Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([CH3:14])[C:10]=1[C:11](Cl)=[O:12])=[O:5])[CH3:2].[C:15]1([C:21]2[N:22]=[C:23]3[N:28]=[C:27]([NH2:29])[CH:26]=[CH:25][N:24]3[CH:30]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([CH3:14])[C:10]=1[C:11](=[O:12])[NH:29][C:27]1[CH:26]=[CH:25][N:24]2[CH:30]=[C:21]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:22]=[C:23]2[N:28]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnn(C)c1C(=O)Cl
Reactant: Nc1ccn2cc(-c3ccccc3)nc2n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1cnn(C)c1C(=O)Nc1ccn2cc(-c3ccccc3)nc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.4 %

Procedure:
5-Chlorocarbonyl-1-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (3.60 g, assumed purity 60%, 10 mmol) was added slowly to a cooled (0° C.) solution of 2-phenylimidazo[1,2-a]pyrimidin-7-amine (example 1, step 1, 2.52 g, 12 mmol) and triethylamine (2.02 g, 20 mmol) in dichloromethane (50 ml), and the suspension was stirred overnight at RT. The mixture was taken up in dichloromethane, and washed with water. The combined organic layers were dried (Na2SO4), filtered, and the solvent was evaporated under reduced pressure. The title compound (2.75 g, 71%) was isolated from the residue by column chromatography (silica gel, heptane:ethyl acetate=100:0-60:40). MS (m/e)=391.2 [M+H+].
Reaction SMILES: [Na].Br[CH2:3][C:4]([OH:6])=[O:5].[CH3:7][CH:8]([OH:11])[CH2:9][CH3:10]>>[CH3:7][CH:8]([O:11][CH2:3][C:4]([OH:6])=[O:5])[CH2:9][CH3:10]
Reactant: O=C(O)CBr
Reactant: CCC(C)O
Agent: [Na]
Product: CCC(C)OCC(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 3-neck 1-liter round-bottom flask equipped with a mechanical stirrer, reflux condenser and addition funnel was added 500 ml of 2-butanol under nitrogen. Sodium spheres (3.31 g, 0.144 moles) were then added and the mixture heated at reflux for 6 hours and then stirred at room temperature overnight. A solution of bromoacetic acid (10.00 g, 0.072 moles) in 10 ml of 2-butanol was then added dropwise and the mixture stirred at room temperature for 24 hours. The mixture was then concentrated in vacuo to remove the 2-butanol and the resulting white solid dissolved in 100 ml of water. This aqueous solution was washed with ether (2×50 ml) and then acidified to pH 1 with concentrated hydrochloric acid. The resulting mixture was extracted with ether (3×100 ml) and the combined extracts washed with saturated sodium chloride solution (1×50 ml), dried over magnesium sulfate and concentrated in vacuo to give 8.1 g of the product as a pale yellow oil.
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]2[CH:7]=C(C#N)[CH:9]=[C:10]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:4]=2[N:3]=1.[OH-:21].[K+].Cl.[CH2:24]([OH:27])[CH2:25]O>>[CH3:1][C:2]1[NH:6][C:5]2[CH:7]=[C:25]([C:24]([OH:27])=[O:21])[CH:9]=[C:10]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:4]=2[N:3]=1
Reactant: Cc1nc2c(OCc3ccccc3)cc(C#N)cc2[nH]1
Reactant: [OH-]
Reactant: OCCO
Agent: Cl
Agent: [K+]
Product: Cc1nc2c(OCc3ccccc3)cc(C(=O)O)cc2[nH]1
Temperature: 25 °C
Yield: 93 %

Procedure:
A solution of 2-methyl-4-[(phenylmethyl)oxy]-1H-benzimidazole-6-carbonitrile (3.82 g, 14.5 mmol, STEP 3) and potassium hydroxide (85%, 10.2 g, 15.4 mmol) in ethylene glycol (50 mL) was heated to 170° C. for 20 minutes in the microwave synthesizer (Biotage, Emrys Optimizer). After cooling to room temperature, the mixture was acidified with 2M hydrochloric acid aqueous solution (pH=3). The precipitated solid was collected by filtration to afford the title compound as a white solid (3.83 g, 93%).
Reaction SMILES: [C-:1]#[N:2].[K+].[CH3:4][C:5]1[CH:6]=[N:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2.[C:15](Cl)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O.ClCCl>[C:15]([N:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:14]=[C:5]([CH3:4])[CH:6]1[C:1]#[N:2])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1cnc2ccccc2c1
Reactant: [C-]#N
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: CC1=Cc2ccccc2N(C(=O)c2ccccc2)C1C#N
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 107.6 %

Procedure:
To a mixture of potassium cyanide (68.22 g, 1.048 mol), and 3-methylquinoline (50 g, 0.349 mol) in water (200 mL) and dichloromethane (500 mL) was added dropwise benzoyl chloride (81 mL, 0.698 mol) over 2 h at room temperature. The mixture was stirred for 4.5 h at room temperature and then the organic layer was separated. The layer was washed successively with water (300 mL), 1N aqueous hydrochloric acid, and water (200 mL×2), dried over magnesium sulfate, and concentrated to give 103.05 g of N-benzoyl-2-cyano-3-methyl-1,2-dihydroquinoline (108%): 1H NMR (270 MHz, CDCl3) δ7.34 (m, 6H), 7.16 (dd, 1H, J=7.6, 1.3 Hz), 7.07 (dt, 1H, J=1.3, 7.6 Hz), 6.87 (dt, 1H, J=1.3, 7.6 Hz), 6.53 (dd, 1H, J=7.6, 1.3 Hz), 2.12 (d, 3H, J=1.3 Hz).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])[CH2:15][NH2:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][C:25](OC(C)=O)=[O:26]>N1C=CC=CC=1.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])[CH2:15][NH:16][C:25](=[O:26])[CH3:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(C(CN)c2ccccc2Cl)CC1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=O)NCC(c1ccccc1Cl)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 60 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
To 4-[2-Amino-1-(2-chloro-phenyl)-ethyl]-piperazine-1-carboxylic acid tert-butyl ester (201) (0.75 g, 2.21 mmol) in pyridine (5 mL) was added Ac2O (5 mL). The reaction was allowed to stir at 60° C. for 1 h and then allowed to cool to room temperature. The reaction mixture was diluted with EtOAc (100 mL) and washed with sat. NaHCO3 (100 mL)), H2O (100 mL) and brine (100 mL). The organic phase was concentrated to dryness yielding 0.85 g (99%) product.
Reaction SMILES: [Br-].[CH:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([CH3:4])[CH3:3].[NH2-].[Na+].O=[C:27]1[CH2:32][CH2:31][CH:30]([C:33]2[CH:38]=[CH:37][C:36]([N:39]3[CH2:43][CH:42]([CH2:44][O:45][CH3:46])[O:41][C:40]3=[O:47])=[CH:35][CH:34]=2)[CH2:29][CH2:28]1.O>O1CCCC1>[CH3:46][O:45][CH2:44][CH:42]1[O:41][C:40](=[O:47])[N:39]([C:36]2[CH:37]=[CH:38][C:33]([CH:30]3[CH2:31][CH2:32][C:27](=[C:2]([CH3:4])[CH3:3])[CH2:28][CH2:29]3)=[CH:34][CH:35]=2)[CH2:43]1
Reactant: COCC1CN(c2ccc(C3CCC(=O)CC3)cc2)C(=O)O1
Reactant: CC(C)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [NH2-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COCC1CN(c2ccc(C3CCC(=C(C)C)CC3)cc2)C(=O)O1

Procedure:
1.60 g (3.3 mmol) of isopropyl-triphenylphosphonium bromide/sodium amide mixture in 30 ml of tetrahydrofuran were stirred at room temperature for 1 hour. Then, a solution of 1.0 g (3.3 mmol) of (RS)-3-[4-(4-oxo-cyclohexyl)-phenyl]-5-methoxymethyl-oxazolidin-2-one in 25 ml of tetrahydrofuran was added dropwise. After boiling at reflux over the weekend the mixture was poured into 100 ml of water and extracted three times with 50 ml of dichloromethane each time. After chromatography over silica gel with ethyl acetate/hexane 1:2 and recrystallization from n-hexane 120 mg (11%) were obtained as white crystals with m.p. 89°-91°.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=O)[CH:2]=1.Cl.[NH2:17][OH:18]>N1C=CC=CC=1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7](=[N:17][OH:18])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:2]=1
Reactant: NO
Reactant: O=C(Cc1ccccc1)c1cccnc1
Agent: Cl
Solvent: c1ccncc1
Product: ON=C(Cc1ccccc1)c1cccnc1
Reaction time: 0.25 h

Procedure:
10.8 g of benzyl 3-pyridyl ketone are stirred together with 40 ml of pyridine and a solution of 8 g of hydroxylamine hydrochloride in 15 ml of pyridine for 6 hours at 100°. The reaction mixture is poured onto ice/water and the resulting mixture is stirred for a further 15 minutes. The crystals which have precipitated are filtered off with suction, washed with water and dried under a high vacuum. Benzyl 3-pyridyl ketone oxime with a melting point of 122°-126° is obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([Cl:9])=[CH:4][N:3]=1.[OH:10][CH2:11][CH2:12][C@H:13]1[CH2:15][C@H:14]1[CH:16]1[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]1>>[Cl:9][C:5]1[C:6]([CH3:8])=[N:7][C:2]([N:19]2[CH2:20][CH2:21][CH:16]([C@H:14]3[CH2:15][C@H:13]3[CH2:12][CH2:11][OH:10])[CH2:17][CH2:18]2)=[N:3][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCC([C@@H]2C[C@@H]2CCO)CC1
Reactant: Cc1nc(Cl)ncc1Cl
Product: Cc1nc(N2CCC([C@H]3C[C@H]3CCO)CC2)ncc1Cl

Procedure:
The titled compound was prepared from 2,5-dichloro-4-methylpyrimidine from step 1 of this example and rac cis-tert-Butyl 4-[-2-(2-hydroxyethyl)cyclopropyl]piperidine-1-carboxylate by a procedure analogous to Example 6, step 2.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([NH2:11])[C:5]=2[CH:4]=[N:3]1.[C:12](Cl)(Cl)=[O:13].[Cl:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH2:22])=[CH:19][CH:18]=1>C1(C)C=CC=CC=1>[Cl:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH:22][C:12]([NH:11][C:6]2[CH:7]=[CH:8][CH:9]=[C:10]3[C:5]=2[CH:4]=[N:3][N:2]3[CH3:1])=[O:13])=[CH:19][CH:18]=1
Reactant: Cn1ncc2c(N)cccc21
Reactant: O=C(Cl)Cl
Reactant: NCc1ccc(Cl)cc1
Solvent: Cc1ccccc1
Product: Cn1ncc2c(NC(=O)NCc3ccc(Cl)cc3)cccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1-Methyl-1H-indazol-4-amine (1.00 g, 6.8 mmol) in toluene (225 mL) was treated with phosgene (20% in toluene, 7 ml, 13.2 mmol). The mixture was heated at reflux for 3 hours, cooled, and the solvent removed under reduced pressure. The residue was taken in diethyl ether (100 ml) and triethyl amine (6 ml), and filtered. The filtrate was treated with 4-chlorobenzylamine (963 mg, 6.8 mmol). After stirring at ambient temperature for 16 hours, the solvent was reduced to half volume under reduced pressure, filtered, and the filter cake washed with diethyl ether:hexanes (1:1) to provide the title compound. The title compound was treated with HCl/ethanol and evaporated to dryness to provide the hydrochloride. 1H NMR (DMSO-d6) δ 9.25 (s, 1H), 8.25 (s, 1H), 7.68 (d, 1H), 7.39 (m, 5H), 7.24 (t, 1H), 7.13 (d, 1H), 4.34 (s, 2H), 3.99 (s, 3H); MS (ESI) m/z 315 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1([C:18]2[CH:23]=[CH:22][C:21](SC)=[CH:20][CH:19]=2)[CH2:8][CH2:7][C:6]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([C:9]([OH:11])=[O:10])[CH2:5][CH2:4]1.Cl[C:27]1C=CC=C(C(OO)=O)C=1.[S:37]([O-:40])([O-])=[O:38].[Na+].[Na+].S([O-])(O)(=O)=O.[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3]1([C:18]2[CH:19]=[CH:20][C:21]([S:37]([CH3:27])(=[O:40])=[O:38])=[CH:22][CH:23]=2)[CH2:8][CH2:7][C:6]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)([C:9]([OH:11])=[O:10])[CH2:5][CH2:4]1
Reactant: O=S([O-])[O-]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC1(c2ccc(SC)cc2)CCC(C(=O)O)(c2ccccc2)CC1
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC1(c2ccc(S(C)(=O)=O)cc2)CCC(C(=O)O)(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
690 mg of 4-methoxy-4-(4-methylsulfanylphenyl)-1-phenylcyclohexanecarboxylic acid were dissolved in 30 ml of DCM and 865 mg of 3-chloroperbenzoic acid were added at room temperature. The reaction mixture was stirred at room temperature was for 5 h and 40 min. 60 ml of a saturated aqueous sodium sulfite solution were then added, the mixture was stirred for 15 min at room temperature, adjusted to pH=3 with a saturated aqueous sodium hydrogensulfate solution and extracted three times with 100 ml each of DCM. The combined extracts were dried over magnesium sulfate and the solvent was removed in vacuo. Chromatography of the residue on silica gel with MTB yielded 464 mg of the title compound as an amorphous solid.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([C:12]([OH:14])=O)[C:6](=[CH:10][CH:11]=1)[C:7]([OH:9])=O.[NH2:17][CH2:18][C:19]([OH:21])=[O:20].[CH3:22]O>>[CH3:22][O:20][C:19](=[O:21])[CH2:18][N:17]1[C:12](=[O:14])[C:5]2[C:6](=[CH:10][CH:11]=[C:3]([C:2]([F:1])([F:16])[F:15])[CH:4]=2)[C:7]1=[O:9]
Reactant: CO
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1C(=O)O
Reactant: NCC(=O)O
Product: COC(=O)CN1C(=O)c2ccc(C(F)(F)F)cc2C1=O

Procedure:
4-trifluoromethyl-phthalic acid was reacted with glycine in analogy to Example D-1 b). The crude product was then reacted with methanol in analogy to Example D-1 c); 1H NMR (CDCl3): δ=8.14 (s, 1H), 8.02 (m, 2H), 4.48 (s, 2H), 3.78 (s, 3H).
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([C:18]4([OH:22])[CH2:21][NH:20][CH2:19]4)[N:14]3[CH3:17])=[C:10]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[N:9]=2)[C:6]2[CH:29]=[CH:30][CH:31]=[CH:32][C:5]=2[N:4]=1)[CH3:2].[O:33]1[CH2:38][CH2:37][C:36](=O)[CH2:35][CH2:34]1.CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(Cl)Cl>[CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([C:18]4([OH:22])[CH2:21][N:20]([CH:36]5[CH2:37][CH2:38][O:33][CH2:34][CH2:35]5)[CH2:19]4)[N:14]3[CH3:17])=[C:10]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[N:9]=2)[C:6]2[CH:29]=[CH:30][CH:31]=[CH:32][C:5]=2[N:4]=1)[CH3:2]
Reactant: O=C1CCOCC1
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(O)CNC3)n(C)c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(O)CN(C4CCOCC4)C3)n(C)c2n1
Reaction time: 2 h

Procedure:
A mixture of 3-[2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purin-8-yl]-azetidin-3-ol (490 mg, 1.13 mmol), tetrahydropyran-4-one (158 mg, 1.58 mmol), AcOH (130 μL, 2.25 mmol) and 4 Å powdered molecular sieves (640 mg) in DCE (15 mL) was allowed to stir for 5 min before the addition of sodium triacetoxyborohydride (478 mg, 2.25 mmol) portion wise over 5 min. The resulting mixture was allowed to stir for 4 h at r.t before the addition of further tetrahydropyran-4-one (158 mg, 1.58 mmol) and sodium triacetoxyborohydride (478 mg, 2.25 mmol). The mixture was stirred for 2 h then diluted with DCM and washed with 1M NaOH. The organic phase was dried (phase separator) and concentrated in vacuo. The resulting oil was purified by column chromatography (Si—PCC, 2M NH3/MeOH:DCM, 0-15%) then (C18, MeOH:H2O, 7.5-25%). The resulting residue was loaded onto an Isolute® SCX-2 cartridge which was washed with DCM and MeOH and the product eluted with 2M NH3/MeOH affording 720 as a white foam (309 mg, 53%). LCMS (method I): RT 2.40 min, [M+H]+ 519.3. 1H NMR (MeOD, 400 MHz): δ 8.01-8.00 (1 H, m), 7.66-7.61 (1 H, m), 7.28-7.27 (2 H, m), 4.38 (4 H, s), 4.24 (2 H, d, J=8.76 Hz), 3.97-3.94 (2 H, m), 3.85 (7 H, s), 3.56 (2 H, d, J=8.75 Hz), 3.31-3.31 (5 H, m), 2.54-2.52 (1 H, m), 1.83-1.73 (2 H, m), 1.38 (5 H, t, J=7.49 Hz)
Reaction SMILES: [CH:1]1([S:4][C:5]2[C:12]([F:13])=[CH:11][C:10]([N+:14]([O-:16])=[O:15])=[CH:9][C:6]=2[CH:7]=O)[CH2:3][CH2:2]1.[CH3:17][NH2:18].[BH4-].[Na+].[CH3:21][C:22]([O:25][C:26]([O:28]C(OC(C)(C)C)=O)=O)([CH3:24])[CH3:23]>CO>[CH:1]1([S:4][C:5]2[C:12]([F:13])=[CH:11][C:10]([N+:14]([O-:16])=[O:15])=[CH:9][C:6]=2[CH2:7][N:18]([CH3:17])[C:26](=[O:28])[O:25][C:22]([CH3:24])([CH3:23])[CH3:21])[CH2:3][CH2:2]1
Reactant: O=Cc1cc([N+](=O)[O-])cc(F)c1SC1CC1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: CN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CN(Cc1cc([N+](=O)[O-])cc(F)c1SC1CC1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 73.8 %

Procedure:
To a solution of 11B (0.965 g, 4.00 mmol) in MeOH (20 mL) was added methylamine (33% in EtOH) (0.598 mL, 4.80 mmol). The mixture was stirred at rt for 1.5 h, then was cooled to 0° C. sodium borohydride (0.182 g, 4.80 mmol) was added, then the mixture was stirred at rt for 1 h, then was concentrated. The resultant residue was taken up in THF (20 mL) and was treated with sat. NaHCO3 (10 mL). The mixture was stirred at rt for 10 min, then was treated with Boc2O (1.048 g, 4.80 mmol). The mixture was stirred at rt for 2 h. The THF was removed in vacuo, then the aqueous phase was extracted with EtOAc. The organic phase was washed with H2O and brine, dried (Na2SO4) and concentrated. The crude product was purified by flash chromatography (loaded in chloroform onto a 80 g column and eluted with a gradient from 0 to 50% ethyl acetate/hexanes) to give 11C (1.05 g, 2.95 mmol, 73.6% yield) as an yellow oil. MS (ESI) m/z: 379.1 [M+Na]+; 1H NMR (400 MHz, chloroform-d) δ ppm 7.78-7.94 (2H, m), 4.57 (2H, br. s.), 2.90 (3H, s), 2.49 (1H, qd, J=7.2, 4.3 Hz), 1.38-1.53 (9H, m), 0.92-0.98 (2H, m), 0.62-0.68 (2H, m).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=2C)[N:3]=1.[Cl:17]C1C=CC(Cl)=CC=1C(O)=O>>[Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=2[Cl:17])[N:3]=1
Reactant: O=C(O)c1cc(Cl)ccc1Cl
Reactant: Cc1ccc(Cl)cc1-c1nc(Cl)nc(Cl)n1
Product: Clc1ccc(Cl)c(-c2nc(Cl)nc(Cl)n2)c1
Yield: 14 %

Procedure:
Using the method described for the synthesis of 2,4-dichloro-6-(5-chloro-2-methyl-phenyl)-[1,3,5]triazine, 2,5-dichlorobenzoic acid afforded 2,4-dichloro-6-(2,5-dichloro-phenyl)-[1,3,5]triazine (2.2 g, 14% yield). 1H NMR (DMSO-d6) 8.10 (s, 1H), 7.50 (m, 2H).
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12](Br)=[C:11]([Br:16])[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)CN1[C:25](=[O:26])C(Br)=C(Br)C=N1>CO>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]([O:26][CH3:25])=[C:11]([Br:16])[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1c(Br)c(Br)cnn1Cc1ccccc1
Reactant: O=c1c(Br)c(Br)cnn1CC(F)(F)F
Solvent: CO
Product: COc1c(Br)cnn(Cc2ccccc2)c1=O

Procedure:
2-Benzyl-4-methoxy-5-bromo-3(2H)-pyridazinone is prepared according to the method of Example 83B starting with 2-benzyl-4,5-dibromo-3(2H)-pyridazinone, in place of 2-(2,2,2-trifluoroethyl)-4,5-dibromo-3(2H)-pyridazinone and substituting methanol in place of isopropanol.
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.Cl.[Br:12][C:13]1[N:17]2[N:18]=[C:19]([N:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[CH:20]=[CH:21][C:16]2=[N:15][CH:14]=1.[C:28](Cl)(=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30]>C(OCC)(=O)C>[Br:12][C:13]1[N:17]2[N:18]=[C:19]([N:22]3[CH2:23][CH2:24][N:25]([C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:26][CH2:27]3)[CH:20]=[CH:21][C:16]2=[N:15][CH:14]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Brc1cnc2ccc(N3CCNCC3)nn12
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)C(=O)N1CCN(c2ccc3ncc(Br)n3n2)CC1
Reaction time: 0.5 h

Procedure:
Hunig's base [7087-99-5] (1.8 mL, 10.3 mmol) was added to an ambient temperature stirred suspension of 3-bromo-6-piperazin-1-yl-imidazo[1,2-b]pyridazine dihydrochloride (907.1 mg, 2.6 mmol) in ethyl acetate (50 mL). After 30 minutes, pivaloyl chloride [3282-30-2] (0.3 mL, 2.5 mmol) was added and the suspension stirred under N2 blanket for 17 h then washed with brine, dried (MgSO4), and diluted with heptane. Chilling the stirred solution crystallized out a white powder which was isolated by filtration, 618.5 mg. LRMS (ESI) m/z 366.0/368.0 [(M+H)]+, calc'd for C16H20BrN6O: 366.26.
Reaction SMILES: Cl.C(OC(=O)C(NC1C=CC(C(=N)N)=CC=1)C1C=C(OCC)C(OCCO)=CC=1F)C.[CH2:32]([O:34][C:35](=[O:69])[CH:36]([NH:51][C:52]1[CH:57]=[CH:56][C:55]([C:58]([NH2:68])=[N:59][C:60]([O:62][CH2:63][C:64]([Cl:67])([Cl:66])[Cl:65])=[O:61])=[CH:54][CH:53]=1)[C:37]1[CH:42]=[C:41]([O:43][CH2:44][CH3:45])[C:40]([O:46][CH2:47][CH2:48][OH:49])=[CH:39][C:38]=1[F:50])[CH3:33].ClC(OCC(Cl)(Cl)Cl)=O>>[CH2:32]([O:34][C:35](=[O:69])[C@@H:36]([NH:51][C:52]1[CH:57]=[CH:56][C:55]([C:58]([NH2:68])=[N:59][C:60]([O:62][CH2:63][C:64]([Cl:66])([Cl:67])[Cl:65])=[O:61])=[CH:54][CH:53]=1)[C:37]1[CH:42]=[C:41]([O:43][CH2:44][CH3:45])[C:40]([O:46][CH2:47][CH2:48][OH:49])=[CH:39][C:38]=1[F:50])[CH3:33].[CH2:32]([O:34][C:35](=[O:69])[C@H:36]([NH:51][C:52]1[CH:57]=[CH:56][C:55]([C:58]([NH2:68])=[N:59][C:60]([O:62][CH2:63][C:64]([Cl:66])([Cl:67])[Cl:65])=[O:61])=[CH:54][CH:53]=1)[C:37]1[CH:42]=[C:41]([O:43][CH2:44][CH3:45])[C:40]([O:46][CH2:47][CH2:48][OH:49])=[CH:39][C:38]=1[F:50])[CH3:33]
Reactant: CCOC(=O)C(Nc1ccc(C(N)=NC(=O)OCC(Cl)(Cl)Cl)cc1)c1cc(OCC)c(OCCO)cc1F
Agent: CCOC(=O)C(Nc1ccc(C(=N)N)cc1)c1cc(OCC)c(OCCO)cc1F
Agent: Cl
Agent: O=C(Cl)OCC(Cl)(Cl)Cl
Product: CCOC(=O)[C@@H](Nc1ccc(C(N)=NC(=O)OCC(Cl)(Cl)Cl)cc1)c1cc(OCC)c(OCCO)cc1F
Product: CCOC(=O)[C@H](Nc1ccc(C(N)=NC(=O)OCC(Cl)(Cl)Cl)cc1)c1cc(OCC)c(OCCO)cc1F

Procedure:
In analogy to example 1.10, the (RS)-(4-carbamimidoyl-phenylamino)-[5-ethoxy-2-fluoro-4-(2-hydroxy-ethoxy)-phenyl]-acetic acid ethyl ester hydrochloride described in example 1.6 was converted to (RS)-{4-[amino-(2,2,2-trichloro-ethoxycarbonylimino)-methyl]-phenylamino}-[5-ethoxy-2-fluoro-4-(2-hydroxy-ethoxy)-phenyl]-acetic acid ethyl ester by a reaction with 2,2,2-trichloroethyl chloroformate. MS: 596 ([M+H]+) This compound was separated into the enantiomers by preparative HPLC on a chiral stationary phase (Chiralpak AD) using heptane/ethanol/diethylamine (60:40:0.2) as a mobile phase to give (S)-{4-[amino-(2,2,2-trichloro-ethoxycarbonylimino)-methyl]-phenylamino}-[5-ethoxy-2-fluoro-4-(2-hydroxy-ethoxy)-phenyl]-acetic acid ethyl ester and (R)-{4-[amino-(2,2,2-trichloro-ethoxycarbonylimino)-methyl]-phenylamino}-[5-ethoxy-2-fluoro-4-(2-hydroxy-ethoxy)-phenyl]-acetic acid ethyl ester. As a by-product, there was obtained (RS)-{4-[amino-(2,2,2-trichloro-ethoxycarbonylimino)-methyl]-phenylamino}-{5-ethoxy-2-fluoro-4-[2-(2,2,2-trichloro-ethoxycarbonyloxy)-ethoxy]-phenyl}-acetic acid ethyl ester. MS: 770.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([OH:33])([C:27]2[N:28]([CH3:32])[CH:29]=[N:30][CH:31]=2)[C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13](=[O:18])[CH:12]=[C:11]3[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25]C)[CH:20]=2)=[CH:4][CH:3]=1.B(Br)(Br)Br.[CH2:38](Cl)Cl>>[Cl:1][C:2]1[S:6][C:5]([C:7]([OH:33])([C:27]2[N:28]([CH3:32])[CH:29]=[N:30][CH:31]=2)[C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH3:38])[C:13](=[O:18])[CH:12]=[C:11]3[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([OH:25])[CH:20]=2)=[CH:4][CH:3]=1
Reactant: ClCCl
Reactant: COc1cccc(-c2cc(=O)[nH]c3ccc(C(O)(c4ccc(Cl)s4)c4cncn4C)cc23)c1
Agent: BrB(Br)Br
Product: Cn1cncc1C(O)(c1ccc2c(c1)c(-c1cccc(O)c1)cc(=O)n2C)c1ccc(Cl)s1
Yield: 67 %

Procedure:
Following the same procedure as that described in Example 34A, the title compound of example 31 (100 mg, 0.203 mmol0 was treated with BBr3 in CH2Cl2 (1M, 1.02 ml, 1.02 mmol) to give the title compound (64 mg, 67% yield).
Reaction SMILES: Cl[C:2]([CH:4]1[CH2:9][CH2:8][C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[O:5]1)=O.S1C=CC=C1.O(C(C)C)C(C)C.[H][H].C[N:29](C)C(=O)C>[Pd]>[O:5]1[C:6]2[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=2[CH2:8][CH2:9][CH:4]1[CH2:2][NH2:29]
Reactant: O=C(Cl)C1CCc2ccccc2O1
Reactant: CC(=O)N(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(C)OC(C)C
Solvent: c1ccsc1
Product: NCC1CCc2ccccc2O1
Yield: 63.5 %

Procedure:
A mixture of 2-chlorocarbonyl-3,4-dihydro-2H-1-benzopyran (0.47 mol) in N,N-dimethylacetamide (100 ml), a solution of thiophene (4%) (3 ml) and 2,2'-oxybispropane (400 ml) was hydrogenated with palladium on activated carbon (10%) (5 g) as a catalyst. After uptake of hydrogen (1 eq.), the catalyst was filtered off and the filtrate was evaporated. The residue, potassium acetate (20 g) and benzenemethanamine (50 g) in N,N-dimethylacetamide (2 ml) and methanol (300 ml) was hydrogenated with palladium on activated carbon (10%) (5 g) as a catalyst. After uptake of hydrogen (1 eq.), the catalyst was filtered off and the filtrate was evaporated. The residue in methanol (500 ml) was hydrogenated with palladium on activated carbon (10%) (5 g) as a catalyst. After uptake of hydrogen (1 eq.), the catalyst was filtered off and the filtrate was evaporated. The residue was taken up in 1,1'-oxybisethane and washed with a NaOH-solution. The organic layer was dried (MgSO4), filtered off and evaporated. The residue (70 g) was distilled at 70° C. (0.1 mm Hg), yielding 48.7 g (63.5%) of (±)-3,4-dihydro-2H-1-benzopyran-2-methanamine (interm. 15-c).