Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:15][CH2:14][C:9]2([O:13][CH2:12][CH2:11][O:10]2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH:16]([N-:19]C(C)C)(C)[CH3:17].[Li+].BrCC#N.Cl>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1([CH2:17][C:16]#[N:19])[CH2:15][CH2:14][C:9]2([O:10][CH2:11][CH2:12][O:13]2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCC2(CC1)OCCO2
Reactant: CC(C)[N-]C(C)C
Agent: Cl
Agent: N#CCBr
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C1(CC#N)CCC2(CC1)OCCO2
Temperature: -5 °C
Reaction time: 1 h
Yield: 45 %

Procedure:
A solution of 1,4-dioxa-spiro[4.5]decane-8-carboxylic acid ethyl ester (1.0 g) in THF (8 mL) was added dropwise over a period of 10 minutes to a solution of lithiumdiisopropylamide (2M in THF/heptane/ethyl benzene, 4.67 mL) in THF (12 mL) kept at −5° C. (ice/methanol bath). Stirring was continued for 1 hour at 0° C. The reaction mixture was re-cooled to −5° C. and a solution of bromoacetonitrile (0.65 mL, [CAS Reg. No. 590-17-0]) in THF (4 mL) was added dropwise over a period of 10 minutes. Stirring was then continued for 16 hours at RT. The reaction mixture was poured into ice/water and was acidified with 1M aqueous HCl solution (50 mL). The aqueous layer was extracted two times with ethyl acetate and the combined organic layers were washed with brine, dried over Na2SO4 and filtered. The solvent was evaporated and the residue was purified by flash chromatography (silica gel, gradient of ethyl acetate in heptane) to give the title compound as a brown liquid (528 mg, 45%). MS (ESI): 254.2 (MH+).
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[C@@H:10]([C:11](OC)=[O:12])[CH2:9][CH:8]=[CH:7][CH2:6]1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].S([O-])([O-])(=O)=O.[Na+].[Na+]>CCOCC>[OH:2][CH2:3][C@@H:5]1[C@@H:10]([CH2:11][OH:12])[CH2:9][CH:8]=[CH:7][CH2:6]1
Reactant: COC(=O)[C@H]1CC=CC[C@@H]1C(=O)OC
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: OC[C@H]1CC=CC[C@@H]1CO
Temperature: 0 °C
Reaction time: 2 h
Yield: 81.5 %

Procedure:
In an atmosphere of argon gas, an ethereal solution (10 ml) of (4S,5S)-4,5-bis(methoxycarbonyl)-1-cyclohexene (1.86 g, 9.4 mmoles) was slowly added at 0° C. to a suspension (100 ml) of lithium aluminum hydride (713 mg, 18.8 mmoles) in ether, and the resulting mixture was stirred at 0° C. for 2 hours. After adding a saturated aqueous solution of sodium sulfate to the reaction mixture and decomposing the excessive reductant, anhydrous sodium sulfate was added and the whole mixture was stirred for a while. After filtering off the inorganic matter and washing the mixture with hot isopropyl alcohol, the filtrate and the washings were united, and the solvent was distilled off therefrom under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=2:1, v/v) and then recrystallized from ethyl acetate-hexane mixture to obtain (4S,5S)4,5-bis(hydroxymethyl)-1-cyclohexene (1.09 g, Yield 82%).
Reaction SMILES: Cl[C:2]1[N:13]=[CH:12][CH:11]=[CH:10][C:3]=1[C:4]([NH:6][CH2:7][C:8]#[CH:9])=[O:5].[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:20]=[C:21]([O:25][CH3:26])[C:22]=1[O:23][CH3:24])[NH2:19]>C(O)CO>[CH2:7]([NH:6][C:4](=[O:5])[C:3]1[CH:10]=[CH:11][CH:12]=[N:13][C:2]=1[NH:19][C:18]1[CH:20]=[C:21]([O:25][CH3:26])[C:22]([O:23][CH3:24])=[C:16]([O:15][CH3:14])[CH:17]=1)[C:8]#[CH:9]
Reactant: C#CCNC(=O)c1cccnc1Cl
Reactant: COc1cc(N)cc(OC)c1OC
Solvent: OCCO
Product: C#CCNC(=O)c1cccnc1Nc1cc(OC)c(OC)c(OC)c1
Temperature: 140 °C

Procedure:
Compound 8 (194 mg, 1 mmol) and 3,4,5-trimethoxyaniline (9j, 183 mg, 1 mmol) were taken in ethylene glycol and heated at 140° C. for 6 h. Then the reaction mixture was cooled and extracted with ethyl acetate from the aqueous layer and concentrated in vacuum. The compound was further purified by column chromatography using 60-120 silica gel to obtain N-(prop-2-ynyl)-2-(3,4,5-trimethoxyphenylamino)nicotinamide 10j as pure product. To a solution of N-(prop-2-ynyl)-2-(3,4,5-trimethoxyphenylamino)nicotinamide (10j, 150 mg, 0.41 mmol) and 1-(azidomethyl)-3-phenoxybenzene (12a, 102 mg, 0.45 mmol), in 2:1 mixture of water and tert-butyl alcohol, sodium ascorbate (0.06 mmol) and copper (II) sulphate (0.004 mmol) were added sequentially. The reaction was stirred at room temperature for 10 h, TLC analysis indicated completion of reaction. The reaction mixture was concentrated under vacuum and extracted with EtOAc to give crude product. The crude was purified by column chromatography to afford pure product 1j (186 mg, 75%); mp: 142-144° C.; 1H NMR (300 MHz, CDCl3) δ 10.42 (s, 1H), 8.27 (d, J=7.5, Hz, 1H), 7.85 (d, J=7.5 Hz 2H), 7.75 (brs, 1H), 7.60 (s, 1H), 7.39-7.27 (m, 3H), 7.11 (t, J=7.5 Hz, 1H), 6.99-6.83 (m, 7H), 6.65 (m, 1H), 5.47 (s, 2H), 4.66 (d, J=5.28 Hz, 2H), 3.85 (s, 6H), 3.81 ppm (s, 3H); MS (ESI m/z): 567 [M+H]+. Yield: 75%
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:12]([O:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])(=[O:22])[CH2:13][C:14]([O:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])=[O:15].O.CCCCCCC.CCOC(C)=O>C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[C:13]([C:14]([O:16][CH2:17][Si:18]([CH3:19])([CH3:21])[CH3:20])=[O:15])[C:12]([O:23][CH2:24][Si:25]([CH3:26])([CH3:27])[CH3:28])=[O:22])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: C[Si](C)(C)COC(=O)CC(=O)OC[Si](C)(C)C
Solvent: CCCCCCC
Solvent: Cc1ccccc1
Solvent: O
Product: C[Si](C)(C)COC(=O)C(=Cc1ccc([N+](=O)[O-])cc1)C(=O)OC[Si](C)(C)C
Yield: 57.8 %

Procedure:
p-Nitrobenzaldehyde (4.65 g, 0.03 mol) and di(trimethylsilylmethyl) malonate (8.5 g, 0.031 mol) are placed in 15 ml of toluene in a round-bottomed flask equipped with a Dean and Stark apparatus surmounted by a reflux condenser and sparged with nitrogen. The catalyst prepared in advance, acetic acid (0.2 ml) and piperidine (0.3 ml) in suspension in 0.5 ml of toluene, is added thereto. The mixture is refluxed for 5 hours with stirring and the water formed is removed via the Dean and Stark apparatus. Two further additions of the same amount of catalyst were necessary. The toluene is removed under vacuum and the residue is taken up in isopropyl ether and then washed twice with water. After drying the organic phase and evaporating the solvent, a red-brown oil is obtained. After purifying on a silica column (eluent: heptane/AcOEt 9/1), 7.1 g (Yield 57%) of clean di(trimethylsilylmethyl) 4-nitrobenzalmalonate fractions are collected in the form of a pale yellow solid used as is in the following stage.
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][N:12]=1)=[O:10].[O:17]1[CH2:22][CH2:21][N:20]([C:23]2[C:24]([NH2:42])=[N:25][C:26]3[C:31]([CH:32]=2)=[CH:30][C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][CH:27]=3)[CH2:19][CH2:18]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(CCC)=CC(CCC)=CC=2CCC)CCCCC1>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[NH2:42][C:24]1[C:23]([N:20]2[CH2:21][CH2:22][O:17][CH2:18][CH2:19]2)=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[C:29]([C:2]3[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=3[C:9]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][N:12]=3)=[O:10])[CH:30]=2)[N:25]=1
Reactant: CC1(C)OB(c2ccc3nc(N)c(N4CCOCC4)cc3c2)OC1(C)C
Reactant: Cc1cccc(C(=O)c2ccncn2)c1Br
Agent: [Pd]
Agent: CCCc1cc(CCC)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(CCC)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: Cc1cccc(C(=O)c2ccncn2)c1-c1ccc2nc(N)c(N3CCOCC3)cc2c1
Temperature: 140 °C

Procedure:
A mixture of (2-bromo-3-methylphenyl)(pyrimidin-4-yl)methanone (0.10 g, 0.361 mmol), 3-morpholino-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-2-amine (0.192 g, 0.541 mmol, prepared as in Example 2, Step 1-2), potassium phosphate tribasic (0.149 mL, 1.804 mmol), Pd2dba3 (0.033 g, 0.036 mmol), and 2-(dicyclohexylphosphino)-2′,4′,6′,-tri-1-propyl-1,1′-biphenyl (0.034 g, 0.072 mmol) in dioxane/water (3/1.5 mL) was heated in mw for 12 min at 140° C. The mixture was concentrated and the resulting crude material was chromatographed on silica gel using 0-5% 2M NH3 in MeOH/DCM to afford a brown oil which was further purified by HPLC to afford (2-(2-amino-3-morpholinoquinolin-6-yl)-3-methylphenyl)(pyrimidin-4-yl)methanone as a yellow solid. MS (ESI, pos. ion) m/z: 426 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][N:5]=[CH:4][CH:3]=1.[F:11][C:12]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:13]=1[NH2:14].F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.C(N(C(C)C)CC)(C)C>ClCCl.CN(C=O)C>[Cl:1][C:2]1[C:7]([C:8]([NH:14][C:13]2[CH:15]=[CH:16][C:17]([F:19])=[CH:18][C:12]=2[F:11])=[O:10])=[CH:6][N:5]=[CH:4][CH:3]=1
Reactant: Nc1ccc(F)cc1F
Reactant: O=C(O)c1cnccc1Cl
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(F)cc1F)c1cnccc1Cl
Temperature: 25 °C
Reaction time: 255 h
Yield: 42.8 %

Procedure:
To a mixture of 4-chloronicotinic acid (Lancaster Synthesis, 0.31 g, 2.0 mmol) and 2,4-difluoroaniline (Aldrich, 0.20 mL, 2.0 mmol) in anhydrous dichloromethane (5 mL) was added bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBroP®, Novabiochem, 1.4 g, 3.0 mmol) followed by diisopropylethylamine (1.1 mL, 6.4 mmol). Anhydrous DMF (2 mL) was added to the mixture and the reaction stirred at ambient temperature. After 255 hours, the reaction mixture was partitioned between chloroform and 10% LiCl (aq). The organic layer was washed three times with 10% LiCl (aq), dried over anhydrous MgSO4, then concentrated in vacuo. Purification of the residue by flash column chromatography (SiO2, eluting with 1:1 hexane/EtOAc) afforded the desired compound (0.23 g, 42%). 1H NMR (DMSO-d6) δ 10.58 (s, 1H), 8.78 (s, 1H), 8.66 (d, 1H, J=5.4 Hz), 7.82-7.88 (m, 1H), 7.71 (d, 1H, J=5.4 Hz), 7.37-7.43 (m, 1H), 7.14-7.19 (m, 1H);
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]([NH2:17])[CH2:10][C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1.Cl[CH2:19][CH2:20][N:21]=[C:22]=[S:23]>ClCCl>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]([N:17]=[C:22]1[NH:21][CH2:20][CH2:19][S:23]1)[CH2:10][C:11]1[CH:12]=[CH:13][N:14]=[CH:15][CH:16]=1
Reactant: S=C=NCCCl
Reactant: NC(Cc1ccncc1)c1cccc(Cl)c1Cl
Solvent: ClCCl
Product: Clc1cccc(C(Cc2ccncc2)N=C2NCCS2)c1Cl
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
1-(2,3-dichlorophenyl)-2-(pyridin-4-yl)ethanamine (0.30 g, 1.13 mmol) in dichloromethane (6 mL) was added chloroethylisothiocyanate (0.097 mL, 0.988 mmol). The solution was stirred at room temperature for 1.5 hour, and quenched with water. The aqueous layer was extracted with dichloromethane (3×). The pooled organic layer was dried over magnesium sulfate. The mixture was filtered. The filtrate was added silica gel, and the solvents were removed under vacuum. Purification by chromatography on silica gel (2 to 10% methanol in dichloromethane) gave a crude material, which was recrystallized in methanol/water to give 1-(2,3-dichlorophenyl)-2-(pyridin-4-yl)-N-(thiazolidin-2-ylidene)ethanamine Compound 18 as a solid (15.9 mg, 0.045 mmol, 4% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15](I)=[CH:14][CH:13]=2)[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].[F:26][C:27]1[CH:32]=[C:31]([F:33])[C:30]([F:34])=[CH:29][C:28]=1B(O)O>O1CCOCC1.O>[CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([C:28]3[CH:29]=[C:30]([F:34])[C:31]([F:33])=[CH:32][C:27]=3[F:26])=[CH:14][CH:13]=2)[CH:5]=1
Reactant: COC(=O)c1cccc(COc2ccc(I)cc2)c1
Reactant: OB(O)c1cc(F)c(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1cccc(COc2ccc(-c3cc(F)c(F)cc3F)cc2)c1
Yield: 77.9 %

Procedure:
Bis(tricyclohexylphosphine)palladium (200 mg, 0.3 mmol) was added to a stirred solution of 3-(4-iodo-phenoxymethyl)-benzoic acid methyl ester (3.68 g, 10 mmol), potassium carbonate (2.76 g, 20 mmol) and 2,4,5-trifluorophenylboronic acid (3.5 g, 20 mmol) in 100 mL dioxane and 10 mL H2O were reacted as above and purified by flash chromatography with a gradient of 0-5% ethyl acetate in hexanes to give 2.9 g (77.9%) of 3-(2′,4′,5′-trifluoro-biphenyl-4-yloxymethyl)-benzoic acid methyl ester.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[CH:11]=[C:12]([CH:16]=O)[CH:13]=[N:14][CH:15]=2)=[CH:4][CH:3]=1.[ClH:18].[NH2:19][OH:20].C(=O)([O-])[O-].[K+].[K+]>>[ClH:18].[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[CH:11]=[C:12]([CH:16]=[N:19][OH:20])[CH:13]=[N:14][CH:15]=2)=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=Cc1cncc(C#Cc2ccc(F)cc2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: ON=Cc1cncc(C#Cc2ccc(F)cc2)c1
Yield: 50.8 %

Procedure:
Prepare in a similar manner as described in EXAMPLE 6 using 5-(4-fluorophenylethynyl)-pyridine-3-carbaldehyde (150 mg, 0.64 mmol), (prepared essentially as described in EXAMPLE 99), hydroxylamine hydrochloride (360 mg, 5.15 mmol) and potassium carbonate (440 mg, 3.22 mmol) to give the title compound (90 mg, 50%).
Reaction SMILES: [OH-].[K+].[F:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1.[C:12]1(=[O:20])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.Cl>O>[F:3][C:4]1[CH:11]=[CH:10][C:7](/[CH:8]=[C:13]2/[C:12](=[O:20])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]/2)=[CH:6][CH:5]=1
Reactant: O=C1CCCCCCC1
Reactant: O=Cc1ccc(F)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C1CCCCCC/C1=C\c1ccc(F)cc1
Temperature: 65 °C
Reaction time: 8 h

Procedure:
A solution of KOH (0.25 g, 4.46 mMol) in water (4.4 mL), was added to 4-fluoro-benzaldehyde Compound 2a (1.07 nl, 10 mMol) and the mixture was heated to 65° C. Cyclooctanone Compound 1a (1.26 g, 10 mMol) was added dropwise over a period of 15 mins. The mixture was refluxed for 5 hrs, then allowed to stir overnight at room temperature. The reaction mixture was acidified with 1N HCl (26 mL) and extracted with EtOAc (100 mL). The organic layer was washed with brine, dried over Na2SO4, then filtered and concentrated. The resulting yellow residue was purified on silica gel column with 3% EtOAc/Hexane to give (2E)-2-(4-fluoro-benzylidene)-cyclooctanone Compound 2b (1.04 g, 44.8%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH3:15])[C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.[Li]CCCC.CN([CH:24]=[O:25])C>C1COCC1>[CH3:15][N:6]1[C:5]2[CH:4]=[CH:3][C:2]([CH:24]=[O:25])=[CH:14][C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2
Reactant: Cn1c2ccccc2c2cc(Br)ccc21
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cn1c2ccccc2c2cc(C=O)ccc21
Temperature: -78 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
To a solution of 2b (1.8 g, 6.9 mmol) in dried THF (45 mL) was added n-BuLi (3.3 mL 8.3 mmol) at −78° C. The resulting mixture was stirred at −78° C. for 1 h and then added with dried DMF (8 mL). The reaction mixture was allowed to warm to room temperature and stirred overnight before quenched with aqueous ammonia chloride solution. Water was added and extracted with ethyl acetate three times. The combined organic phase was washed with brine and dried over anhydrous sodium sulfate. After removing the solvent, the residue was purified by silica gel chromatography using ethyl acetate and petroleum ether (EA:PE=1:4) as eluent to afford 3b (0.86 g) in 60% yield. 1H NMR (400 MHz, CDCl3) δ 9.58 (s, 1H), 7.79 (s, 1H), 7.49 (d, J=7.6 Hz, 1H), 7.41 (d, J=8.8 Hz, 1H), 7.09 (t, J=7.6 Hz,), 6.90 (t, J=7.6 Hz, 1H), 6.77 (d, J=8.0 Hz, 1H), 6.61 (d, J=8.4 Hz, 1H), 3.00 (s, 3H). 13C NMR (400 MHz, CDCl3) δ 190.9, 143.2, 140.5, 127.4, 125.8, 122.7, 121.7, 119.6, 119.4, 108.3, 107.6, 28.0.
Reaction SMILES: OO.[CH3:3][C:4]([CH3:12])([C:6](=[O:11])[C:7]([CH3:10])([CH3:9])[CH3:8])[CH3:5]>>[CH3:3][C:4]([CH3:12])([CH:6]([OH:11])[C:7]([CH3:10])([CH3:9])[CH3:8])[CH3:5]
Reactant: CC(C)(C)C(=O)C(C)(C)C
Agent: OO
Product: CC(C)(C)C(O)C(C)(C)C

Procedure:
Thus, advantageously, the hydrogen peroxide and the 2,2,4,4-tetramethyl-3-pentanone are introduced into or formed in the reaction medium as products resulting from the autoxidation by air or molecular oxygen of 2,2,4,4-tetramethyl-3-pentanol.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]2[S:15][C:14]([C:16](=O)[CH2:17][CH2:18][C:19]([OH:21])=O)=[CH:13][CH:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.O.[NH2:24][NH2:25]>O>[N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]2[S:15][C:14]([C:16]3[CH2:17][CH2:18][C:19](=[O:21])[NH:24][N:25]=3)=[CH:13][CH:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C(O)CCC(=O)c1ccc(CCCCCn2ccnc2)s1
Reactant: NN
Solvent: O
Product: O=C1CCC(c2ccc(CCCCCn3ccnc3)s2)=NN1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
3.2 g of 4-{5-[5-(1-imidazolyl)-pentyl]-thien-2-yl}-4-oxo-butyric acid are suspended in 10 ml of water, 0.52 g of hydrazine hydrate are added and the mixture is stirred at 90° C. for 2 hours. After the mixture has been cooled, the precipitate formed is filtered off with suction, washed with water and dried.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH3:9])[CH:3]=1.N1C=CC=CC=1.[Br:16]Br>C(Cl)Cl>[Br:16][C:7]1[CH:8]=[C:2]([Cl:1])[CH:3]=[C:4]([CH3:9])[C:5]=1[NH2:6]
Reactant: Cc1cc(Cl)ccc1N
Reactant: BrBr
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cc(Cl)cc(Br)c1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.7 %

Procedure:
2.83 g (20 mmol) of 4-chloro-2-methyl aniline and 1.74 g (22 mmol) of pyridine were dissolved in 20 ml DCM. 3.20 g (20 mmol) of bromine were added dropwise under cooling. The reaction mixture was stirred for 2 h at rt. The solvent was removed and the residue was dissolved in diethyl ether. The organic layer was washed with water, dried over sodium sulfate, filtered and the solvent was evaporated. The crude product was purified by column chromatography (silica gel; diethyl ether/heptane 1:1) to yield 3.91 g (89%) of 2-bromo-4-chloro-6-methyl aniline as a light green solid. 1H NMR (CDCl3, 300 MHz): δ 7.30 (s, 1H), 6.99 (s, 1H), 4.04 (br s, 2H), 2.19 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:14]([S:23][CH2:24][C:25]3[C:30]([F:31])=[CH:29][C:28]([S:32]([OH:35])(=O)=[O:33])=[CH:27][C:26]=3[F:36])=[N:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:4][C:3]=1[O:37][CH3:38].S(Cl)(Cl)=O.Cl.[Cl-].[NH2:45][C@H:46]([C:54]([O:56][CH3:57])=[O:55])[CH2:47][CH2:48][CH2:49][N+:50]([CH3:53])([CH3:52])[CH3:51].C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl.CN(C=O)C>[Cl-:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:14]([S:23][CH2:24][C:25]3[C:30]([F:31])=[CH:29][C:28]([S:32]([NH:45][C@H:46]([C:54]([O:56][CH3:57])=[O:55])[CH2:47][CH2:48][CH2:49][N+:50]([CH3:52])([CH3:51])[CH3:53])(=[O:33])=[O:35])=[CH:27][C:26]=3[F:36])=[N:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:4][C:3]=1[O:37][CH3:38]
Reactant: COC(=O)[C@@H](N)CCC[N+](C)(C)C
Reactant: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(S(=O)(=O)O)cc3F)n2-c2ccc(F)cc2)ccc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: COC(=O)[C@H](CCC[N+](C)(C)C)NS(=O)(=O)c1cc(F)c(CSc2ncc(C(C)(C)c3ccc(Cl)c(OC)c3)n2-c2ccc(F)cc2)c(F)c1
Temperature: 40 °C
Reaction time: 0.17 h
Yield: 188.1 %

Procedure:
To 4-((5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)-3,5-difluorobenzenesulfonic acid (1.2 g, 2.1 mmol, 1.1 eq) in DCM (6 mL) was added thionyl chloride (3 mL) followed by catalytic DMF (30 drops). After heating at 40° C. for 1 h, the reaction mixture was concentrated under reduced pressure and the resulting sulfonyl chloride was further dried on a high-vacuum pump for several hours. A solution of this sulfonyl chloride in MeCN (12 mL) was added to another flask containing (S)-4-amino-5-methoxy-N,N,N-trimethyl-5-oxopentan-1-aminium chloride hydrochloride (2.0 g, 7.5 mmol, 4.0 eq) and aq. Na2CO3 (2.0 g, 18.7 mmol, 10 eq, in 12 mL of water). The reaction mixture was stirred vigorously for 10 min. The organic layer was removed by pipette and concentrated to yield (S)-4-(4-((5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)-3,5-difluorophenylsulfonamido)-5-methoxy-N,N,N-trimethyl-5-oxopentan-1-aminium chloride (1.56 g, over theoretical), which was used in the next step without purification. MS (EI) m/z 601 (M+).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][O:8][C@@H:9]1[CH2:17][N:16]2[C@@H:11]([CH2:12][C:13](N3CCCC3)=[CH:14][C:15]2=O)[CH2:10]1.[OH-].[Na+].C([OH:28])C>O1CCCC1>[CH3:7][O:8][C@@H:9]1[CH2:17][N:16]2[C@H:11]([CH2:12][C:13](=[O:28])[CH2:14][CH2:15]2)[CH2:10]1
Reactant: CO[C@H]1C[C@@H]2CC(N3CCCC3)=CC(=O)N2C1
Reactant: CCO
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CO[C@H]1C[C@H]2CC(=O)CCN2C1
Yield: 51 %

Procedure:
2.10 g (55 mmol) of lithium aluminum hydride were added, with stirring and ice-cooling, to a solution of 4.26 g (18.1 mmol) of (2S,8aS)-2-methoxy-7-(1-pyrrolidinyl)-1,2,3,5,8,8a-hexahydroindolizin-5-one [obtained as described in Preparative Example 10(iv)′ above] in 50 ml of tetrahydrofuran, and the resulting mixture was then stirred for a further 3 hours at room temperature. At the end of this time, 8.40 ml of a 1N aqueous solution of sodium hydroxide were carefully added to the reaction mixture, followed by the addition of ethanol, and then any insoluble materials were removed by filtration. The filtrate thus obtained was concentrated by evaporation under reduced pressure and the resulting residue was purified by chromatography on an alumina column using ethyl acetate as the eluant afford to 1.60 g (yield: 51%) of the title compound as a pale brown oil.
Reaction SMILES: [C:1]([N:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([N:20]3[CH2:29][C:28]4[C:23](=[N:24][C:25](SC)=[N:26][CH:27]=4)[N:22]([CH3:32])[C:21]3=[O:33])[C:17]([Cl:34])=[CH:16][C:15]=2[F:35])=[O:12])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].C1C=C(Cl)C=C(C(OO)=O)C=1.[CH3:47][NH2:48]>>[C:1]([N:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([N:20]3[CH2:29][C:28]4[C:23](=[N:24][C:25]([NH:48][CH3:47])=[N:26][CH:27]=4)[N:22]([CH3:32])[C:21]3=[O:33])[C:17]([Cl:34])=[CH:16][C:15]=2[F:35])=[O:12])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN
Reactant: CSc1ncc2c(n1)N(C)C(=O)N(c1cc(NC(=O)Nc3cnn(C(C)(C)C)c3)c(F)cc1Cl)C2
Agent: O=C(OO)c1cccc(Cl)c1
Product: CNc1ncc2c(n1)N(C)C(=O)N(c1cc(NC(=O)Nc3cnn(C(C)(C)C)c3)c(F)cc1Cl)C2
Yield: 73 %

Procedure:
Using a procedure analogous to Example A2, the sulfide was oxidized with mCPBA to the sulfone and then treated with methylamine to provide 1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea (0.448 mmol, 73% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.76 (s, 1H), 8.72 (brs, 1H), 8.32 (d, J=8.5 Hz, 1H), 7.96 (brs, 1H), 7.82 (s, 1H), 7.60 (d, J=11 Hz, 1H), 7.41 (s, 1H), 7.04 m, 1H), 6.34 s, 1H), 4.56 (d, J=14 Hz, 1H), 4.41 (d, J=14 Hz, 1H), 3.25 (brs, 3H), 2.78 (d, J=5 Hz, 3H), 1.47 (m, 9H); MS (ESI) m/z: 502.2 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([CH:19]=O)=[CH:15][CH:14]=3)[C:10]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:9][N:8]2[CH:27]=1)=[O:4].[NH:28]1[CH2:31][CH:30]([C:32]2[NH:36][N:35]=[C:34]([C:37]3[CH:42]=[CH:41][CH:40]=[C:39]([CH3:43])[N:38]=3)[N:33]=2)[CH2:29]1>>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([CH2:19][N:28]4[CH2:31][CH:30]([C:32]5[N:33]=[C:34]([C:37]6[CH:42]=[CH:41][CH:40]=[C:39]([CH3:43])[N:38]=6)[NH:35][N:36]=5)[CH2:29]4)=[CH:15][CH:14]=3)[C:10]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[CH:9][N:8]2[CH:27]=1)=[O:4]
Reactant: COC(=O)c1cn2cc(-c3ccccc3)c(-c3ccc(C=O)cc3)nc2n1
Reactant: Cc1cccc(-c2n[nH]c(C3CNC3)n2)n1
Product: COC(=O)c1cn2cc(-c3ccccc3)c(-c3ccc(CN4CC(c5n[nH]c(-c6cccc(C)n6)n5)C4)cc3)nc2n1
Yield: 9.7 %

Procedure:
The title compound has been prepared in analogy to the aforementioned descriptions by reacting 500 mg (1.4 mmol) 7-(4-formylphenyl)-6-phenyl-imidazo[1,2-a]pyrimidine-2-carboxylic acid methyl ester with 671.9 mg (1.4 mmol) 2-(5-azetidine-3-yl-[1,2,4]triazole-3-yl)-6-methylpyridine×2HCl (60% pure), yielding 75.6 mg (9.2%) of the desired product after purification.