Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:24]I>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])[CH3:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccccc2Cl)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(c1ccccc1Cl)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 45 °C
Reaction time: 0.5 h
Yield: 46.5 %

Procedure:
To a solution of 4-(2-chloro-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester (0.166 g, 0.00053 mole), in DMF (10 mL) was added, NaH (60% w/w dispersion in oil) (0.0512 g, 0.0021 mole) and the resulting mixture was stirred at ambient temperature for 10 minutes under an atmosphere of nitrogen. Methyl iodide (0.303 g, 0.0021 mole) was then added, and the stirring was continued for 30 minutes at ambient temperature. The reaction mixture was heated to 45° C. for 30 minutes. The reaction mixture was then quenched with aqueous 10% NH4Cl solution and the product was extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous NaHCO3 solution followed by brine solution. The organic layer was collected, dried over sodium sulfate and concentrated under reduced pressure to afford 0.08 g (46%) of 4-[(2-chloro-phenyl)-methyl-amino]-piperidine-1-carboxylic acid tert-butyl ester. 1H NMR (CDCl3): δ 7.6-7.54 (m, 1H), 7.28-7.2 (m, 1H), 7.14-7.08 (m, 1H), 6.96-6.88 (m, 1H), 4.2-4.0 (m, 2H), 3.3-3.2 (m, 1H), 2.8-2.7 (m, 2H), 2.7 (s, 3H), 1.7-1.6 (m, 2H), 1.6 (m, 1H), 1.45 (s, 9H). A solution of 4-(2-chloro-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester (0.078 g, 0.00024 mole) in dioxane.HCl (1 mL) was stirred for 30 minutes. The reaction mixture was then concentrated under reduced pressure to afford 0.072 g (99%) of (2-chloro-phenyl)-methyl-piperidin-4-yl-amine hydrochloride which was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[CH:12][NH:13]3)[CH:5]=[C:6]([F:8])[CH:7]=1.C([OH:20])C.C(O)(=O)C.[Br-].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>CC(O)(C)C.[Zn]>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:20])[NH:13]3)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CCO
Reactant: Fc1cc(F)cc(-c2cccc3[nH]ccc23)c1
Agent: [Br-]
Agent: [Zn]
Agent: c1cc[nH+]cc1
Solvent: CC(C)(C)O
Solvent: CC(=O)O
Product: O=C1Cc2c(cccc2-c2cc(F)cc(F)c2)N1
Temperature: 25 °C
Reaction time: 3 h
Yield: 68 %

Procedure:
To the suspension of 4-(3,5-difluoro-phenyl)-1H-indole (13.52 g, 59 mmol) in t-BuOH:ethanol:acetic acid (375 mL:225 mL:115 mL) was added pyridinium tribromide (57 g, 177 mmol) portionwise. The mixture was stirred at room temperature for 3 hours, and then to the mixture was added with acetic acid (286 mL). Zinc dust (19.25 g, 295 mmol) was added to the reaction mixture portionwise. After stirring for one hour, any unreacted zinc was filtered off and most of the solvent was removed under reduced pressure. The residue was diluted with ethyl acetate, washed with water (5×), neutralized with 1N HCl, washed with sat. NaHCO3, brine, dried over Na2SO4, concentrated and triturated with ether to give 9.88 g (68%) of 4-(3,5-difluoro-phenyl)-1,3-dihydro-indol-2-one.
Reaction SMILES: [CH3:1][N:2]1[CH2:5][CH:4]([NH2:6])[CH2:3]1.C(N(CC)CC)C.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][C:24]=1[N+:25]([O-:27])=[O:26])[C:19](Cl)=[O:20]>C(Cl)Cl>[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][C:24]=1[N+:25]([O-:27])=[O:26])[C:19]([NH:6][CH:4]1[CH2:5][N:2]([CH3:1])[CH2:3]1)=[O:20]
Reactant: COc1cc(C(=O)Cl)ccc1[N+](=O)[O-]
Reactant: CN1CC(N)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(C(=O)NC2CN(C)C2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 46.4 %

Procedure:
To a solution of 1-methylazetidin-3-amine (1 equiv) in dry DCM (0.13 M) was added triethylamine (1.8 equiv). A solution of 3-methoxy-4-nitrobenzoyl chloride (0.91 equiv) in dry DCM was added and the reaction was stirred at room temperature for 5 min. The mixture was then concentrated and purified by silica gel chromatography (5% MeOH in DCM) to afford the title compound (46.4% yield) as a yellow solid. MS (ESI) m/z 266.1 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[S:7][C:6]([N:8]2[CH:13]([OH:14])[CH2:12][CH2:11][N:10]([CH3:15])[C:9]2=[O:16])=[N:5][N:4]=1.[CH3:19][N:20]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30][Cl:31])[CH:25]=1)[C:21](Cl)=[O:22].N1C=CC=CC=1>C1(C)C=CC=CC=1>[F:18][C:2]([F:1])([F:17])[C:3]1[S:7][C:6]([N:8]2[CH:13]([O:14][C:21](=[O:22])[N:20]([CH3:19])[C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30][Cl:31])[CH:25]=3)[CH2:12][CH2:11][N:10]([CH3:15])[C:9]2=[O:16])=[N:5][N:4]=1
Reactant: CN1CCC(O)N(c2nnc(C(F)(F)F)s2)C1=O
Reactant: CN(C(=O)Cl)c1cccc(CCl)c1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CN1CCC(OC(=O)N(C)c2cccc(CCl)c2)N(c2nnc(C(F)(F)F)s2)C1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Tetrahydro-1-(5-trifluoromethyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-hydroxy-2(1H)-pyrimidinone (0.05 mole), N-methyl-N-(3-chloromethylphenyl)carbamoyl chloride (0.06 mole), pyridine (0.06 mole) and toluene (150 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated at reflux with stirring for a period of about 3 hours. After this time the reaction mixture is cooled to room temperature and is filtered to remove pyridine hydrochloride. The filtrate is then washed with water, dried over anhydrous magnesium sulfate and stripped of solvent leaving a residue. The residue is recrysallized to yield the desired product tetrahydro-1-(5-trifluoromethyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-[N-methyl-N-(3-chloromethylphenyl)carbamoyloxy]-2(1H)-pyrimidinone.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[F:11].CCN=C=NCCCN(C)C.[NH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1.O>ClCCl.CN(C1C=CN=CC=1)C>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[O:8])=[CH:4][C:3]=1[F:11]
Reactant: C1COCCN1
Reactant: O=C(O)c1ccc(Br)c(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Product: O=C(c1ccc(Br)c(F)c1)N1CCOCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 65.5 %

Procedure:
To a room temperature solution containing 10 g of 4-bromo-3-fluorobenzoic acid (45.7 mmols) in 228 mL of dichloromethane was added 1.67 g of DMAP (13.7 mmols), 11.3 g of EDCI (59.2 mmols), and 5.11 mL of morpholine (59.4 mmols). After stirring at ambient temperature for 18 h, 20 mL of water was added to the reaction mixture. The layers were separated, and the organic layer was washed with water (3×20 mL), dried over MgSO4, and filtered through a frit. The resulting solution was concentrated to a pale yellow oil which was purified by silica gel chromatography (120 g redisep column, silica 40 um, 60 A, 85 ml/min, A: EtOAc, B: hexanes, A: 50% for 5 min, then 50-70% for 8 min) to give 8.62 g (66%) of title compound as a yellow oil. MS (ES) m/e 288 [M+]+.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH2:5].[CH3:7][N:8]1[C:16]2[CH:15]=[CH:14][C:13](OS(C3C=CC(C)=CC=3)(=O)=O)=[C:12]3[C:28](=[O:35])[C:29]4[CH:30]=[CH:31][N:32]=[CH:33][C:34]=4[C:10]([C:11]=23)=[N:9]1>N1C=CC=CC=1>[CH3:7][N:8]1[C:16]2[CH:15]=[CH:14][C:13]([NH:5][CH2:4][CH2:3][N:2]([CH3:6])[CH3:1])=[C:12]3[C:28](=[O:35])[C:29]4[CH:30]=[CH:31][N:32]=[CH:33][C:34]=4[C:10]([C:11]=23)=[N:9]1
Reactant: CN(C)CCN
Reactant: Cc1ccc(S(=O)(=O)Oc2ccc3c4c(nn3C)-c3cnccc3C(=O)c24)cc1
Solvent: c1ccncc1
Product: CN(C)CCNc1ccc2c3c(nn2C)-c2cnccc2C(=O)c13
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 1M solution of N,N-dimethylethylenediamine in pyridine (0.10 mL) is added to a stirred suspension of 2-methyl-5-(p-toluenesulfonyloxy)isoquino[8,7,6-cd]indazole-6(2H)-one of Example 1 (0.02 g) in dry pyridine (2 mL). After stirring at room temperature for one hour the reaction mixture is heated at 70° C. for 13 hours while additional amounts of N,N-dimethylethylenediamine solution (0.1; 0.05; 0.05 mL) are added after 2, 4 and 11 hours respectively. Pyridine and excess N,N-dimethylethylenediamine are removed by distillation at reduced pressure and the obtained residue is partitioned between CH2Cl2 (50 mL) and brine (10 mL) to which NaHCO3 saturated solution is added (1 mL). The organic solution is dried over anhydrous Na2SO4 and the solvent removed by distillation. The orange residue obtained is purified by silica-gel column chromatography (eluant: CHCl3 /MeOH 95/5 (30 mL) followed by CHCl3 /MeOH/NH4OH 90/15/0.5 (50 mL) to give 2-methyl-5-[[2-(dimethylamino)ethyl]amino]isoquino[8,7,6-cd]indazole-6(2H)-one (0.011 g) as a reddish orange solid.
Reaction SMILES: C(O[CH:4]=[N:5][C:6]1[S:17][C:9]2[CH2:10][N:11]([C:14](=[O:16])[CH3:15])[CH2:12][CH2:13][C:8]=2[C:7]=1[C:18]([O:20]CC)=O)C.[NH2:23][CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][N:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[O:38][CH3:39])[CH2:28][CH2:27]1>C(O)C>[C:14]([N:11]1[CH2:12][CH2:13][C:8]2[C:7]3[C:18](=[O:20])[N:23]([CH2:24][CH2:25][N:26]4[CH2:27][CH2:28][N:29]([C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=5[O:38][CH3:39])[CH2:30][CH2:31]4)[CH:4]=[N:5][C:6]=3[S:17][C:9]=2[CH2:10]1)(=[O:16])[CH3:15]
Reactant: CCOC=Nc1sc2c(c1C(=O)OCC)CCN(C(C)=O)C2
Reactant: COc1ccccc1N1CCN(CCN)CC1
Solvent: CCO
Product: COc1ccccc1N1CCN(CCn2cnc3sc4c(c3c2=O)CCN(C(C)=O)C4)CC1
Yield: 79.5 %

Procedure:
5.8 g (23.4 mmol) of 2-ethoxymethyleneamino-3-carboethoxy-6-acetyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine in 50 ml of ethanol were mixed with 5.5 g (23.4 mmol) of 1-(2-aminoethyl)-4-(2-methoxyphenyl)piperazine and refluxed for 2 h. The mixture was then concentrated in a rotary evaporator, and the residue was taken up in 30 ml of ethyl acetate, heated to boiling and left to cool with stirring. The solid which crystallized out was filtered off with suction after cooling in an ice bath and was washed with ethyl acetate. 8.7 g (80%) of product with melting point 170-172° C. were isolated.
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[NH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19].CCN(C(C)C)C(C)C>CCO>[CH3:7][N:6]1[C:2]([NH:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[C:3]([N+:8]([O-:10])=[O:9])[CH:4]=[N:5]1
Reactant: CC(C)(C)OC(=O)NCCCN
Reactant: Cn1ncc([N+](=O)[O-])c1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cn1ncc([N+](=O)[O-])c1NCCCNC(=O)OC(C)(C)C
Temperature: 130 °C
Yield: 86.9 %

Procedure:
A mixture of 5-chloro-1-methyl-4-nitro-1H-pyrazole (0.81 g, 5 mmol), tert-butyl 3-aminopropylcarbamate (0.85 g, 4.88 mmol) and DIPEA (1.8 mL, 10.5 mmol) in EtOH (5 mL) was heated at 130° C. in the microwave for 90 min. On cooling the reaction mixture was concentrated under reduced pressure and the residue purified via silica gel column chromatography (0-100% EtOAc/isohexane) to afford tert-butyl 3-(1-methyl-4-nitro-1H-pyrazol-5-ylamino)propylcarbamate as a yellow gum (1.27 g, 85%). A mixture of this gum (0.3 g, 1 mmol), K2CO3 (0.41 g, 3 mmol) and methyl iodide (0.1 mL, 1.58 mmol) in DMF (5 mL) was stirred at 60° C. for 18 hr. More methyl iodide (0.1 mL, 1.58 mmol) was added and stirring at 60° C. was continued for 24 hr. The reaction mixture was cooled and concentrated under reduced pressure. The residue was triturated in DCM (100 mL), filtered and the filtrate concentrated under reduced pressure. Purification via silica gel column chromatography (0-100% EtOAc/isohexane) gave tert-butyl 3-(methyl(1-methyl-4-nitro-1H-pyrazol-5-yl)amino)propylcarbamate as a pale yellow gum (0.122 g, 38%). 1H-NMR (400 MHz, CDCl3) δ 8.03 (s, 1H), 4.60 (s, 1H), 3.77 (s, 3H), 3.20-3.14 (m, 4H), 2.86 (s, 3H), 1.72-1.61 (m, 2H), 1.42 (s, 9H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH2:16][O:17][CH3:18])[C:11]([N:19]2[CH:23]=[CH:22][CH:21]=[CH:20]2)=[CH:10][C:9]=1[NH2:24])([CH3:4])([CH3:3])[CH3:2].CC1(C)[O:32][C:31]([C:33]2[CH:34]=[C:35]([CH:38]=[CH:39][CH:40]=2)[C:36]#[N:37])=[CH:30][C:29](=O)[O:28]1>>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH2:16][O:17][CH3:18])[C:11]([N:19]2[CH:23]=[CH:22][CH:21]=[CH:20]2)=[CH:10][C:9]=1[NH:24][C:29](=[O:28])[CH2:30][C:31]([C:33]1[CH:40]=[CH:39][CH:38]=[C:35]([C:36]#[N:37])[CH:34]=1)=[O:32])([CH3:4])([CH3:2])[CH3:3]
Reactant: COCCOc1cc(NC(=O)OC(C)(C)C)c(N)cc1-n1cccc1
Reactant: CC1(C)OC(=O)C=C(c2cccc(C#N)c2)O1
Product: COCCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(C#N)c2)cc1-n1cccc1

Procedure:
The title compound was prepared from [2-amino-5-(2-methoxy-ethoxy)-4-pyrrol-1-yl-phenyl]-carbamic acid tert.-butyl ester (Example J3) (186 mg, 0.54 mmol) and 3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example L1) (153 mg, 0.67 mmol) according to the general procedure M. Obtained as a beige solid (179 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([Cl:18])[CH:9]=2)[C:5]([CH3:19])=[CH:4][N:3]=1.[CH3:20][N:21]1[CH2:26][CH2:25][N:24]([CH2:27][C:28]2[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=2)[CH2:23][CH2:22]1>C(Cl)Cl.CO>[Cl:18][C:10]1[CH:9]=[C:8]([C:6]2[C:5]([CH3:19])=[CH:4][N:3]=[C:2]([NH:32][C:31]3[CH:30]=[CH:29][C:28]([CH2:27][N:24]4[CH2:23][CH2:22][N:21]([CH3:20])[CH2:26][CH2:25]4)=[CH:34][CH:33]=3)[N:7]=2)[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=1
Reactant: CN1CCN(Cc2ccc(N)cc2)CC1
Reactant: Cc1cnc(Cl)nc1-c1cc(Cl)cc(C(F)(F)F)c1
Solvent: CO
Solvent: ClCCl
Product: Cc1cnc(Nc2ccc(CN3CCN(C)CC3)cc2)nc1-c1cc(Cl)cc(C(F)(F)F)c1
Yield: 76 %

Procedure:
The title compound was prepared according to synthesis procedure B described above from 2-chloro-4-(3-chloro-5-(trifluoromethyl)phenyl)-5-methylpyrimidine and 4-((4-methylpiperazin-1-yl)methyl)aniline in 76% yield (yellow solid) after flash chromatography (CH2Cl2/CH3OH 99:1 gradually increasing to 95:5). 1H NMR (400 MHz, CDCl3): δ 8.35 (s, 1H), 7.79 (d, 2H, J=7.8 Hz), 7.69 (s, 1H), 7.55 (d, 2H, J=8.2 Hz), 7.26 (d, 2H, J=8.6 Hz), 3.47 (s, 2H), 2.50 (bs, 8H), 2.31 (s, 3H), 2.25 (s, 3H); MS (ESI): 476.3 [M+H]+, 238.7 [M+2H]2+.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:13][OH:14])[CH:10]=2)[NH:5][CH2:4][CH2:3]1.[CH:21](=O)[CH3:22].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C(Cl)Cl>[CH2:21]([N:5]1[C:6]2[C:11](=[CH:10][C:9]([CH:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:13][OH:14])=[CH:8][CH:7]=2)[C:2]([CH3:20])([CH3:1])[CH2:3][CH2:4]1)[CH3:22]
Reactant: CC=O
Reactant: CCCCCC(CO)c1ccc2c(c1)C(C)(C)CCN2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCCCCC(CO)c1ccc2c(c1)C(C)(C)CCN2CC
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1.5 g of (RS)-2-(4,4-dimethyl-1,2,3,4-tetrahydroquinolin-6-yl)-heptanol, dissolved in 25 ml of methylene chloride, were treated at 0° C. with 0.46 ml of acetaldehyde and 3.46 g of sodium triacetoxyborohydride, then 0.62 ml of acetic acid was added. The mixture was stirred at room temperature for 18 hours. The reaction mixture was quenched with the addition of one portion of 25 ml of water and then, was extracted with two portions of 25 ml of methylene chloride. The combined organic phases were dried over MgSO4 and concentrated in vacuo. The product was purified by flash chromatography (SiO2, 25% ethyl acetate/hexanes). 1H NMR (CDCl3): 6.98 (d, J=2.2 Hz, 1H), 6.85 (dd, J=8.4, 2.2 Hz, 1H), 6.56 (d, J=8.4 Hz, 1H), 3.75-3.55 (m, 2H), 3.33 (q, J=7.1 Hz, 2H), 3.30-3.20 (m, 2H), 2.70-2.55 (m, 1H), 1.80-1.70 (m, 2H), 1.70-1.45 (m, 2H), 1.45-1.20 (m, 6H), 1.26 (s, 6H), 1.14 (t, J=7.1 Hz, 3H), 0.84 (t, J=6.5 Hz, 3H).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[CH:10]=[CH:9][N:8]([C:11]3[CH:16]=[C:15]([F:17])[C:14]([CH2:18][N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[C:13]([F:25])[CH:12]=3)[C:6]=2[N:7]=1.[NH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([N:35]2[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]2)=[O:34])=[CH:29][CH:28]=1.CC([O-])(C)C.[K+]>C1COCC1>[F:25][C:13]1[CH:12]=[C:11]([N:8]2[C:6]3[N:7]=[C:2]([NH:26][C:27]4[CH:28]=[CH:29][C:30]([C:33]([N:35]5[CH2:36][CH2:37][N:38]([CH3:41])[CH2:39][CH2:40]5)=[O:34])=[CH:31][CH:32]=4)[N:3]=[CH:4][C:5]=3[CH:10]=[CH:9]2)[CH:16]=[C:15]([F:17])[C:14]=1[CH2:18][N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1
Reactant: CN1CCN(C(=O)c2ccc(N)cc2)CC1
Reactant: Fc1cc(-n2ccc3cnc(Cl)nc32)cc(F)c1CN1CCOCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CN1CCN(C(=O)c2ccc(Nc3ncc4ccn(-c5cc(F)c(CN6CCOCC6)c(F)c5)c4n3)cc2)CC1
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
In a sealed tube, 2-chloro-7-(3,5-difluoro-4-morpholin-4-ylmethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidine (50.0 mg, 0.130 mmol), (4-Amino-phenyl)-(4-methyl-piperazin-1-yl)-methanone (42.1 mg, 0.182 mmol), KOtBu (21.1 mg, 0.182 mmol) and SK-CC02-A (12.5 mg, 0.020 mmol, Pd catalyst 2-(Dimethylaminomethyl)-ferrocen-1-yl-palladium(II)-chlorid Dinorbornylphosphin Complex, Fluka No. 44696) are suspended in THF (2 ml) under Ar. The reaction mixture is stirred at 80° C. for 1.5 h, cooled to rt, and then filtered through a Celite plug. The filtrate is concentrated under reduce pressure. The residue is purified by reverse phase prep-HPLC (Waters) to afford the title compound (2) as a white solid. HPLC: tR=0.89 min (Method A); MS-ES: (M+H)+=548.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[CH3:11][N:12]([CH3:16])[CH2:13][CH2:14][OH:15].C(N(CC)CC)C>C(Cl)Cl>[C:2](=[O:3])([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[O:15][CH2:14][CH2:13][N:12]([CH3:16])[CH3:11]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CN(C)CCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)CCOC(=O)Oc1ccccc1
Reaction time: 0.5 h

Procedure:
A 391 mg (2.5 mmole) portion of phenyl chloroformate was added dropwise to a solution of 223 mg (2.5 mmole) of N,N-dimethylethanolamine and 253 mg (2.5 mmole) of triethylamine in 5 ml of methylene chloride under ice-cooling with stirring, followed by stirring further under ice-cooling for 10 minutes and then at room temperature for 30 minutes. The reaction solution was diluted with methylene chloride, and the solution was washed with 1% aqueous sodium hydrogencarbonate solution and dried over sodium sulfate. The solvent was distilled off, and there was obtained 465 mg of the crude 2-dimethylaminoethyl phenyl carbonate in the form of a colorless oil. 880 mg (2.2 mmole) of the compound as obtained in Example 80 was added to the compound, followed by warming at 90° C. for 2 hours. The reaction solution was subjected to separation and purification by chromatography on a column of silica gel (40 g). After impurities were removed with n-hexane-ethyl acetate (1:4) as an eluent, there was obtained the objective compound in the form of a colorless powder from the eluate of chloroform-methanol (10:1). Yield of 800 mg (71%).
Reaction SMILES: C([Li])CCC.CC1(C)CCCC(C)(C)N1.[CH3:16][O:17][C:18]1[N:19]=[N:20][C:21]([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)=[CH:22][CH:23]=1.[I:30]I>CCCCCC.C1COCC1>[I:30][C:23]1[CH:22]=[C:21]([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)[N:20]=[N:19][C:18]=1[O:17][CH3:16]
Reactant: II
Reactant: COc1ccc(-c2ccncc2)nn1
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1nnc(-c2ccncc2)cc1I
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 76.9 %

Procedure:
45 ml 1.6M solution of n-Butyllithium in hexane are added at −30° C. to a 10.2 g 2,2,6,6-tetramethylpiperidine in 100 ml THF, and the mixture is stirred at 0° C. for 30 min. After cooling to −75° C., 11.2 g 3-Methoxy-6-pyridin-4-yl-pyridazine dissolved 300 ml THF are added, and the solution is stirred at −75° C. for 35 min. The cold (−75° C.) reaction mixture is subsequently added to a cold (−75° C.) solution of 18.3 g iodine in 400 ml THF and stirred at −75° C. for 1.5 h. The reaction is quenched by adding 80 ml methanol/THF (1:1) at −75° C. and 300 ml saturated aqueous NaHCO3 at room temperature and extracted with dichloromethane. The organic layer is washed with 5% aqueous Na2S2O3 and saturated sodium chloride solution, dried (MgSO4) and the solvent removed. The crude product is purified by chromatography on silica gel to yield 14.4 g of 4-Iodo-3-methoxy-6-pyridin-4-yl-pyridazine.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[CH:43]=[CH:42][C:19]([CH2:20][CH:21]([C:32]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:33])[C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])=[CH:18][CH:17]=1.[H-].[Na+].Br[CH2:47][C:48]([O:50][CH2:51][CH3:52])=[O:49].S([O-])(O)(=O)=O.[Na+]>O1CCCC1.O>[CH2:51]([O:50][C:48]([CH2:47][C:21]([CH2:20][C:19]1[CH:42]=[CH:43][C:16]([O:15][CH2:14][CH2:13][C:3]2[N:4]=[C:5]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[O:6][C:2]=2[CH3:1])=[CH:17][CH:18]=1)([C:32]([O:34][CH2:35][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)=[O:33])[C:22]([O:24][CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:23])=[O:49])[CH3:52]
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CC(C(=O)OCc2ccccc2)C(=O)OCc2ccccc2)cc1
Reactant: CCOC(=O)CBr
Agent: O=S(=O)([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)CC(Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1)(C(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 101 %

Procedure:
Dibenzyl 2-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzyl]malonate (26.0 g, 45.2 mmol) synthesized according to the method described in WO95/18125 was dissolved in tetrahydrofuran (250 ml), and sodium hydride (60% in oil, 2.2 g, 54.2 mmol) was added at 0° C., which was followed by stirring at room temperature for 30 min. To the reaction mixture was added a solution of ethyl bromoacetate (15.3 ml, 135.6 mmol) in tetrahydrofuran (50 ml) at room temperature. After stirring for 1 hr, sodium hydride (60% in oil, 1.1 g, 27.1 mmol) and ethyl bromoacetate (5.1 ml, 45.2 mmol) were added. After stirring for 1 hr, sodium hydride (60% in oil, 2.2 g, 54.2 mmol) was added and the mixture was stirred for 1 hr. Water and 1N aqueous sodium hydrogensulfate solution were added to the reaction mixture and extracted three times with ethyl acetate (200 ml). The extracted organic layers were combined, washed with brine, dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (developing solvent; hexane:ethyl acetate=5:1→3:1) to give the title compound (30.2 g, yield 100%) as an oil.
Reaction SMILES: C(OC[O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH:13](C)C)=[C:8]([O:16]COCC)[C:7]=1C)C.Cl.O>CO>[CH3:13][O:12][C:9]1[CH:10]=[CH:11][C:6]([OH:5])=[CH:7][C:8]=1[OH:16]
Reactant: CCOCOc1ccc(OC(C)C)c(OCOCC)c1C
Agent: Cl
Solvent: CO
Solvent: O
Product: COc1ccc(O)cc1O
Yield: 127.9 %

Procedure:
A solution of 5c (157 mg, 0.53 mmol) in MeOH (4.40 mL) at room temperature was treated dropwise with 3 M HCl (1.40 mL, 4.21 mmol), then heated to reflux for one hour. Water (5 mL) was added and the solution was extracted with EtOAc (3×10 mL). Combined organic fractions were washed with saturated aqueous NaCl, dried (Na2SO4), filtered, and concentrated to afford 6c as a red amorphous solid (95 mg, 99%): 1H NMR (CDCl3, 500 MHz) δ 6.54 (d, J=8.7 Hz, 1H), 6.21 (d, J=8.7 Hz, 1H), 5.78 (s, 1H), 4.37-4.32 (m, 1H), 2.09 (s, 3H), 1.25 (d, J=6.1 Hz, 6H); 13C NMR (CDCl3, 125 MHz) δ 147.7, 144.9, 137.5, 110.8, 109.8, 104.0, 71.7, 21.3 (2C); IR (film) νmax 3526, 2974, 2924, 2853, 1717, 1607, 1475, 1238, 1113, 1067, 928, 887, 791 cm−1.