Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][C:9]([CH3:37])([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:10][O:11][CH2:12][C:13]1[CH:14]=[C:15]([CH:19]=[C:20]([N:22]([S:26]([CH3:29])(=[O:28])=[O:27])[CH2:23][CH2:24][CH3:25])[CH:21]=1)[C:16]([OH:18])=[O:17])=O)(C)(C)C.CCOC(C)=O>Cl>[NH2:8][C:9]([CH3:37])([CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[CH2:10][O:11][CH2:12][C:13]1[CH:14]=[C:15]([CH:19]=[C:20]([N:22]([S:26]([CH3:29])(=[O:28])=[O:27])[CH2:23][CH2:24][CH3:25])[CH:21]=1)[C:16]([OH:18])=[O:17]
Reactant: CCCN(c1cc(COCC(C)(Cc2ccccc2)NC(=O)OC(C)(C)C)cc(C(=O)O)c1)S(C)(=O)=O
Agent: Cl
Solvent: CCOC(C)=O
Product: CCCN(c1cc(COCC(C)(N)Cc2ccccc2)cc(C(=O)O)c1)S(C)(=O)=O
Reaction time: 0.5 h

Procedure:
3-({2-[(tert-butoxycarbonyl)amino]-2-methyl-3-phenylpropoxy}methyl)-5-[(methylsulfonyl)(propyl)amino]benzoic acid (intermediate XI, 15.0 mg, 0.028 mmol) was taken up in HCl(g) saturated EtOAc (1 mL). After 30 min, it was concentrated under a flow of nitrogen to give 3-[(2-amino-2-methyl-3-phenylpropoxy)methyl]-5-[(methylsulfonyl)(propyl)amino]benzoic acid as a white solid which was then taken up in DMF (800 μL) with BOP reagent (15.0 mg, 0.033 mmol), ethyl(diisopropyl)amine (12.0 μL, 0.069 mmol), and (1,1-dimethylprop-2-yn-1-yl)amine (23.0 mg, 0.276 mmol). After sitting at RT for 5 hr, the reaction was purified by preparative HPLC (5->95% CH3CN/H2O, 0.1% added TFA, C18 PRO YMC 20×150 mm) to afford 3-[(2-amino-2-methyl-3-phenylpropoxy)methyl]-N-(1,1-dimethylprop-2-yn-1-yl)-5-[(methylsulfonyl)(propyl)amino]benzamide as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.81 (br s, 3H), 7.77 (s, 1H), 7.69 (s, 1H), 7.47 (s, 1H), 7.35-7.27 (m, 3H), 7.22-7.16 (m, 2H), 6.89 (s, 1H), 4.61 (A of AB, d, J=11.7 Hz, 1H), 4.54 (B of AB, d, J=11.7 Hz, 1H), 3.64 (t, J=7.1 Hz, 2H), 3.51 (A of AB, d, J=9.8 Hz, 1H), 3.45 (B of AB, d, J=9.8 Hz, 1H), 3.17 (A of AB, d, J=13.2 Hz, 1H), 3.00 (B of AB, d, J=13.2 Hz, 1H), 2.86 (s, 3H), 1.75 (s, 6H), 1.54-1.44 (m, 2H), 1.32 (s, 3H), 1.27 (s, 3H), 0.89 (t, J=7.3 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N+:9]([O-])=[CH:8][C:7]([N+:14]([O-:16])=[O:15])=[CH:6]2.P(Cl)(Cl)([Cl:19])=O>ClCCl>[Cl:19][C:8]1[C:7]([N+:14]([O-:16])=[O:15])=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=1
Reactant: COc1ccc2c(c1)cc([N+](=O)[O-])c[n+]2[O-]
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1ccc2nc(Cl)c([N+](=O)[O-])cc2c1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
A suspension of 8.0 g of 6-methoxy-3-nitroquinoline-1-oxide (compound D3) in 80 ml of phosphorus oxychloride is stirred at 100° C. for 30 min. After cooling to room temperature, the reaction mixture is added to 500 ml of ice water, diluted with 250 ml of dichloromethane and extracted three times each with 250 ml of a halfsaturated aqueous potassium carbonate solution. The organic layer is dried using magnesium sulfate, filtered and evaporated in vacuo. The residue is recrystallized from diethylether to give 5.6 g of the title compound as violet solid.
Reaction SMILES: CC1(C)[O:6][C@@H:5]([CH2:7][O:8][NH:9][C:10]([C:12]2[CH:13]=[C:14]([F:30])[C:15]3[N:16]([CH:27]=[N:28][CH:29]=3)[C:17]=2[NH:18][C:19]2[CH:24]=[CH:23][C:22]([I:25])=[CH:21][C:20]=2[F:26])=[O:11])[CH2:4][O:3]1.Cl.O1CCOCC1>CO>[OH:6][C@H:5]([CH2:4][OH:3])[CH2:7][O:8][NH:9][C:10]([C:12]1[CH:13]=[C:14]([F:30])[C:15]2[N:16]([CH:27]=[N:28][CH:29]=2)[C:17]=1[NH:18][C:19]1[CH:24]=[CH:23][C:22]([I:25])=[CH:21][C:20]=1[F:26])=[O:11]
Reactant: CC1(C)OC[C@H](CONC(=O)c2cc(F)c3cncn3c2Nc2ccc(I)cc2F)O1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: O=C(NOC[C@H](O)CO)c1cc(F)c2cncn2c1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.9 %

Procedure:
To a solution of 8-fluoro-5-(2-fluoro-4-iodo-phenylamino)-imidazo[1,5-a]pyridine-6-carboxylic acid ((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-amide (298 mg, 0.55 mmol) in methanol (5 mL) was added hydrochloric acid in dioxane (2 mL, 4N, 8.0 mmol). The reaction mixture was stirred at room temperature for 1 hour then concentrated in vacuo. The resultant residue was dissolved in ethyl acetate (5 mL), washed with aqueous saturated sodium bicarbonate solution (10 mL) and the aqueous fraction extracted twice with ethyl acetate (2×5 mL). The combined organic fractions were washed with brine (10 mL), dried (MgSO4) and concentrated in vacuo. The resultant residue was subjected to reverse phase preparative HPLC (10-90% acetonitrile/water 0.1% formic acid, Phenominex gemini PhC6, 5 micron, 250×20 mm). The resultant product was dissolved in ethyl acetate (5 mL) and washed with aqueous saturated sodium bicarbonate solution (10 mL). The aqueous fraction was extracted twice with ethyl acetate (2×10 mL) and the combined organics washed with brine (20 mL), dried (MgSO4) and concentrated in vacuo to yield the title compound as a white solid (83 mg, 30%). LCMS (Method A): RT=7.11 min, [M+H]+=505. 1H NMR (DMSO-d6): 11.63 (1 H, s), 8.97 (1 H, s), 8.22 (1 H, d, J=3.06 Hz), 7.61 (1 H, s), 7.57 (1 H, dd, J=10.74, 1.93 Hz), 7.26 (1 H, d, J=8.50 Hz), 6.82 (1 H, d, J=11.09 Hz), 6.32 (1 H, t, J=8.74 Hz), 3.72-3.65 (1 H, m), 3.59-3.50 (2 H, m), 3.29 (2 H, m).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.[CH3:17][O-:18].[Na+].CS(C)=O>O>[CH3:17][O:18][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1
Reactant: C[O-]
Reactant: Clc1ccc(-c2nc3ccccc3o2)cc1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(-c2nc3ccccc3o2)cc1
Yield: 88.8 %

Procedure:
A mixture of 1.15 g (5 mmoles) of 2-(p-chlorophenyl)benzoxazole, 2.5 g of sodium methoxide and 10 ml of dimethyl sulfoxide is heated at 80° C.-90° C. under nitrogen atmosphere for one hour. The mixture is cooled and diluted with 100 ml of water. The title compound (1 g, 87 percent yield) precipitates and is recovered. It has a melting point of 99.5° C.-101.5° C.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Br:13][C:14]1[CH:15]=[C:16]([CH2:20][C:21]([OH:23])=[O:22])[CH:17]=[N:18][CH:19]=1.[F:24][C:25]1[CH:32]=[CH:31][C:28]([CH:29]=[O:30])=[CH:27][CH:26]=1>O1CCCC1>[Br:13][C:14]1[CH:15]=[C:16]([C@H:20]([C@@H:29]([C:28]2[CH:31]=[CH:32][C:25]([F:24])=[CH:26][CH:27]=2)[OH:30])[C:21]([OH:23])=[O:22])[CH:17]=[N:18][CH:19]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: O=C(O)Cc1cncc(Br)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=C(O)[C@H](c1cncc(Br)c1)[C@H](O)c1ccc(F)cc1
Temperature: -30 °C
Reaction time: 0.08 h

Procedure:
To a solution of diisopropylamine (8.98 mL, 63 mmol) in tetrahedrofuran (22.5 mL) in 1 L flask at −78° C. was added n-butyllithium (25.2 mL, 2.5M in hexane, 63.0 mmol) dropwise. The reaction was allowed to gradually warm in the bath to −30° C., and held there for 5 minutes. It was re-cooled to −78° C. and treated with solid 2-(5-bromopyridin-3-yl)acetic acid (6.80 g, 31.5 mmol) and tetahydrofuran (78 mL). The ice bath was removed and stirring continued for 1.5 h. The reaction was again cooled to 0° C., and treated with a solution of 4-fluorobenzaldehyde (3.38 mL, 31.5 mmol) in tetrahydrofuran (22.5 mL). The reaction was allowed to gradually warm to room temperature overnight. The reaction solution, after removal of the solid by filtration, was acidified with citric acid to pH ca. 4. It was extracted with diethyl ether and concentrated. The resulting residue was dried three times with toluene and the crude product (ca. 10.1 g) was used in the next reaction without further purification. Mass spec.: 340.9 (MH)+.
Reaction SMILES: [O:1]=[C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=[N:4][N:3]1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CN1CCOCC1.[F:45][C:46]1[CH:47]=[C:48]([CH:50]=[CH:51][C:52]=1[O:53][C:54]1[CH:59]=[CH:58][N:57]=[C:56]2[N:60]([CH2:70][C:71]3[CH:76]=[CH:75][C:74]([O:77][CH3:78])=[CH:73][CH:72]=3)[N:61]=[C:62]([N:63]3[CH2:68][CH2:67][N:66]([CH3:69])[CH2:65][CH2:64]3)[C:55]=12)[NH2:49]>C(Cl)Cl.C(Cl)Cl.CN(C=O)C>[CH3:78][O:77][C:74]1[CH:73]=[CH:72][C:71]([CH2:70][N:60]2[C:56]3=[N:57][CH:58]=[CH:59][C:54]([O:53][C:52]4[CH:51]=[CH:50][C:48]([NH:49][C:8]([C:7]5[C:2](=[O:1])[N:3]([C:11]6[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=6)[N:4]=[CH:5][CH:6]=5)=[O:10])=[CH:47][C:46]=4[F:45])=[C:55]3[C:62]([N:63]3[CH2:68][CH2:67][N:66]([CH3:69])[CH2:65][CH2:64]3)=[N:61]2)=[CH:76][CH:75]=1
Reactant: COc1ccc(Cn2nc(N3CCN(C)CC3)c3c(Oc4ccc(N)cc4F)ccnc32)cc1
Reactant: O=C(O)c1ccnn(-c2ccccn2)c1=O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COc1ccc(Cn2nc(N3CCN(C)CC3)c3c(Oc4ccc(NC(=O)c5ccnn(-c6ccccn6)c5=O)cc4F)ccnc32)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
3-Oxo-2-(pyridin-2-yl)-2,3-dihydropyridazine-4-carboxylic acid (0.0282 g, 0.130 mmol; prepared as in Example 141, Steps A-C) was dissolved in 5 mL of CH2Cl2 and cooled to 0° C. HOBt (0.0351 g, 0.259 mmol), EDCI (0.0497 g, 0.259 mmol), and NMM (0.0333 ml, 0.303 mmol) were added and the reaction mixture was stirred under N2(g) for 15 minutes. 4-(1-(4-Methoxybenzyl)-3-(4-methylpiperazin-1-yl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorobenzenamine (0.020 g, 0.0432 mmol; prepared according to Example 86, Step A) in 2 mL of 1:1 CH2Cl2/DMF was added and the reaction was stirred at ambient temperature for 5 hours. The mixture was partitioned between EtOAc and aqueous NaHCO3. The organic layer washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (Flash 5 g) eluting with 3% MeOH/CH2Cl2 to afford the desired product as yellow semi-solid. Yield: 25.8 mg, 86%. LRMS (APCI pos) m/e 662 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:23])[CH:5]=[CH:6][C:7]=1[CH:8]([CH3:22])[C:9]([OH:21])([C:14]1[CH:19]=[CH:18][N:17]=[C:16]([CH3:20])[CH:15]=1)[C:10]([F:13])([F:12])[F:11].[H-].[Na+].[CH3:26][O:27][C:28](=[O:37])[CH2:29][N:30]1[CH:34]=[C:33]([CH2:35]Cl)[CH:32]=[N:31]1.[Na+].[I-]>CN(C=O)C>[CH3:26][O:27][C:28](=[O:37])[CH2:29][N:30]1[CH:34]=[C:33]([CH2:35][O:23][C:4]2[CH:5]=[CH:6][C:7]([CH:8]([CH3:22])[C:9]([OH:21])([C:14]3[CH:19]=[CH:18][N:17]=[C:16]([CH3:20])[CH:15]=3)[C:10]([F:13])([F:11])[F:12])=[C:2]([Cl:1])[CH:3]=2)[CH:32]=[N:31]1
Reactant: COC(=O)Cn1cc(CCl)cn1
Reactant: Cc1cc(C(O)(C(C)c2ccc(O)cc2Cl)C(F)(F)F)ccn1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)Cn1cc(COc2ccc(C(C)C(O)(c3ccnc(C)c3)C(F)(F)F)c(Cl)c2)cn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 9.7 %

Procedure:
A solution of 3-chloro-4-[3,3,3-trifluoro-2-hydroxy-1-methyl-2-(2-methyl-pyridin-4-yl)-propyl]-phenol (93 mg, obtained in Example 93, step 6) in DMF (2 mL) was added to a suspension of NaH (60% in mineral oil, 24 mg) in DMF (1 mL) over 10 minutes. Stirring was continued for 30 minutes at r.t. The mixture was cooled to 0° C. and (4-chloromethyl-pyrazol-1-yl)-acetic acid methyl ester (61 mg, obtained in Example 103, step 4) dissolved in DMF (2 mL) was added dropwise over a period of 5 minutes. Stirring was continued for 2 hours at r.t. followed by the addition of NaI (3 mg). The mixture was heated to 50° C. overnight. The reaction mixture was cooled, poured into ice and extracted two times with chloroform. The combined organic layers were washed with brine, dried over Na2SO4, filtered and the solvent was evaporated. The residue was purified by flash chromatography (silica gel, gradient of heptane in ethyl acetate) to give the title compound as a light yellow gum (13 mg, 10%). MS (m/e)=498.2 [MH−].
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH2:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[O:13]1[CH:15]([CH2:16][CH2:17][CH3:18])[CH2:14]1>CO>[CH3:1][S:2]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH:10][CH2:14][CH:15]([OH:13])[CH2:16][CH2:17][CH3:18])=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CCCC1CO1
Reactant: CS(=O)(=O)c1ccc(CN)cc1
Solvent: CO
Product: CCCC(O)CNCc1ccc(S(C)(=O)=O)cc1
Yield: 34.1 %

Procedure:
A solution (50 ml) of 4-methanesulfonylbenzylamine (5.0 g) and 1,2-epoxypentane (2.8 g) in methanol was stirred at room temperature for 96 hrs. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate-ethyl acetate:methanol=10:1) to give the title compound (2.5 g).
Reaction SMILES: [CH3:1][S:2]([CH2:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12]C)=[O:11])=[CH:8][N:7]=1)(=[O:4])=[O:3].[OH-].[Li+]>O1CCCC1.CO.O>[CH3:1][S:2]([CH2:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([OH:12])=[O:11])=[CH:8][N:7]=1)(=[O:4])=[O:3]
Reactant: COC(=O)c1ccc(CS(C)(=O)=O)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CS(=O)(=O)Cc1ccc(C(=O)O)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.2 %

Procedure:
To a stirred solution of methyl 6-[(methylsulfonyl)methyl]nicotinate (800 mg) in 1:1.1 tetrahydrofuran/methanol/water (30 mL) was added lithium hydroxide (440 mg). The mixture was stirred at room temperature for 1 h, and concentrated under reduced pressure. The residue was partitioned between water (10 mL) and chloroform (10 mL). The aqueous layer was acidified to pH 4 with 1 N hydrochloric acid and extracted with 3:1 chloroform/2-propanol (3×30 mL). The combined organic layers were dried (sodium sulfate), filtered, and concentrated under reduced pressure to provide 700 mg of the title compound: 1H NMR (300 MHz, CD3OD) δ 9.07, 8.33, 7.65, 4.77, 3.06.
Reaction SMILES: [Br-].[C:2]([CH2:4][CH2:5][CH2:6][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)#[N:3].CC([O-])(C)C.[K+].[CH2:32]([N:39]1[CH2:44][CH2:43][CH2:42][C:41](=O)[CH2:40]1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C1(C)C=CC=CC=1>[CH2:32]([N:39]1[CH2:44][CH2:43][CH2:42][C:41](=[CH:6][CH2:5][CH2:4][C:2]#[N:3])[CH2:40]1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: N#CCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1CCCN(Cc2ccccc2)C1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: N#CCCC=C1CCCN(Cc2ccccc2)C1
Reaction time: 8 h

Procedure:
77.3 g (188.3 mmol) 3-cyanopropyl-triphenylphosphonium bromide are suspended in 300 ml toluene and added to 22.0 g (191.9 mmol) potassium tert-butylate. The mixture is cooled to ca 0° C. under moisture exclusion and a solution of 34.6 g (182.8 mmol) 1-benzyl-3-piperidone in 50 ml toluene is added dropwise under cooling. The batch is left to stand overnight at ca. 0° C. and subsequently diluted with 200 ml toluene and washed twice, each with 100 ml water. The organic phase is extracted with 150 ml half concentrated hydrochloric acid. Subsequently, the aqueous phase is made basic with 200 ml 10% sodium hydroxide solution and extracted twice, each with 250 ml toluene.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[C:9]1([C:15]#[CH:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.O1CCCC1.Cl>[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.C(N(CC)CC)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:16]#[C:15][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: C#Cc1ccccc1
Reactant: Brc1ccc(I)cc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Brc1ccc(C#Cc2ccccc2)cc1

Procedure:
In a 500 mL three-necked flask were placed 14 g (51 mmol) of p-bromoiodobenzene, 5.2 g (52 mmol) of phenylacetylene, and 98 mg (0.50 mmol) of copper(I) iodide. After the atmosphere in the flask was replaced with nitrogen, 200 mL of tetrahydrofuran and 9.0 mL of triethylamine were added to the flask, and the mixture was degassed by being stirred under reduced pressure. To this mixture was added 0.34 mg (0.50 mmol) of bis(triphenylphosphine)palladium(II)dichloride, and the mixture was stirred under nitrogen stream at room temperature for 20 hours. After a predetermined time, a 3% aqueous hydrochloric acid solution was added to the mixture, and an organic substance was extracted with ethyl acetate from the aqueous layer. The obtained extract was washed with a saturated aqueous sodium chloride solution together with the organic layer and then dried over magnesium sulfate. The mixture was subjected to suction filtration through Celite (produced by Wako Pure Chemical Industries, Ltd., Catalog No. 531-16855), Florisil (produced by Wako Pure Chemical Industries, Ltd., Catalog No. 540-00135), and alumina, and the filtrate was condensed to obtain a solid. The obtained solid was recrystallized with hexane; thus, 7.4 g of target light-brown powder was obtained with a yield of 55%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11]2[NH:12][CH:13]=[C:14]([CH2:18][C:19]3[CH:20]=[N:21][C:22]([O:25][CH3:26])=[N:23][CH:24]=3)[C:15](=[O:17])[N:16]=2)[CH:5]=[CH:6][C:7]=1[F:8].[Cu][C:28]#[N:29]>CN1C(=O)CCC1>[F:8][C:7]1[CH:6]=[CH:5][C:4]([CH2:9][CH2:10][C:11]2[NH:12][CH:13]=[C:14]([CH2:18][C:19]3[CH:20]=[N:21][C:22]([O:25][CH3:26])=[N:23][CH:24]=3)[C:15](=[O:17])[N:16]=2)=[CH:3][C:2]=1[C:28]#[N:29]
Reactant: COc1ncc(Cc2c[nH]c(CCc3ccc(F)c(Br)c3)nc2=O)cn1
Reactant: N#C[Cu]
Solvent: CN1CCCC1=O
Product: COc1ncc(Cc2c[nH]c(CCc3ccc(F)c(C#N)c3)nc2=O)cn1
Temperature: 200 °C
Yield: 30.6 %

Procedure:
The mixture of 2-[2-(3-bromo-4-fluorophenyl)ethyl]-5-{[2-(methyloxy)-5-pyrimidinyl]methyl}-4(1H)-pyrimidinone (300 mg, 0.716 mmol) and copper(I) cyanide (77 mg, 0.859 mmol) in NMP (2 mL) was heated with a microwave reactor at 200° C. for 2 h. Purification via Biotage then afforded the title compound (80 mg, 30.6% yield). LCMS: rt=2.21 min, [M+H+]=366
Reaction SMILES: Cl.[NH2:2][C:3]12[CH2:10][CH2:9][C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])([CH2:7][CH2:8]1)[CH2:5][CH2:4]2.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Cl[CH2:25][C:26]([N:28]1[CH2:32][C@@H:31]([F:33])[CH2:30][C@H:29]1[C:34]([NH2:36])=[O:35])=[O:27]>O.CN(C)C=O>[CH2:14]([O:13][C:11]([C:6]12[CH2:5][CH2:4][C:3]([NH:2][CH2:25][C:26]([N:28]3[CH2:32][C@@H:31]([F:33])[CH2:30][C@H:29]3[C:34]([NH2:36])=[O:35])=[O:27])([CH2:10][CH2:9]1)[CH2:8][CH2:7]2)=[O:12])[CH3:15]
Reactant: NC(=O)[C@@H]1C[C@H](F)CN1C(=O)CCl
Reactant: CCOC(=O)C12CCC(N)(CC1)CC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C12CCC(NCC(=O)N3C[C@@H](F)C[C@H]3C(N)=O)(CC1)CC2
Temperature: 25 °C
Reaction time: 6 h
Yield: 73.8 %

Procedure:
Ethyl 4-aminobicyclo[2.2.2]octane-1-carboxylate hydrochloride (68.8 g), potassium carbonate (77.6 g), potassium iodide (46.6 g) and N,N-dimethylformamide (167 mL) were mixed, and (2S,4S)-1-(chloroacetyl)-4-fluoropyrrolidine-2-carboxamide (55.8 g) was added dropwise thereto for 6 hours, while stirring at room temperature. After further stirring at the same temperature for 1 hour, water (1400 mL) was added to the reaction solution, followed by stirring at an inner temperature of 10° C. or lower for 1 hour. The precipitate were collected by filtration, washed with cold water (279 mL) and then dried under a reduced pressure at an outer temperature of 60° C., thereby obtaining white crystals of (2S,4S)-1-[2-[(4-ethoxycarbonylbicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carboxamide (obtained amount: 72.9 g, yield: 74%).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([NH:8][CH2:9][CH2:10][C:11]#[N:12])[CH:5]=[CH:6][CH:7]=1.[CH:13]1([C:16](Cl)=[O:17])[CH2:15][CH2:14]1>C(Cl)Cl.C(N(CC)CC)C>[C:11]([CH2:10][CH2:9][N:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([I:1])[CH:3]=1)[C:16]([CH:13]1[CH2:15][CH2:14]1)=[O:17])#[N:12]
Reactant: N#CCCNc1cccc(I)c1
Reactant: O=C(Cl)C1CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#CCCN(C(=O)C1CC1)c1cccc(I)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.2 %

Procedure:
1.0 g of 3-(3-iodo-phenylamino)-propionitrile are dissolved in a mixture of 25 ml of methylene chloride and 0.45 ml of triethylamine and treated dropwise at 0° with a solution of 0.42 g of cyclopropanecarbonyl chloride in 5 ml of methylene chloride. The solution is stirred at room temperature for a further 2 hrs., then poured into ice-water and extracted three times with ethyl acetate. Concentration yields 1.19 g of crude cyclopropanecarboxylic acid (2-cyano-ethyl)-(3-iodo-phenyl)-amide which is used in Example 12av) without further purification. Yield: 95%.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]3[C:15]4[NH:16][C:17]5[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=5[C:14]=4[CH2:13][CH:12]4[C:23](=[O:29])[N:24]([CH3:28])[CH2:25][C:26](=[O:27])[N:11]34)=[CH:9][C:4]=2[CH2:3][CH2:2]1.CC([O-:34])(C)C.[K+].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CO.C(Cl)Cl>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]3[C:15]4[NH:16][C:17]5[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=5[C:14](=[O:34])[C:13]=4[CH:12]4[N:11]3[C:26](=[O:27])[CH2:25][N:24]([CH3:28])[C:23]4=[O:29])=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: CC(C)(C)[O-]
Reactant: CN1CC(=O)N2C(Cc3c([nH]c4ccccc34)C2c2ccc3c(c2)CCO3)C1=O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CN1CC(=O)N2C(C1=O)c1c([nH]c3ccccc3c1=O)C2c1ccc2c(c1)CCO2
Reaction time: 3 h

Procedure:
6-(2,3-Dihydro-benzofuran-5-yl)-2-methyl-2,3,6,7,12,12a-hexahydro pyrazino[1′,2′:1,6]pyrido[3,4-b]indole-1,4-dione (39.6 mg, 0.1019 mmol), prepared according to Example 1 or 2 as described in WO97/03675, was dissolved in DMF (1.0 mL). To the solution was added KOt-Bu (0.173 mL, 1.0 M in THF). The solution was stirred under air (passed through drying tube) for 3 hours. Additional KOt-Bu (0.15 mL, 1.0 M in THF) was added and the reaction mixture stirred for another 3 hours under dry air. The reaction mixture was quenched by HCl (0.323 mL, 1.0 M HCl in ether) and the ether solvent evaporated. PyBrOP (53 mg, 0.1019 mmol) and DIPEA (0.036 mL, 0.204 mmol) were added, then DMF (0.2 mL) was added to make the total volume 1 mL. The resulting mixture was stirred at room temperature for 16 hours. Preparative TLC (1% CH3OH/CH2Cl2) yield the title product as a yellow solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8](F)=[C:9]([O:12][CH2:13][CH2:14][O:15][CH3:16])[CH:10]=2)[CH:5]=[C:4]([NH:18][C:19]2[CH:23]=[C:22]([CH3:24])[NH:21][N:20]=2)[N:3]=1.[CH3:25][CH:26]([OH:28])[CH3:27]>>[CH:26]([O:28][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH:9]([CH3:10])[CH3:8])=[C:9]([O:12][CH2:13][CH2:14][O:15][CH3:16])[CH:10]=2)[CH:5]=[C:4]([NH:18][C:19]2[CH:23]=[C:22]([CH3:24])[NH:21][N:20]=2)[N:3]=1)([CH3:27])[CH3:25]
Reactant: CC(C)O
Reactant: COCCOc1cc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2cc1F
Product: COCCOc1cc2c(OC(C)C)nc(Nc3cc(C)[nH]n3)cc2cc1OC(C)C

Procedure:
Similar procedure as described in example 10 was used, starting from [1-Chloro-6-fluoro-7-(2-methoxy-ethoxy)-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine and 2-propanol to give [1,6-Diisopropoxy-7-(2-methoxy-ethoxy)-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 415(MH+).
Reaction SMILES: [CH:1]([OH:3])=[O:2].[NH2:4][C:5]1[C:10]([NH:11][C:12](=[O:15])[O:13][CH3:14])=[C:9]([NH2:16])[N:8]=[C:7]([C:17]2[N:18]=[C:19]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[F:33])[N:20]3[C:25]=2[CH:24]=[CH:23][CH:22]=[N:21]3)[N:6]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:44](Br)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>C1COCC1>[CH:1]([OH:3])=[O:2].[CH2:44]([N:11]([C:10]1[C:5]([NH2:4])=[N:6][C:7]([C:17]2[N:18]=[C:19]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[F:33])[N:20]3[C:25]=2[CH:24]=[CH:23][CH:22]=[N:21]3)=[N:8][C:9]=1[NH2:16])[C:12](=[O:15])[O:13][CH3:14])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)Nc1c(N)nc(-c2nc(Cc3ccccc3F)n3ncccc23)nc1N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O=CO
Product: COC(=O)N(Cc1ccccc1)c1c(N)nc(-c2nc(Cc3ccccc3F)n3ncccc23)nc1N
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
At 0° C., 100 mg (0.22 mmol) of methyl {4,6-diamino-2-[7-(2-fluorobenzyl)imidazo[1,5-b]pyridazin-5-yl]pyrimidin-5-yl}carbamate formate were initially charged in THF (0.94 ml), and 44.4 mg (0.24 mmol) of a 2 N solution of sodium bis(trimethylsilyl)amide in THF were added. After 30 min at 0° C., 52 μl (0.44 mmol) of benzyl bromide were added and the mixture was stirred at 20° C. for 20 hours. The reaction mixture was then concentrated and the residue was purified by preparative HPLC (acetonitrile/water (+0.1% formic acid) gradient). This gave 105 mg of the target compound (87% of theory).