O)[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C=CC(O)=CC=1)O.O>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH2:10][C:9]2[C:4]([CH:3]=1)=[CH:5][CH:6]=[CH:7][CH:8]=2
Reactant: CC1(O)Cc2ccccc2C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Oc1ccc(O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC1=Cc2ccccc2C1
Temperature: 0 °C
Yield: 81.2 %

Procedure:
2-Methyl-2-indanol (66.2 g) was dissolved in toluene (500 ml) in a 1 liter flask equipped with a Dean-Stark trap. To this solution p-toluene sulfonic acid (2 g) and a small amount of hydroquinone were added, and the mixture was refluxed for 2.5 hours. After 8 ml of H2O was generated, the reaction mixture was cooled to 0° C. and H2O (1 liter), also cooled to 03C., was added. The organic phase was separated and washed three times with water (500 ml). The toluene was evaporated and the residue (with trace of hydroquinone added) was distilled at reduced pressure to give 2-methylindene (47.2 g, 48%) as clear slightly green liquid.
Reaction SMILES: [OH:1][CH:2]([CH3:31])[CH:3]([N:5]1[C:9](=[O:10])[N:8]([C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][N:20]([C:23]4[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=4)[CH2:19][CH2:18]3)=[CH:13][CH:12]=2)[CH:7]=[N:6]1)[CH3:4].[C:32]1([CH3:42])[CH:37]=[CH:36][C:35]([S:38](Cl)(=[O:40])=[O:39])=[CH:34][CH:33]=1.C(N(CC)CC)C.CN(C1C=CC=CN=1)C>C(Cl)Cl>[CH3:30][O:29][C:26]1[CH:25]=[CH:24][C:23]([N:20]2[CH2:19][CH2:18][N:17]([C:14]3[CH:13]=[CH:12][C:11]([N:8]4[CH:7]=[N:6][N:5]([CH:3]([CH3:4])[CH:2]([O:1][S:38]([C:35]5[CH:36]=[CH:37][C:32]([CH3:42])=[CH:33][CH:34]=5)(=[O:40])=[O:39])[CH3:31])[C:9]4=[O:10])=[CH:16][CH:15]=3)[CH2:22][CH2:21]2)=[CH:28][CH:27]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1ccc(N2CCN(c3ccc(-n4cnn(C(C)C(C)O)c4=O)cc3)CC2)cc1
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(N2CCN(c3ccc(-n4cnn(C(C)C(C)OS(=O)(=O)c5ccc(C)cc5)c4=O)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A mixture of [S-(R*,S*)]-2,4-dihydro-2-(2-hydroxy-1-methylpropyl)4-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]-3H-1,2,4-triazol-3-one (0.01 mol), p-toluene-sulfonyl chloride (0.012 mol), triethylamine (2 g) and dimethylaminopyridine (0.5 g) in CH2Cl2 (100 ml) was stirred at room temperature for 4 days. The mixture was taken up in CH2Cl2 and purified by column chromatography over silica gel (eluent: CH2Cl2 100%). The pure fractions were collected and the solvent was evaporated. The residue was triturated in methylisobutyl keton, filtered off and dried, yielding 4.6 g (79%) [S-(R*,S*)]-2,4-dihydro-4-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]-2-[1-methyl-2-[[(4-methylphenyl)sulfonyl]oxy]propyl]-3H-1,2,4-triazol-3-one (interm. 134).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9].C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][C:18]#[CH:19].[I-].[K+]>C(C(C)=O)C.C1(C)C=CC=CC=1>[CH2:19]([O:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][OH:1])[C:18]#[CH:17]
Reactant: C#CCBr
Reactant: OCc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: Cc1ccccc1
Product: C#CCOc1ccccc1CO

Procedure:
To 2-(hydroxymethyl)phenol (10.0 g, 80.6 mmol) slurried in 300 ml of methyl ethyl ketone was added 1.2 equivalents of potassium carbonate. Then 3-bromopropyne (121 mmol, 18 g of an 80% solution in toluene) and potassium iodide (0.5 g) were added and the reaction was refluxed overnight. After cooling the salts were filtered off. The filtrate was concentrated and the residue was dissolved in water and extracted twice with ether. After washing with water and brine, the organic layer was dried over MgSO4 and concentrated to afford the subtitle compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1)[CH3:2].Cl[C:14](OC(Cl)(Cl)Cl)=[O:15]>C1COCC1>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([N:11]=[C:14]=[O:15])=[CH:7][CH:6]=1)[CH3:2]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: CCOC(=O)c1ccc(N)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(N=C=O)cc1

Procedure:
To a solution of 1.5 g (9.08 mmol) 4-amino-benzoic acid ethyl ester in 16 ml of THF was added 0.621 ml (5 mmol) of trichloromethyl chloroformate. The reaction mixture was stirred under reflux for 1 h and then concentrated under reduced pressure to dryness. The crude 4-Isocyanato-benzoic acid ethyl ester was used in the next step.
Reaction SMILES: [CH3:1][C@@H:2]([OH:6])[C@H:3]([OH:5])[CH3:4].O.[H-].[Na+].[Br:10][C:11]1[C:12](Cl)=[N:13][C:14]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[NH:26])=[O:25])=[CH:20][CH:19]=2)=[N:15][CH:16]=1>CS(C)=O>[Br:10][C:11]1[C:12]([O:5][C@H:3]([CH3:4])[C@H:2]([OH:6])[CH3:1])=[N:13][C:14]([NH:17][C:18]2[CH:19]=[CH:20][C:21]([S:24]([CH3:27])(=[NH:26])=[O:25])=[CH:22][CH:23]=2)=[N:15][CH:16]=1
Reactant: C[C@@H](O)[C@@H](C)O
Reactant: CS(=N)(=O)c1ccc(Nc2ncc(Br)c(Cl)n2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: C[C@@H](O)[C@@H](C)Oc1nc(Nc2ccc(S(C)(=N)=O)cc2)ncc1Br
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A solution of 674 mg (7.5 mmol) of (R,R)-(−)-2,3-butanediol in 6 ml of DMSO is mixed while being cooled with water in portions with 330 mg of sodium hydride (55-60%), and then stirred for 45 minutes at room temperature. The batch is mixed with 196 mg (0.54 mmol) of (RS)—S-{4-[(5-bromo-4-chloropyrimidin-2-yl)amino]phenyl}-S-methyl sulfoximide in 0.5 ml of DMSO and stirred overnight. It is mixed again with 191 mg (0.53 mmol) of (RS)—S-{4-[(5-bromo-4-chloropyrimidin-2-yl)amino]phenyl}-S-methyl sulfoximide in 0.5 ml of DMSO and stirred for another two hours. Finally, it is mixed with 190 mg of (RS)—S-{4-[(5-bromo-4-chloropyrimidin-2-yl)amino]phenyl}-S-methyl sulfoximide (0.53 mmol) in 0.5 ml of DMSO and stirred for one hour. The batch is added to ice water and extracted from ethyl acetate (4×). The combined organic phases are washed with NaCl solution, filtered through a Whatman filter and concentrated by evaporation. The remaining residue is purified by chromatography (DCM/EtOH 9:1). 166 mg (0.41 mmol, corresponding to 25% of theory) of the product is obtained.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([CH3:26])[N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)=[N:14][O:15][C:16]=2[CH2:17][OH:18])[CH:9]=1)=O.[F:27][C:28]([F:35])([C:31]([F:34])([F:33])[F:32])[CH2:29][NH2:30]>>[F:27][C:28]([F:35])([C:31]([F:34])([F:33])[F:32])[CH2:29][NH:30][C:3]([C:5]1[N:6]([CH3:26])[N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:19]3[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=3)=[N:14][O:15][C:16]=2[CH2:17][OH:18])[CH:9]=1)=[O:2]
Reactant: NCC(F)(F)C(F)(F)F
Reactant: COC(=O)c1cc(OCc2c(-c3ccc(Cl)cc3)noc2CO)nn1C
Product: Cn1nc(OCc2c(-c3ccc(Cl)cc3)noc2CO)cc1C(=O)NCC(F)(F)C(F)(F)F
Yield: 26 %

Procedure:
As described for example 100f, 5-[3-(4-chloro-phenyl)-5-hydroxymethyl-isoxazol-4-ylmethoxy]-2-methyl-2H-pyrazole-3-carboxylic acid methyl ester (100 mg, 0.27 mmol) was converted, using 2,2,3,3,3-pentafluoropropylamine instead of isopropylamine, to the title compound (35 mg, 26%) which was obtained as a white solid. MS: m/e=495.1 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH:5]([NH:9][C:10](=[O:12])[CH3:11])[CH2:6][C:7]#[CH:8])[CH3:2].[F:14][C:15]1[C:16](I)=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19](=[O:24])/[C:18]/2=[CH:25]\[C:26]1[NH:30][CH:29]=[N:28][C:27]=1[CH3:31]>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.CN(C=O)C.CCN(CC)CC>[CH2:1]([O:3][C:4](=[O:13])[CH:5]([NH:9][C:10](=[O:12])[CH3:11])[CH2:6][C:7]#[C:8][C:16]1[C:15]([F:14])=[CH:23][CH:22]=[C:21]2[C:17]=1/[C:18](=[CH:25]/[C:26]1[NH:30][CH:29]=[N:28][C:27]=1[CH3:31])/[C:19](=[O:24])[NH:20]2)[CH3:2]
Reactant: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Reactant: C#CCC(NC(C)=O)C(=O)OCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)C(CC#Cc1c(F)ccc2c1/C(=C/c1[nH]cnc1C)C(=O)N2)NC(C)=O

Procedure:
Using Method C above, 2-(acetylamino)-4-pentynoic acid ethyl ester (92.6 mg, 0.51 mmol) (Bachem) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one (Starting Material 3 supra) (75 mg, 0.203 mmol) using (Ph3P)4Pd (23.5 mg) and Cul (4 mg) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 80° C. for 5 h to give rac-(Z)-2-(acetylamino)-5-[5-fluoro-2,3,dihydro-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2-oxo-1H-indol-4-yl]-4-pentynoic acid ethyl ester. (Yield 70 mg, 81%).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]([CH2:14][OH:15])=[C:12]([C:16]([F:22])([F:21])[C:17]([F:20])([F:19])[F:18])[S:11][N:10]=2)=[CH:5][CH:4]=1)[CH3:2].[CH3:23][S:24](Cl)(=[O:26])=[O:25].C(N(CC)CC)C>ClCCl>[CH3:23][S:24]([O:15][CH2:14][C:13]1[C:9]([C:6]2[CH:5]=[CH:4][C:3]([CH2:1][CH3:2])=[CH:8][CH:7]=2)=[N:10][S:11][C:12]=1[C:16]([F:22])([F:21])[C:17]([F:18])([F:19])[F:20])(=[O:26])=[O:25]
Reactant: CCc1ccc(-c2nsc(C(F)(F)C(F)(F)F)c2CO)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1ccc(-c2nsc(C(F)(F)C(F)(F)F)c2COS(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a 100-mL round-bottom flask, was placed [3-(4-ethylphenyl)-5-(pentafluoroethyl)-1,2-thiazol-4-yl]methanol (108 mg, 0.32 mmol, 1.00 equiv), dichloromethane (10 mL). The solution was cooled to 0 degree C. MsCl (73 mg, 0.64 mmol, 2.00 equiv) and triethylamine (0.097 g, 0.96 mmol, 3.00 equiv) were added dropwise. The resulting solution was stirred for 2 h at 25° C. The reaction progress was monitored by LCMS. The reaction was then quenched by the addition of 5 mL of water. Organic phase was separated and the aqueous phase was extracted with 3×10 mL of dichloromethane and the organic layers combined. The resulting mixture was washed with 2×20 mL of sodium chloride. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 0.150 g (crude) of [3-(4-ethylphenyl)-5-(pentafluoroethyl)-1,2-thiazol-4-yl]methyl methanesulfonate as a white solid. And it could been used for the next step directly. Mass spectrum (ESI, m/z): Calcd. for C15H14F5NO3S2, 416.4 (M+H). found 416.4.
Reaction SMILES: C(=O)(O)[O-].[Na+].CO.[CH3:8][CH:9]([CH3:29])[CH2:10][CH2:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[S:19][C:18]([C:23]([O:25]CC)=[O:24])=[CH:17][C:16]2=[O:28]>O>[CH3:8][CH:9]([CH3:29])[CH2:10][CH2:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[S:19][C:18]([C:23]([OH:25])=[O:24])=[CH:17][C:16]2=[O:28]
Reactant: CCOC(=O)c1cc(=O)c2cc(OCCC(C)C)ccc2s1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)CCOc1ccc2sc(C(=O)O)cc(=O)c2c1

Procedure:
A mixture of 9 parts of ethyl 6-hydroxy-1-thiachromone-2-carboxylate, 15 parts of isoamyl bromide and 14 parts of anhydrous potassium carbonate in 130 parts of acetone was stirred and heated under reflux for 18 hours. Insoluble material was then filtered off and washed with acetone and the total acetone solution was evaporated to leave a yellow solid, which was crystallized from ethanol to give 4.1 parts of ethyl 6-(3-methylbutoxy)-1-thiachromone-2-carboxylate, melting point 83°-84°C. This entire product was heated under reflux for 2 hours with a solution of 1.5 parts of sodium bicarbonate in 35 parts of water and 25 parts of methanol. The methanol was then boiled off and the solution was diluted with 70 parts of water. The aqueous solution was thoroughly washed with ether, filtered then acidified with concentrated hydrochloric acid. A precipitate was obtained which was filtered off, washed with water and dried, then extracted with boiling benzene. The product was then filtered off and dried to leave 3.95 parts of 6-(3-methylbutoxy)-1-thiachromone-2-carboxylic acid, melting point 208°-209°C.
Reaction SMILES: [N:1]1([C:6]2[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[C:13]1([C:19]2[O:23][N:22]=[CH:21][C:20]=2[CH2:24][CH2:25][CH2:26][C:27](O)=[O:28])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>O.CN(C)C=O>[N:1]1([C:6]2[CH:12]=[CH:11][C:9]([NH:10][C:27](=[O:28])[CH2:26][CH2:25][CH2:24][C:20]3[CH:21]=[N:22][O:23][C:19]=3[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: Nc1ccc(-n2ccnc2)cc1
Reactant: O=C(O)CCCc1cnoc1-c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CCCc1cnoc1-c1ccccc1)Nc1ccc(-n2ccnc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.2 %

Procedure:
A mixture of 4-(1-imidazolyl)aniline (0.85 g), 4-(5-phenyl-4-isoxazolyl)butanoic acid (1.21 g), 1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.95 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.20 g) and N,N-dimethylformamide (20 ml) was stirred at room temperature overnight. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, saturated aqueous sodium hydrogencarbonate and then saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and N-[4-(1-imidazolyl)phenyl]-4-(5-phenyl-4-isoxazolyl)butaneamide (1.68 g, yield 86%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point: 132–133° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([C:11]3[CH:12]=[C:13]([N:23]4[CH:28]=[CH:27][C:26](=[O:29])[NH:25][C:24]4=[O:30])[CH:14]=[C:15]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:16]=3[O:17][CH3:18])[CH:8]=[CH:7][C:5]=2[N:6]=1.N(O[C:34](C)([CH3:36])[CH3:35])=O>C(#N)C.[Cu](Cl)Cl>[C:19]([C:15]1[CH:14]=[C:13]([N:23]2[CH:28]=[CH:27][C:26](=[O:29])[NH:25][C:24]2=[O:30])[CH:12]=[C:11]([C:9]2[CH:8]=[CH:7][C:5]3[N:6]=[C:2]([NH:1][CH2:35][CH2:34][CH3:36])[S:3][C:4]=3[CH:10]=2)[C:16]=1[O:17][CH3:18])([CH3:22])([CH3:21])[CH3:20]
Reactant: COc1c(-c2ccc3nc(N)sc3c2)cc(-n2ccc(=O)[nH]c2=O)cc1C(C)(C)C
Reactant: CC(C)(C)ON=O
Agent: Cl[Cu]Cl
Solvent: CC#N
Product: CCCNc1nc2ccc(-c3cc(-n4ccc(=O)[nH]c4=O)cc(C(C)(C)C)c3OC)cc2s1
Temperature: 0 °C
Reaction time: 1 h
Yield: 78.4 %

Procedure:
To a mixture of the product from Example 53 (50 mg, 0.118 mmol) and copper(II) chloride (24 mg, 0.178 mmol) in acetonitrile (3 mL) at 0° C. was added tert-butyl nitrite (21 μL, 0.178 mmol). The mixture was stirred at 0° C. for 1 h, and then warmed to 65° C. and stirred for 2 h. The mixture was concentrated in vacuo and purified by column chromatography on silica gel using 5% MeOH in CH2Cl2 to give the title compound as an off-white solid (43 mg, 82%).
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:9](Cl)=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH:12]2[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13]2)[CH:3]=1.[OH-].[NH4+:24]>>[NH2:24][C:9]1[C:10]2[C:2]([Br:1])=[CH:3][N:4]([CH:12]3[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13]3)[C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: CC(C)(C)OC(=O)N1CC(n2cc(Br)c3c(Cl)ncnc32)C1
Reactant: [NH4+]
Agent: [OH-]
Product: CC(C)(C)OC(=O)N1CC(n2cc(Br)c3c(N)ncnc32)C1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 15 %

Procedure:
To 1,1-dimethylethyl 3-(5-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-1-azetidinecarboxylate (690 mg, 1.780 mmol) was added ammonium hydroxide (69.3 μl, 1.780 mmol) in a 20 mL microwave vial. The vial was capped heated at 100° C. for a total of 2 hr in the microwave reactor. The reaction was checked every 0.5 hr. Only 15% desired product was observed. The reaction was filtered. The solid was added NH4OH (4 mL) into a 20 ml microwave vial and the vial was heated in an oil bath at 90° C. for 24 hr. The reaction observed 80% product. Additional 1 ml of NH4OH was added and heating continued overnight. The reaction was filtered and washed to give 1,1-dimethylethyl 3-(4-amino-5-bromo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-1-azetidinecarboxylate (538 mg) in 78% purity. LC-MS (ES) m/z=368.2, 370.2 [M+H]+.
Reaction SMILES: [O:1]1[CH:3]2[CH2:4][CH2:5][CH:6]=[CH:7][CH2:8][CH2:9][CH:10]=[CH:11][CH2:12][CH2:13][CH:2]12.[I-].[Na+]>>[C:2]1(=[O:1])[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]=[CH:8][CH2:7][CH2:6][CH:5]=[CH:4][CH2:3]1
Reactant: C1=CCCC2OC2CCC=CCC1
Agent: [I-]
Agent: [Na+]
Product: O=C1CC=CCCC=CCCCC1
Yield: 98.7 %

Procedure:
Also, German Patent DE3601380 discloses a technique where 1,2-epoxycyclododeca-5,9-diene is isomerized in the presence of sodium iodide in a polyethylene glycol solvent (NaI: 3 wt %, 195° C., 9 hours) and thereby cyclododeca-3,7-dien-1-one is produced in a yield of 98.7%.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]2[N:8]=[CH:9][CH:10]=[N:11][C:12]=2[C:13]([C:16]2[C:21]([F:22])=[C:20]([O:23][CH3:24])[CH:19]=[C:18]([O:25][CH3:26])[C:17]=2[F:27])=[CH:14][CH:15]=1)=O)C.[NH2:28][C:29]1[N:34]=[CH:33][C:32]([CH2:35][N:36]([CH3:42])[CH2:37][CH2:38][N:39]([CH3:41])[CH3:40])=[CH:31][CH:30]=1.C[Al](C)C.C([O-])(O)=O.[Na+]>C(Cl)Cl.CO.C(Cl)Cl>[CH3:40][N:39]([CH3:41])[CH2:38][CH2:37][N:36]([CH2:35][C:32]1[CH:31]=[CH:30][C:29]([NH:28][C:4]([C:6]2[C:7]3[N:8]=[CH:9][CH:10]=[N:11][C:12]=3[C:13]([C:16]3[C:17]([F:27])=[C:18]([O:25][CH3:26])[CH:19]=[C:20]([O:23][CH3:24])[C:21]=3[F:22])=[CH:14][CH:15]=2)=[O:3])=[N:34][CH:33]=1)[CH3:42]
Reactant: CN(C)CCN(C)Cc1ccc(N)nc1
Reactant: CCOC(=O)c1ccc(-c2c(F)c(OC)cc(OC)c2F)c2nccnc12
Agent: C[Al](C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COc1cc(OC)c(F)c(-c2ccc(C(=O)Nc3ccc(CN(C)CCN(C)C)cn3)c3nccnc23)c1F
Temperature: 80 °C
Reaction time: 5 h

Procedure:
The title compound was prepared in analogy to the procedure described in Example 115 but using 8-(2,6-difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid ethyl ester (Step 124.1), N-(6-amino-pyridin-3-ylmethyl)-N,N′,N′-trimethyl-ethane-1,2-diamine (prepared as described in Example 26 but using N,N,N′-trimethyl-ethane-1,2-diamine in Step 26.2 and purified by column chromatography), 1.5 equiv of trimethyl aluminum, stirring the reaction mixture for 5 h at 80° C. and pouring it onto a saturated aqueous solution of NaHCO3 and DCM. The title compound: ESI-MS: 537.1 [M+H]+; tR=3.31 min (System 1); TLC: Rf=0.13 (DCM/MeOH, 95:5).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12]COCCOC)[CH:7]=O)[CH3:2].[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[CH2:24][C:25]#[N:26]>>[CH3:19][O:20][C:21]1[CH:22]=[C:23](/[C:24](=[CH:7]/[C:6]2[CH:9]=[CH:10][C:11]([OH:12])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=2)/[C:25]#[N:26])[CH:27]=[CH:28][C:29]=1[O:30][CH3:31]
Reactant: COc1ccc(CC#N)cc1OC
Reactant: CCOc1cc(C=O)ccc1OCOCCOC
Product: CCOc1cc(/C=C(\C#N)c2ccc(OC)c(OC)c2)ccc1O
Yield: 37.7 %

Procedure:
The hydroxyl group of 3-ethoxy-4-hydroxybenzaldehyde (2.0 g) was protected by use of 2-methoxyethoxymethyl chloride (1.5 g) in accordance with (production process 1), to thereby produce 3-ethoxy-4-methoxyethoxymethoxybenzaldehyde (2.8 g, yield: 91%). The thus-produced 3-ethoxy-4-methoxyethoxymethoxybenzaldehyde (2.8 g) and 3,4-dimethoxybenzyl cyanide (2.0 g) were subjected to condensation in accordance with process A of (production process 2), to thereby yield an MEM form of the target product. Subsequently, the protective group was removed from the MEM form in accordance with (production process 3), to thereby produce the target product (1.35 g, yield: 37%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=O)=[CH:5]2.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[NH2:35][CH:36]1[CH2:45][C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[N:38]([CH2:46][C:47]([O:49][CH3:50])=[O:48])[C:37]1=[O:51]>O.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH:35][CH:36]1[CH2:45][C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[N:38]([CH2:46][C:47]([O:49][CH3:50])=[O:48])[C:37]1=[O:51])=[O:13])=[CH:5]2
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Reactant: COC(=O)CN1C(=O)C(N)Cc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: COC(=O)CN1C(=O)C(NC(=O)c2cc3cc(Cl)ccc3[nH]2)Cc2ccccc21
Reaction time: 18 h

Procedure:
5-Chloro-1H-indole-2-carboxylic acid (493 mg, 2.52 mmol), HOBT (340 mg, 2.52 mmol), DCM (100 mL) and finally EDCI (483 mg, 2.52 mmol) were added to methyl 2-(3-amino-2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetate (Method 1; 590 mg, 2.52 mmol) and the reaction was stirred for 18 h. The reaction was then diluted with water (50 mL) and stirred vigorously for 30 min. The resultant precipitate was filtered and washed with Et2O (2×20 mL). After filtration the resultant solid was then triturated with refluxing Et2O (25 mL) and after cooling the title compound (608 mg, 59%) was collected again by filtration as a white solid.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:9][N:10]([CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)[C:11]1[N:16]=[C:15]([N:17]([CH3:19])[CH3:18])[CH:14]=[CH:13][N:12]=1.C(N(CC)CC)C>CN(C)C(=O)C>[CH3:9][N:10]([CH:20]1[CH2:25][CH2:24][N:23]([CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH2:22][CH2:21]1)[C:11]1[N:16]=[C:15]([N:17]([CH3:18])[CH3:19])[CH:14]=[CH:13][N:12]=1
Reactant: CN(C)c1ccnc(N(C)C2CCNCC2)n1
Reactant: ClCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: CN(C)c1ccnc(N(C)C2CCN(Cc3ccccc3)CC2)n1
Temperature: 75 °C
Reaction time: 2 h
Yield: 55.4 %

Procedure:
A mixture of chloromethylbenzene (1.9 g), intermediate 2 (3 g) and triethylamine (2.62 g) in N,N-dimethylacetamide (55 ml) was stirred for 2 hours at 75° C. The reaction mixture was poured out into ice-water and extracted with toluene. The separated organic layer was washed three times with water, dried, filtered and the solvent evaporated. The residue was dissolved in boiling petroleum ether and treated with activated charcoal. The mixture was filtered warm over dicalite, and the filtrate was concentrated. The concentrate was cooled on an ice-bath and the resulting precipitate was filtered off and dried, yielding 2.3 g (54.4%) of N2,N4,N4-trimethyl-N2-[1-(phenylmethyl)-4-piperidinyl]-2,4-pyrimidinediamine (comp. 8).
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:17])=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]([O:14][CH3:15])=[O:13])[C@@H:7]([CH3:16])[CH2:6][CH2:5]2.[Cl:18][C:19]1[CH:20]=[CH:21][C:22](F)=[C:23]([CH:26]=1)[C:24]#[N:25].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[Br:1][C:2]1[C:3]([O:17][C:22]2[CH:21]=[CH:20][C:19]([Cl:18])=[CH:26][C:23]=2[C:24]#[N:25])=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]([O:14][CH3:15])=[O:13])[C@@H:7]([CH3:16])[CH2:6][CH2:5]2
Reactant: COC(=O)N1c2ccc(Br)c(O)c2CC[C@@H]1C
Reactant: N#Cc1cc(Cl)ccc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)N1c2ccc(Br)c(Oc3ccc(Cl)cc3C#N)c2CC[C@@H]1C
Temperature: 100 °C
Yield: 93.5 %

Procedure:
A mixture of (S)-methyl 6-bromo-5-hydroxy-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate (0.050 g, 0.167 mmol), 5-chloro-2-fluorobenzonitrile (0.065 g, 0.416 mmol), and cesium carbonate (0.136 g, 0.416 mmol) in DMF (2.0 mL) was heated at 100° C. for 16 h. The reaction mixture was cooled to room temperature and water was added. The mixture was partitioned between ethyl acetate and water. The aqueous phase was separated and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford a brown oil. This material was purified via column chromatography on silica gel (Biotage 25 g column, gradient elution with 0-25% ethyl acetate-hexane) to afford (S)-methyl 6-bromo-5-(4-chloro-2-cyanophenoxy)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate (0.068 g, 94%) as an off-white solid. MS (ESI, pos. ion) m/z 435, 437 [M+H]+.