Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]3[N:18]=[CH:19][C:20]([C:21]#[CH:22])=[C:10]3[N:9]=2)=[CH:4][C:3]=1[CH3:23].[CH3:24][N:25]([CH3:38])[CH2:26][CH2:27][NH:28][S:29]([C:32]1[S:33][C:34](Br)=[CH:35][CH:36]=1)(=[O:31])=[O:30]>>[CH3:24][N:25]([CH3:38])[CH2:26][CH2:27][NH:28][S:29]([C:32]1[S:33][C:34]([C:22]#[C:21][C:20]2[CH:19]=[N:18][N:11]3[C:12]([C:14]([F:15])([F:17])[F:16])=[CH:13][C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH3:23])[CH:4]=4)=[N:9][C:10]=23)=[CH:35][CH:36]=1)(=[O:31])=[O:30]
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(Cl)c(C)c3)nc12
Reactant: CN(C)CCNS(=O)(=O)c1ccc(Br)s1
Product: Cc1cc(-c2cc(C(F)(F)F)n3ncc(C#Cc4ccc(S(=O)(=O)NCCN(C)C)s4)c3n2)ccc1Cl

Procedure:
The title compound was prepared from 5-(4-chloro-3-methyl-phenyl)-3-ethynyl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine (example C. 11) (168 mg, 0.5 mmol) and 5-bomo-thiophene-2-sulfonic acid (2-dimethylamino-ethyl)-amide (example B.49) (157 mg, 0.5 mmol) according to general procedure II. Obtained as a yellow solid (200 mg, 70%). MS (ISN) 566.2 [(M−H)−]; mp 179° C.
Reaction SMILES: C(O)C.[C:4]1([NH:10][NH2:11])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[C:13]([O:15][CH2:16][CH3:17])=[O:14]>C(N(CC)CC)C>[C:4]1([NH:10][NH:11][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: NNc1ccccc1
Reactant: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)NNc1ccccc1
Temperature: 0 °C
Yield: 86 %

Procedure:
Into 200 ml of ethanol were poured 21.6 g (0.2 mol) of phenylhydrazine and 30 ml of triethylamine, and 21.6 g (0.2 mol) of ethyl chloroformate was slowly added dropwise thereto. After the addition, the mixture was refluxed for 30 minutes and then poured into ice-water. The mixture was extracted with ethyl acetate, and the extract was concentrated and purified by column chromatography to obtain 31 g of N-phenyl-N'-ethoxycarbonylhydrazine as an oily substance.
Reaction SMILES: [C:1]([O:4][CH:5]([C:11]([O:13][CH2:14][CH:15]=[CH2:16])=[O:12])[CH2:6][CH2:7][C:8](O)=[O:9])(=[O:3])[CH3:2].C(Cl)(=O)C([Cl:20])=O>>[C:1]([O:4][CH:5]([C:11]([O:13][CH2:14][CH:15]=[CH2:16])=[O:12])[CH2:6][CH2:7][C:8]([Cl:20])=[O:9])(=[O:3])[CH3:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: C=CCOC(=O)C(CCC(=O)O)OC(C)=O
Product: C=CCOC(=O)C(CCC(=O)Cl)OC(C)=O

Procedure:
According to a similar procedure to that described in Example 1-(12), 4-acetoxy-5-allyloxy-5-oxopentanoic acid (345.3 mg, 1.50 mmol) obtained from Example 2-(4) and oxalyl chloride (209.4 mg, 1.65 mmol) were reacted, and the reaction mixture was worked up to afford 4-acetoxy-5-allyloxy-5-oxopentanoyl chloride as a crude product.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[NH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1>CN(C=O)C.O.C(N(CC)CC)C>[CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:36]2[CH2:41][CH2:40][O:39][CH2:38][CH2:37]2)=[O:8])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: Cc1ccc(C(=O)O)cc1[N+](=O)[O-]
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(C(=O)N2CCOCC2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The compound ([5]-(53)-278) (6.5272 g) prepared in Example 72 was dissolved in anhydrous DMF (98 ml). Then, 1-hydroxybenzotriazole (6.3297 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (8.9795 g), triethylamine (6.5 ml), and morpholine (4.1 ml) were added to the solution. The mixture was stirred at room temperature for 4 hours. A small amount of water was added to the resulting yellowish orange solution including the white salt to obtain a homogeneous solution. The solution was concentrated. The residue was dissolved in chloroform, and the solution was washed with 1N HCl aqueous solution and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and concentrated to obtain yellowish brown crystals (8.9903 g). The product was recrystallized from n-hexane/ethyl acetate to obtain the above-captioned compound ([5]-(54)-278) (7.8455 g) as light yellow crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C(N(CC)CC)C.[Cl:16][CH2:17][C:18](Cl)=[O:19]>C(OCC)(=O)C>[Cl:16][CH2:17][C:18]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8])=[O:19]
Reactant: Nc1ccccc1O
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C(CCl)Nc1ccccc1O
Temperature: 0 °C
Reaction time: 1.67 h

Procedure:
To a mixture of 8.90 g (81.5 mmol) of 2-aminophenol and 11.4 ml (81.5 mmol) of triethylamine in 250 ml of ethyl acetate cooled at 0° C. were added over several minutes 6.5 ml (81.5 mmol) of chloroacetyl chloride. The reaction mixture was stirred at 0° C. for 100 min and then washed with saline, aqueous sodium bicarbonate, and saline. The organic layers were dried over magnesium sulfate and concentrated. Dichloromethane was added to the residue and the resulted solid collected and dried to give the title compound, mp 133°-134°; NMR (CDCl3) 4.27, 6.93, 7.02, 7.17, 7.25, 7.80 and 8.53 δ.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[CH2:9]([Sn](CCCC)(CCCC)CCCC)[CH:10]=[CH2:11]>>[CH2:11]([C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)[CH:10]=[CH2:9]
Reactant: Brc1ccc(I)cc1
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Product: C=CCc1ccc(Br)cc1

Procedure:
In a Stille coupling reaction, 1-bromo-4-iodobenzene and allyltri-n-butyltin were reacted to yield Compound 1. Thus, tetrakistriphenylphosphine palladium(0) (1.976 g, 1.710×10−3 mol) was weighed out in a nitrogen-filled glove box and transferred to a Schlenk line. Allyltri-n-butyltin (10.60 mL, 3.419×10−2 mol) and 1-bromo-4-iodobenzene (9.680 g, 3.422×10−2 mol) were added along with 115 mL distilled, degassed 1,4-dioxane to yield a yellow reaction mixture that darkened to orange as the reaction progressed. The reaction mixture was stirred at 70° C. for 46 h until analysis by TLC (hexanes) and GC/MS showed that reaction was complete. The mixture was next cooled to room temperature, filtered through Celite (rinsing with hexanes), and resulting solution washed with both hexanes and water, to remove PPh3. Then the organic portion was dried over MgSO4. Filtration through Celite and removal of the solvent in a rotary evaporator at <75° C. yielded an orange oil. Column chromatography on silica gel with hexanes as eluant afforded only Compound 1 and tri-n-butyltin iodide. These were separated via vacuum distillation at 160 mTorr, where Compound 1 distills at about 50° C. (never exceed 75° C., which can potentially cause allyl group isomerization) as a clear colorless oil (2.810 g, 42% yield). GC/MS: single peak; m/z (rel. intensity) 198 (M+, 46), 196 (M+, 46), 117 (100), 115 (86). 1H NMR (CDCl3): δ7.41 (d, J=8.5 Hz, 2H), 7.07 (d, J=8.0 Hz, 2H), 5.90 (m, 1H), 5.09 (m, 2H), 3.36 (d, J=7.0 Hz, 2H).
Reaction SMILES: [C:1]([NH:5][C:6]1[C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([C:16]([NH:18][C:19]3[CH:24]=[C:23]([C:25](=[O:37])[NH:26][C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=4)[CH:22]=[CH:21][C:20]=3[CH3:38])=[O:17])[C:10]=2[CH:9]=[CH:8][N:7]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:39]([N:41]1[CH2:46][CH2:45][N:44]([CH2:47]C2C=CC(N)=CC=2C(F)(F)F)[CH2:43][CH2:42]1)[CH3:40].NC1C=CC=CC=1>>[C:1]([NH:5][C:6]1[C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([C:16]([NH:18][C:19]3[CH:24]=[C:23]([C:25](=[O:37])[NH:26][C:27]4[CH:32]=[CH:31][C:30]([CH2:47][N:44]5[CH2:45][CH2:46][N:41]([CH2:39][CH3:40])[CH2:42][CH2:43]5)=[C:29]([C:33]([F:34])([F:35])[F:36])[CH:28]=4)[CH:22]=[CH:21][C:20]=3[CH3:38])=[O:17])[C:10]=2[CH:9]=[CH:8][N:7]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(C(=O)Nc2cccc(C(F)(F)F)c2)cc1NC(=O)c1cccc2c(NC(C)(C)C)nccc12
Reactant: CCN1CCN(Cc2ccc(N)cc2C(F)(F)F)CC1
Solvent: Nc1ccccc1
Product: CCN1CCN(Cc2ccc(NC(=O)c3ccc(C)c(NC(=O)c4cccc5c(NC(C)(C)C)nccc45)c3)cc2C(F)(F)F)CC1
Yield: 12 %

Procedure:
The procedures of Steps (1), (2) and (3) of Example 2 were repeated step by step, except for using 4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)aniline obtained in Step (3) above instead of aniline in Step (1) of Example 2 to obtain the title compound (0.032 g, 12%).
Reaction SMILES: Br[C:2]1[C:11]([CH2:12][CH2:13][CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])=[CH:10][C:9]2[C:8]([CH3:24])([CH3:23])[CH2:7][CH2:6][C:5]([CH3:26])([CH3:25])[C:4]=2[CH:3]=1.[Li]CCCC.[CH:32](N1CCCCC1)=[O:33]>O1CCCC1>[CH:32]([C:2]1[C:11]([CH2:12][CH2:13][CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:20])[CH3:21])([CH3:18])[CH3:17])=[CH:10][C:9]2[C:8]([CH3:24])([CH3:23])[CH2:7][CH2:6][C:5]([CH3:25])([CH3:26])[C:4]=2[CH:3]=1)=[O:33]
Reactant: CC1(C)CCC(C)(C)c2cc(CCCO[Si](C)(C)C(C)(C)C)c(Br)cc21
Reactant: O=CN1CCCCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1(C)CCC(C)(C)c2cc(CCCO[Si](C)(C)C(C)(C)C)c(C=O)cc21
Reaction time: 1 h
Yield: 89.2 %

Procedure:
To a solution of 14 g (32 mmol) of 2-bromo-3-(3-t-butyldimethylsiloxypropyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalene in 200 mL of dry tetrahydrofuran at −78° C. was added 24.9 mL (64 mmol) of n-BuLi (2.5 M in hexane) via syringe under N2 atmosphere. The reaction mixture was stirred at this condition for 1 hour. Then it was quenched with a solution of 7 mL (64 mmol) of N-formyl piperidine in 10 mL of dry tetrahydrofuran. The resulting solution was stirred for an additional 30 minutes, when it was quenched with 100 mL of NH4Cl solution. The reaction mixture was extracted with 3×100 mL of ethyl acetate. The organic layers were combined, dried over MgSO4 and the solvent was removed under reduced pressure. The residue was purified by flash chromatography on silica gel (gradient elution: 30% ethyl acetate/hexanes) to afford 11.1 g (90%) of 2-formyl-3-(3-t-butyldimethylsiloxypropyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalene. (M+=386).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH2:11][C:12]([OH:14])=O.B.O1CCCC1.C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>ClCCl.C1COCC1>[CH3:28][S:29]([O:14][CH2:12][CH2:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[CH3:1])(=[O:31])=[O:30]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccc([N+](=O)[O-])cc1CC(=O)O
Agent: B
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1ccc([N+](=O)[O-])cc1CCOS(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 39.1 %

Procedure:
A 500 mL round bottom flask was charged with (2-methyl-5-nitrophenyl)acetic acid (15 g, 77 mmol) and dry THF (300 mL). The mixture was cooled on ice-water and treated dropwise with borane-tetrahydrofurane complex (90 mL, 1M in THF, 90 mmol) during one hour. The reaction mixture was stirred for two hours at room temperature and then poured on ice. The aqueous phase was extracted with ethyl acetate (3×600 mL). The combined organic phases were washed with brine (2×1L) and water (2×1L), dried (Na2SO4) and concentrated in vacuo. The residue was redissolved in dichloromethane (200 mL) and triethylamine (10.8 mL, 78 mmol). The mixture was cooled on ice-water and a mixture of methanesulfonyl chloride (6.05 mL, 78 mmol) dissolved in dichloromethane (100 mL) was added dropwise during 20 minutes. The reaction mixture was stirred for 2 hours at room temperature. The reaction mixture was concentrated in vacuo. The residue was purified by flash chromatography on silicagel (eluent:ethyl acetate/heptane 2:3) to give the title compound (7.8 g). 1H NMR (CDCl3): 2.45 (s, 3H); 2.96 (s, 3H); 3.15 (t, 2H); 4.45 (t, 2H); 7.33 (d, 1H); 7.98-8.11 (m, 2H).
Reaction SMILES: [CH:1]1([N:4]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]3[CH:26]=[CH:25][C:19]([C:20]([O:22]CC)=[O:21])=[CH:18][CH:17]=3)=[CH:10][C:9]=2[CH:27]([CH3:29])[CH3:28])[CH2:5][CH3:6])[CH2:3][CH2:2]1.[OH-].[Na+]>C(O)C.O1CCCC1>[CH:1]1([N:4]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]3[CH:26]=[CH:25][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=3)=[CH:10][C:9]=2[CH:27]([CH3:28])[CH3:29])[CH2:5][CH3:6])[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc(CN(CC)C3CC3)c(C(C)C)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCN(Cc1ccc(C#Cc2ccc(C(=O)O)cc2)cc1C(C)C)C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.2 %

Procedure:
Using General Procedure I; a solution of ethyl 4-{4-[(cyclopropyl-ethyl-amino)-methyl]-3-isopropyl-phenylethynyl}-benzoate (Compound 133, 68.0 mg, 0.17 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) was treated with NaOH (600.0 mg, 15.0 mmols, 3.0 mL of a 5N aqueous solution) and stirred overnight at room temperature and then at 55° C. for 9 hours. Work-up followed by crystallization of the solid residue from hot CH3CN afforded 45.0 mg (72%) of the title compound as a pale-yellow solid.
Reaction SMILES: [CH2:1]([N:8]([CH3:27])[C:9](=O)[CH2:10][N:11]1[C:24]2[CH:23]=[C:22]([Cl:25])[CH:21]=[CH:20][C:19]=2[S:18][C:17]2[C:12]1=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1COCC1.Cl.CO>[CH2:1]([N:8]([CH2:9][CH2:10][N:11]1[C:24]2[CH:23]=[C:22]([Cl:25])[CH:21]=[CH:20][C:19]=2[S:18][C:17]2[C:12]1=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH3:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(Cc1ccccc1)C(=O)CN1c2ccccc2Sc2ccc(Cl)cc21
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: CN(CCN1c2ccccc2Sc2ccc(Cl)cc21)Cc1ccccc1
Reaction time: 0.5 h
Yield: 118.3 %

Procedure:
N-Benzyl-2-(2-chlorophenothiazin-10-yl)-N-methylacetamide (140 mg, 0.355 mmol) was dissolved in THF (5 mL). A solution of borane• THF complex in THF (1.0 M, 5 mL, 5 mmol) was added, and the solution heated to reflux for 4 h. The mixture was carefully diluted with saturated HCl in methanol and stirred for 30 min. The solvent was removed under vacuum, and the residue dissolved in ethyl acetate and aqueous sodium hydroxide (1 N). The layers were separated and the aqueous layer extracted with ethyl acetate. The organic layers were combined, dried (Na2SO4), filtered, and concentrated to provide benzyl-[2-(2-chlorophenothiazin-10-yl)-ethyl]methyl amine as a white solid (160 mg). The crude product was purified by SiO2 chromatography to provide pure product (50 mg, 34%) and 100 mg of impure product. The pure product was dissolved in acetone and a solution of fumaric acid (0.8 mL, 0.02 g/mL in methanol) was added. The solvents were removed under vacuum, and the residue slurried in chloroform and filtered to provide the sub-titled compound (47 mg) as an off-white solid.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH2:12][C:13]1[CH:17]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:15]([S:24]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([NH:35][CH3:36])=[O:34])[CH:28]=2)(=[O:26])=[O:25])[CH:14]=1)[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].I[CH3:38].O>O1CCCC1.CN(C)C=O>[CH3:36][N:35]([CH3:38])[C:33]([C:29]1[CH:28]=[C:27]([S:24]([N:15]2[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:17][C:13]([CH2:12][N:4]([CH3:3])[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[CH:14]2)(=[O:26])=[O:25])[CH:32]=[CH:31][CH:30]=1)=[O:34]
Reactant: CI
Reactant: CNC(=O)c1cccc(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)cc2-c2ccccc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1cccc(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)cc2-c2ccccc2)c1
Reaction time: 0.25 h
Yield: 68 %

Procedure:
To a suspension (3 mL) of sodium hydride (60% in oil, 36 mg) in tetrahydrofuran was added a solution (2 mL) of tert-butyl methyl{[1-({3-[(methylamino)carbonyl]phenyl}sulfonyl)-5-phenyl-1H-pyrrol-3-yl]methyl}carbamate (240 mg) in N,N-dimethylformamide at room temperature. After stirring at the same temperature for 15 min, iodomethane (106 mg) was added, and the mixture was stirred for 30 min. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:1→1:1) to give the title compound as a colorless oil (yield 168 mg, 68%).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1([CH2:10][C:11]([OH:13])=[O:12])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.Cl.[CH3:15]O>>[NH2:2][CH2:3][C:4]1([CH2:10][C:11]([O:13][CH3:15])=[O:12])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: CO
Reactant: NCC1(CC(=O)O)CCCCC1
Agent: Cl
Product: COC(=O)CC1(CN)CCCCC1

Procedure:
In an analogous manner as described in Example 2, 1-aminomethyl-1-cyclohexane-acetic acid hydrochloride is reacted with methanol in the presence of hydrogen chloride. After evaporation in a vacuum the residue is recrystallised from methanol/ether to give pure methyl 1-aminomethyl-1-cyclohexane-acetate; m.p. 150° - 152° C. (hydrochloride)
Reaction SMILES: [NH2:1][CH:2]([OH:29])[C:3]([N:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[S:14][C:15]3[N:16]=[C:17](Cl)[N:18]=[C:19]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:20]=3[N:21]=2)[CH2:8][CH2:7]1)([CH3:5])[CH3:4].[CH3:30][C:31]1[O:32][C:33]2[CH:48]=[CH:47][CH:46]=[CH:45][C:34]=2[C:35]=1B1OC(C)(C)C(C)(C)O1.C([O-])([O-])=O.[Cs+].[Cs+]>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>[CH3:4][C:3]([N:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[S:14][C:15]3[N:16]=[C:17]([C:35]4[C:34]5[CH:45]=[CH:46][CH:47]=[CH:48][C:33]=5[O:32][C:31]=4[CH3:30])[N:18]=[C:19]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:20]=3[N:21]=2)[CH2:8][CH2:7]1)([CH3:5])[C:2]([NH2:1])=[O:29]
Reactant: Cc1oc2ccccc2c1B1OC(C)(C)C(C)(C)O1
Reactant: CC(C)(C(N)O)N1CCN(Cc2nc3c(N4CCOCC4)nc(Cl)nc3s2)CC1
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: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1oc2ccccc2c1-c1nc(N2CCOCC2)c2nc(CN3CCN(C(C)(C)C(N)=O)CC3)sc2n1
Temperature: 140 °C
Yield: 60.9 %

Procedure:
A mixture of 1-amino-2-[4-(5-chloro-7-morpholin-4-ylthiazolo[5,4-d]pyrimidin-2-ylmethyl)piperazin-1-yl]-2-methylpropan-1-ol (100 mg, 0.23 mmol), 2-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzofuran (88 mg, 0.34 mmol), tetrakis(triphenylphosphine)palladium (26 mg, 0.02 mmol) and Cs2CO3 (148 mg, 0.45 mmol) in dioxane (6 mL) and H2O (3 mL) was purged with argon then heated at 140° C. for 30 min in a microwave reactor. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with DCM/MeOH and the product eluted with 2M NH3/MeOH. The resulting residue was purified by column chromatography (Si—PCC, EtOAc:cyclohexane, 50-100%) to afford 211 as a cream solid (75 mg, 61%). LCMS (Method G): RT 10.35 min, [M+H]+ 536.4. 1H NMR (CDCl3, 400 MHz): δ 8.40-8.37 (m, 1 H); 7.46-7.42 (m, 1 H); 7.32-7.23 (m, 2 H); 7.10 (d, J=5.3 Hz, 1 H); 5.22 (d, J=5.3 Hz, 1 H); 4.40 (m, 4 H); 3.93-3.87 (m, 6 H); 2.92 (s, 3 H); 2.69 (m, 4 H); 2.62 (m, 4 H) and 1.26 (s, 6 H)
Reaction SMILES: [C:1]([O:7][C:8]1[C:9]([CH3:18])=[C:10]2[N:15]([CH:16]=1)[N:14]=[CH:13][N:12]=[C:11]2Cl)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[F:19][C:20]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:21]=1[OH:29].C1N2CCN(CC2)C1>C(#N)C>[C:1]([O:7][C:8]1[C:9]([CH3:18])=[C:10]2[N:15]([CH:16]=1)[N:14]=[CH:13][N:12]=[C:11]2[O:29][C:21]1[CH:22]=[CH:23][C:24]([N+:26]([O-:28])=[O:27])=[CH:25][C:20]=1[F:19])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Reactant: Cc1c(OC(=O)C(C)(C)C)cn2ncnc(Cl)c12
Agent: C1CN2CCN1CC2
Solvent: CC#N
Product: Cc1c(OC(=O)C(C)(C)C)cn2ncnc(Oc3ccc([N+](=O)[O-])cc3F)c12
Temperature: 50 °C

Procedure:
To a homogeneous solution of 4-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl pivalate (1.00 g, 3.74 mmol, Compound D of Example 1) and 2-fluoro-4-nitrophenol (588 mg, 3.74 mmol) in anhydrous acetonitrile (25 mL), at room temperature under a nitrogen atmosphere, was added DABCO (462 mg, 4.12 mmol). The mixture was then heated at 50° C. for 3 h. The mixture was cooled to room temperature then partitioned between chloroform and saturated aqueous ammonium chloride. The aqueous layer was extracted twice with chloroform. The combined organic layers were washed once each with saturated aqueous ammonium chloride and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated in vacuo to yield a pale yellow solid that was used in the next step without further purification. MS(ESI+) m/z 389.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:13]/[OH:14])/[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.C(N(C(C)C)C(C)C)C.Cl[CH2:25][C:26]1[N:30]([CH3:31])[N:29]=[N:28][N:27]=1.[I-].[Na+]>C(#N)C.C(OCC)(=O)C>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:13]/[O:14][CH2:25][C:26]2[N:30]([CH3:31])[N:29]=[N:28][N:27]=2)/[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1
Reactant: CCOC(=O)/C(=N\O)c1csc(N)n1
Reactant: Cn1nnnc1CCl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCOC(=O)/C(=N\OCc1nnnn1C)c1csc(N)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 154.7 %

Procedure:
17.7 g of ethyl 2-(2-amino-4-thiazolyl)-2-(Z)-hydroxyimino-acetate are suspended in 320 ml of acetonitrile, treated successively with 27.6 ml of N-ethyldiisopropylamine, 16 g of 5-chloromethyl-1-methyl-tetrazole and 24 g of sodium iodide and the mixture is stirred at room temperature for 12 hours. The mixture is subsequently diluted with 1.5 l of ethyl acetate, washed three times with 500 ml of water each time, dried over magnesium sulphate and concentrated. There are obtained 39.6 g of ethyl 2-(2-amino-4-thiazolyl)-2-[(Z)-[(1-methyl-1H-tetrazol-5-yl)methoxy]imino]-acetate as an oil which is used directly.
Reaction SMILES: Cl.Cl.[N:3]1([C:9]2[CH:10]=[CH:11][C:12]3[N:13]([C:15]([C:18]([F:21])([F:20])[F:19])=[N:16][N:17]=3)[N:14]=2)[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.CCN(C(C)C)C(C)C.[F:31][C:32]1[CH:40]=[CH:39][CH:38]=[CH:37][C:33]=1[CH2:34][CH2:35]Br>CN(C=O)C>[F:31][C:32]1[CH:40]=[CH:39][CH:38]=[CH:37][C:33]=1[CH2:34][CH2:35][N:6]1[CH2:5][CH2:4][N:3]([C:9]2[CH:10]=[CH:11][C:12]3[N:13]([C:15]([C:18]([F:19])([F:20])[F:21])=[N:16][N:17]=3)[N:14]=2)[CH2:8][CH2:7]1
Reactant: Fc1ccccc1CCBr
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Fc1ccccc1CCN1CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 66.4 %

Procedure:
A stirred solution of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine dihydrochloride (0.173 g, 0.5 mmol), DIPEA (0.300 mL, 1.75 mmol) and 2-fluorophenethyl bromide (0.084 mL, 0.60 mmol) in DMF (2 mL) was heated at 100° C. for 2.5 hours. The reaction was incomplete and further DIPEA (0.300 mL, 1.75 mmol) and 2-fluorophenethyl bromide (0.084 mL, 0.60 mmol) were added. The solution was stirred at 100° C. for a further 90 minutes. The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% ammonia) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford 6-[4-[2-(2-fluorophenyl)ethyl]piperazin-1-yl]-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine (0.131 g, 66.4%) as a crisp foam.