Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]#[N:12])([CH3:3])[CH3:2].Cl.[C:14]1([NH2:24])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1>ClC1C=CC=CC=1.NC1C2C(=CC=CC=2)C=CC=1>[C:14]1([NH:24][C:11]([NH:10][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:1]([CH3:3])[CH3:2])=[NH:12])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)c1ccccc1NC#N
Reactant: Nc1cccc2ccccc12
Agent: Cl
Solvent: Clc1ccccc1
Product: CC(C)c1ccccc1NC(=N)Nc1cccc2ccccc12
Yield: 44 %

Procedure:
A solution of o-isopropylphenylcyanamide (1.13 g, 7.05 mmol), 1-naphthylamine hydrochloride (1.1 g, 7.04 mmol) and 1-aminonaphthalene (14.38 mg, 0.1 mmol) in chlorobenzene (20 ml) was heated to 150° C. for 4 hours and at room temperature for 10 hours. It was concentrated and the residue was partitioned between dichloromethane and 10% NaOH solution. The organic layer was concentrated and the resulting solid was recrystallized from EtOH-H2O (10:1) to give N-(1-naphthyl)-N'-(o-isopropylphenyl)guanidine (940 mg, 44%) as white crystals. mp 175°-177° C.
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[C:10]([CH2:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:11][N:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][N:15]=3)[CH:13]=2)O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]([N:41]([CH3:49])[CH2:42][CH2:43][C:44]([O:46]CC)=[O:45])=[O:40])=[CH:35][CH:34]=1>>[CH:1]1([CH:7]([NH:32][C:33]2[CH:34]=[CH:35][C:36]([C:39]([N:41]([CH3:49])[CH2:42][CH2:43][C:44]([OH:46])=[O:45])=[O:40])=[CH:37][CH:38]=2)[C:9]2[C:10]([CH2:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:11][N:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:22])([F:21])[F:23])=[CH:16][N:15]=3)[CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(N)cc1
Reactant: OC(c1cn(-c2ccc(C(F)(F)F)cn2)nc1CCc1ccccc1)C1CCCCC1
Product: CN(CCC(=O)O)C(=O)c1ccc(NC(c2cn(-c3ccc(C(F)(F)F)cn3)nc2CCc2ccccc2)C2CCCCC2)cc1
Yield: 40.7 %

Procedure:
Using cyclohexyl{3-(2-phenylethyl)-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazol-4-yl}methanol (0.50 g) synthesized in Example 11(3) and ethyl 3-{[(4-aminophenyl)carbonyl](methyl)amino}propanoate (0.35 g) synthesized in Example 2(2) and in the same manner as in Example 1(7), the title object compound (0.30 g, 41%) was obtained as a white solid.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=[C:4]([CH3:11])[N:3]=1.[NH2:12][C:13]1[NH:17][N:16]=[C:15]([CH3:18])[CH:14]=1>CO>[CH3:18][C:15]1[CH:14]=[C:13]2[NH:12][C:2]3[N:3]=[C:4]([CH3:11])[CH:5]=[CH:6][C:7]=3[C:8](=[O:10])[N:17]2[N:16]=1
Reactant: Cc1cc(N)[nH]n1
Reactant: Cc1ccc(C(=O)O)c(Cl)n1
Solvent: CO
Product: Cc1ccc2c(=O)n3nc(C)cc3[nH]c2n1
Temperature: 25 °C

Procedure:
17.1 g. of 2-chloro-6-methylpyridine-3-carboxylic acid and 19.4 g. of 5-amino-3-methylpyrazole are heated together for 10 minutes at 180°-190°. The mixture is cooled to room temperature and treated with methanol. The crystalline 2,6-dimethylpyrazolo[1,5-a]pyrido[2,3-d]pyrimidin-9(4H)-one is filtered off and recrystallized from dimethylformamide, yield: 13.5 g. (64%); m.p. >300°.
Reaction SMILES: [CH3:1][N:2]1[CH2:21][CH2:20][C:5]2[N:6]([CH2:14][C:15]([O:17]CC)=O)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[NH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1>>[CH3:1][N:2]1[CH2:3][CH2:4][C:5]2[N:6]([CH2:14][C:15]([N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[O:17])[C:7]3[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:8]=3[C:20]=2[CH2:21]1
Reactant: C1CCNC1
Reactant: CCOC(=O)Cn1c2c(c3cc(C)ccc31)CN(C)CC2
Product: Cc1ccc2c(c1)c1c(n2CC(=O)N2CCCC2)CCN(C)C1
Temperature: 100 °C

Procedure:
A mixture of ethyl 2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)acetate (100 mg) and pyrrolidine (1 ml) was heated at 100° C. for 15 h to obtain 60 mg of 2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)-1-(pyrrolidin-1-yl)ethanone as off white solid after purification by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min, injection vol. 5 mL).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:12])=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[NH2:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[N:26]=[C:25]([CH3:30])[C:24]([CH3:31])=[N:23]2.C([O-])(O)=O.[Na+]>ClCCl>[Cl:1][C:2]1[C:3]([CH3:12])=[C:4]([S:8]([NH:19][C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[N:26]=[C:25]([CH3:30])[C:24]([CH3:31])=[N:23]3)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Reactant: Cc1nc2ccc(N)cc2nc1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1nc2ccc(NS(=O)(=O)c3cccc(Cl)c3C)cc2nc1C
Reaction time: 0.08 h
Yield: 91.3 %

Procedure:
To a solution of 3-chloro-2-methylbenzenesulphonyl chloride (109 mg, 0.485 mmol) in dichloromethane (3 mL) was added pyridine (90 μL, 1.2 mmol) and the mixture was stirred under N2 for 5 min, after which time 6-amino-2,3-dimethylquinoxaline [22] (80 mg, 0.46 mmol) was added. The resulting mixture was stirred for 6 h at room temperature, then saturated NaHCO3 solution (8 mL) was added and the mixture was extracted into ethyl acetate (15 mL). The organic phase was washed with brine, dried (Na2SO4), filtered and evaporated to give a residue that was purified using flash chromatography to afford an off-white solid (152 mg, 91%), single spot at Rf 0.70 (ethyl acetate). mp 225.3-225.7° C. HPLC purity 99+% (tR 2.29 min in 10% water-acetonitrile). 1H NMR (CDCl3): δ 7.99 (1H, d, 4=7.9. Hz), 7.85 (1H, d, J=9.2 Hz), 7.54-7.52 (2H, m), 7.40 (1H, dd, J=9.1, 2.6 Hz), 7.21 (1H, t, J=7.9 Hz), 6.95 (1H, s, N—H, 2.75 (3H, s), 2.67 (6H, s). LCMS: 360.24 (M−). FAB-MS (MH+, C17H16ClN3O2S): calcd 362.0730, found 362.0732.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[NH:16][C:15](=[O:17])[CH2:14][CH2:13][CH2:12]1.Br[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH:27]([F:29])[F:28])[N:21]=1>>[F:29][CH:27]([F:28])[O:26][C:22]1[N:21]=[C:20]([CH2:19][N:16]2[CH:11]([C:4]3[C:5]([O:9][CH3:10])=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[CH2:12][CH2:13][CH2:14][C:15]2=[O:17])[CH:25]=[CH:24][CH:23]=1
Reactant: FC(F)Oc1cccc(CBr)n1
Reactant: COc1cccc(OC)c1C1CCCC(=O)N1
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1cccc(OC(F)F)n1

Procedure:
Prepared according to the described general procedure 4 (GP4) by reaction of 6-(2,6-dimethoxyphenyl)piperidin-2-one with 2-(bromomethyl)-6-(difluoromethoxy)pyridine. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.83 min.; [M+H]+: 393.19 g/mol.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]2[O:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[C:6]=2[N:7]=1.[NH:21]1[C:29]2[C:24](=[CH:25][C:26](B3OC(C)(C)C(C)(C)O3)=[CH:27][CH:28]=2)[CH:23]=[CH:22]1>COCCOC.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>[NH:21]1[C:29]2[C:24](=[CH:25][C:26]([C:2]3[N:3]=[C:4]([N:15]4[CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)[C:5]4[O:10][C:9]5[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=5[C:6]=4[N:7]=3)=[CH:27][CH:28]=2)[CH:23]=[CH:22]1
Reactant: Clc1nc(N2CCOCC2)c2oc3ccccc3c2n1
Reactant: CC1(C)OB(c2ccc3[nH]ccc3c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: c1ccc2c(c1)oc1c(N3CCOCC3)nc(-c3ccc4[nH]ccc4c3)nc12
Temperature: 90 °C
Yield: 34.2 %

Procedure:
Argon gas was bubbled through a mixture of 2-chloro-4-morpholinobenzofuro[3,2-d]pyrimidine (ASA75) (80 mg, 0.276 mmol, 1.0 eq) and Indole-5-boronic acid pinacol ester (MW 243) (267 mg, 1.10 mmol, 4.0 eq) in 1,2 dimethoxyethan and 2 M Na2CO3 (3:1) (6 mL) for 5 min. dichloro 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloromethane complex (MW 732) (5.05 mg, 0.00690 mmol, 0.025 eq) was added and the reaction mixture was heated to reflux (90° C.) for 15 h, cooled and diluted with EtOAc (20 mL). The organic solution was washed with a mixture of H2O:Na2CO3:NH4OH (conc. 32 (% in water)=5:4:1 (9 mL), then NH4Cl (sat.) and brine (2×), dried over Na2CO3, filtered and concentrated. Purification by silica gel chromatography (gradient from 100% hexane in EtOAc to 70% hexane) gave a colorless solid (35 mg, 34%).
Reaction SMILES: [O:1]=[C:2]1[CH:7]2[CH2:8][CH:4]([CH2:5][CH:6]2[C:9]([OH:11])=O)[O:3]1.[NH2:12][CH:13]([C:28]([CH3:31])([CH3:30])[CH3:29])[C:14]([NH:16][CH:17]([CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)[C:18](=[O:21])[NH:19][CH3:20])=[O:15].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:22]1([C@H:17]([NH:16][C:14]([C@@H:13]([NH:12][C:9]([C@@H:6]2[CH2:5][C@@H:4]3[CH2:8][C@H:7]2[C:2](=[O:1])[O:3]3)=[O:11])[C:28]([CH3:30])([CH3:29])[CH3:31])=[O:15])[C:18]([NH:19][CH3:20])=[O:21])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: O=C(O)C1CC2CC1C(=O)O2
Reactant: CNC(=O)C(NC(=O)C(N)C(C)(C)C)C1CCCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@@H]1C[C@@H]2C[C@H]1C(=O)O2)C(C)(C)C)C1CCCCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 93.2 %

Procedure:
To a solution of compound 32 (53 mg, 0.34 mmol) in DMF (9 mL) was added compound 65 (80 mg, 0.28 mmol) and DIEA (290 □L, 1.66 mmol). The solution was cooled to 0° C. and HATU (127 mg, 0.33 mmol) was added. After stirring at 0° C. for 1 h and at rt for 1 h the solvent was evaporated, and the crude product was purified by flash column chromatography (EtOAc/toluene 2:1) to give compound 72 (110 mg, 92%) as a white solid.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([Cl:15])=[CH:10][C:9]=1[NH2:16])(C)(C)C.C(O[C:23](=[O:43])[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]2[CH:38]=[C:37]([CH3:39])[N:36]=[C:35]([N:40]([CH3:42])[CH3:41])[N:34]=2)[CH:28]=1)=O)(C)(C)C>>[Cl:15][C:11]1[C:12]([CH3:14])=[CH:13][C:8]2[N:7]=[C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33]4[CH:38]=[C:37]([CH3:39])[N:36]=[C:35]([N:40]([CH3:41])[CH3:42])[N:34]=4)[CH:28]=3)[CH2:24][C:23](=[O:43])[NH:16][C:9]=2[CH:10]=1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)nc(N(C)C)n1
Product: Cc1cc(-c2cccc(C3=Nc4cc(C)c(Cl)cc4NC(=O)C3)c2)nc(N(C)C)n1

Procedure:
The title compound was prepared from (2-amino-4-chloro-5-methyl-phenyl)-carbamic acid tert-butyl ester (Example J22) (103 mg, 0.4 mmol) and 3-[3-(2-dimethylamino-6-methyl-pyrimidin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K49) (171 mg, 0.48 mmol) according to the general procedure M and subsequent treatment of the crude product according to the general procedure N. Obtained as a light yellow solid (133 mg).
Reaction SMILES: [Cl:1][C:2]1[N:6]2[CH2:7][CH2:8][N:9]([C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[C:14]=3[Cl:23])=[O:12])[CH2:10][C:5]2=[N:4][CH:3]=1.C1C(=O)N([Cl:31])C(=O)C1>CN(C)C=O>[Cl:31][C:3]1[N:4]=[C:5]2[CH2:10][N:9]([C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:21])([F:22])[F:20])[C:14]=3[Cl:23])=[O:12])[CH2:8][CH2:7][N:6]2[C:2]=1[Cl:1]
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=C(c1cccc(C(F)(F)F)c1Cl)N1CCn2c(Cl)cnc2C1
Solvent: CN(C)C=O
Product: O=C(c1cccc(C(F)(F)F)c1Cl)N1CCn2c(nc(Cl)c2Cl)C1

Procedure:
3-Chloro-7-{[2-chloro-3-(trifluoromethyl)phenyl]carbonyl}-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine (E43) (300 mg, 0.824 mmol) and NCS (121 mg, 0.906 mmol) were stirred at RT for 16 h in N,N-dimethylformamide (DMF) (2 mL). Solvents were concentrated in vacuo and the residue purified by MDAP to afford desired product in 145 mg.
Reaction SMILES: [C:1]([C:3]([C:7]([O:9][CH3:10])=[O:8])=[CH:4]OC)#[N:2].[N:11]1([CH:16]=[CH:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:15][CH2:14][CH2:13][CH2:12]1>O1CCCC1>[C:1]([C:3]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][C:17]1[CH2:18][CH2:19][CH2:20][CH2:21][C:16]=1[N:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)#[N:2]
Reactant: CCCCC=CN1CCCC1
Reactant: COC=C(C#N)C(=O)OC
Solvent: C1CCOC1
Product: COC(=O)C(C#N)=CC1=C(N2CCCC2)CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.8 %

Procedure:
1-Cyano-2methoxy-1-methoxycarbonyl-ethene (8.5 g, 0.06 mol) in tetrahydrofuran (60 ml) was chilled to -25° C. At this temperature, a solution of 1-pyrrolidino-hexene (9.1 g, 0.06 mol) in tetrahydrofuran (30 ml) was added dropwise. Cooling was then stopped and the reaction mixture was allowed to warm up to room temperature. The solution was then stirred for 1 hour and then evaporated. The resulting gum was triturated with isopropanol and the resulting solid material collected by vacuum filtration. After drying, yellowish crystals of 1-cyano-1-methoxycarbonyl-2-(2-pyrrolidino-cyclohexenyl)-ethene (9.5 g, 60.9% of theoretical yield; m.pt. 133° C.-134° C.) Were obtained. The compound migrated in tlc uniformly and was used for the next step without further purification.
Reaction SMILES: Cl.Cl.[C:3]([C:5]([C:9]1[CH:10]=[CH:11][C:12]([O:29]C)=[C:13]([CH:28]=1)CN[C@H]1CCCN[C@H]1C1C=CC=CC=1)([C:7]#N)[CH3:6])#[N:4].I[CH:32]([CH3:34])[CH3:33].C([O-])([O-])=O.[Cs+].[Cs+]>CC(C)=O.CCOC(C)=O>[CH:32]([O:29][C:12]1[CH:11]=[CH:10][C:9]([C:5]([CH3:7])([CH3:6])[C:3]#[N:4])=[CH:28][CH:13]=1)([CH3:34])[CH3:33]
Reactant: COc1ccc(C(C)(C#N)C#N)cc1CN[C@H]1CCCN[C@H]1c1ccccc1
Reactant: CC(C)I
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CC(C)Oc1ccc(C(C)(C)C#N)cc1
Yield: 96.8 %

Procedure:
To a stirred solution of Compound 39 (500 mg, 3.10 mmol) and 2-Iodopropane (0.930 ml, 9.30 mmol) in acetone (8 ml) was added Cs2CO3 (4.55 g, 14.0 mmol), and refluxed for 2 h. The mixture was filtered over celite and washed with acetone. The filtrate was concentrated to give crude Compound 40. This was diluted with AcOEt, washed with water and brine, dried (MgSO4), and concentrated. This was purified by a column chromatography on silica gel to give Compound 40 (610 mg, 97%) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5](B2OC(C)(C)C(C)(C)O2)=[C:6]2[C:10]=1[C@H:9]([O:11][C:12]1[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=1)[CH2:8][CH2:7]2.Br[C:36]1[C:48]([CH3:49])=[CH:47][C:39]([O:40][CH2:41][CH2:42][C:43]([CH3:46])([OH:45])[CH3:44])=[CH:38][C:37]=1[CH3:50]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:36]2[C:48]([CH3:49])=[CH:47][C:39]([O:40][CH2:41][CH2:42][C:43]([OH:45])([CH3:44])[CH3:46])=[CH:38][C:37]=2[CH3:50])=[C:6]2[C:10]=1[C@H:9]([O:11][C:12]1[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=1)[CH2:8][CH2:7]2
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Reactant: Cc1cc(OCCC(C)(C)O)cc(C)c1Br
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(OCCC(C)(C)O)cc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from methyl 2-((S)-6-((R)-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate and 4-(4-bromo-3,5-dimethylphenoxy)-2-methylbutan-2-ol following a procedure analogous to that described in Step 5 of Intermediate 1. LC (method 4): tR=1.90 min; Mass spectrum (ESI+): m/z=571 [M+Na]+.
Reaction SMILES: Cl.C(OCC)C.[NH2:7][C:8]1[CH:22]=[CH:21][C:11]([C:12]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[O:13])=[CH:10][CH:9]=1.Cl[CH2:24][CH2:25][C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=O>C(O)C.[Cl-].[Cl-].[Zn+2]>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([C:12]([C:11]2[CH:21]=[C:22]3[C:8](=[CH:9][CH:10]=2)[N:7]=[CH:24][CH:25]=[C:26]3[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:13])=[CH:15][CH:16]=1
Reactant: Nc1ccc(C(=O)c2ccc(Cl)cc2)cc1
Reactant: O=C(CCCl)c1ccccc1
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCOCC
Solvent: CCO
Product: O=C(c1ccc(Cl)cc1)c1ccc2nccc(-c3ccccc3)c2c1
Reaction time: 0.25 h
Yield: 37.4 %

Procedure:
HCl/diethyl ether (30.8 ml) was added to a solution of 4-amino-4'-chlorobenzophenone (35 g) in ethanol (250 ml) at room temperature and the mixture was stirred for 15 minutes. FeCl3.6H2O (69.4 g) and then ZnCl2 (2.05 g) were added portionwise and the mixture was stirred at 65° C. for 30 minutes. 3-Chloro-1-phenyl-1-propanone (25.46 g) was added and the mixture was stirred and refluxed for one night. The mixture was poured into ice and extracted with DCM. The organic layer was washed with K2CO3 10%, dried (MgSO4), filtered off and evaporated. The residue was crystallized from ACN. The mother layers were purified by column chromatography over silica gel (eluent: CH2Cl2 /CH3OH 99/1). The pure fractions were collected and evaporated, yielding 19.4 g (37%) of (4-chlorophenyl)(4-phenyl-6-quinolinyl)methanone (interm. 8-a).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:35]=[CH:34][C:17]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([P:26](=[O:33])([O:30]CC)[O:27]CC)([F:25])[F:24])=[CH:16][C:15]=3[CH3:36])=[CH:7][C:6]=2[C:5]2[CH:37]=[CH:38][C:39]([CH3:41])=[CH:40][C:4]=2[N:3]=1.C(O)(C(F)(F)F)=O>>[NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:35]=[CH:34][C:17]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([P:26](=[O:27])([OH:30])[OH:33])([F:24])[F:25])=[CH:16][C:15]=3[CH3:36])=[CH:7][C:6]=2[C:5]2[CH:37]=[CH:38][C:39]([CH3:41])=[CH:40][C:4]=2[N:3]=1
Reactant: CCOP(=O)(OCC)C(F)(F)CCCCOc1ccc(CCc2cnc3c(N)nc4cc(C)ccc4c3c2)c(C)c1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(OCCCCC(F)(F)P(=O)(O)O)cc3C)cc12

Procedure:
5-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)-1,1-difluoropentylphosphonic acid (4) was prepared according to the procedure described in Example 1—Step 3, but using diethyl 5-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)-1,1-difluoropentylphosphonate from step 2. TFA was added to the 1H NMR sample to solubilize the compound for analysis. The 1H NMR (Dimethylsulfoxide-d6) obtained for 5-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)-1,1-difluoropentylphosphonic acid (4) was: δ 9.70 (br, 1H), 9.33 (br, 1H), 8.98 (s, 1H), 8.84 (s, 1H), 8.50 (d, 1H, J=8.4 Hz), 7.52 (s, 1H), 7.40 (d, 1H, J=8.4 Hz), 7.06 (d, 1H, J=8.4 Hz), 6.74 (s, 1H), 6.68 (d, 1H, J=10.8 Hz), 3.91 (t, 2H, J=6.2 Hz), 3.14 (t, 2H, J=8.4 Hz), 2.97 (t, 2H, J=8.4 Hz), 2.50 (s, 3H), 2.27 (s, 3H), 2.13-1.94 (m, 2H), 1.78-1.70 (m, 2H), 1.66-1.59 (m, 2H). LRMS [M+H]=530.2
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH:12]=[N:13][CH:14]=2)O1.Br[C:27]1[CH:36]=[C:35]2[C:30]([N:31]=[CH:32][C:33]([N:37]3[CH2:42][CH2:41][N:40]([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=4[O:49][CH3:50])[CH2:39][CH2:38]3)=[N:34]2)=[CH:29][CH:28]=1>O1CCOCC1.C(=O)([O-])[O-].[K+].[K+]>[CH3:50][O:49][C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=1[N:40]1[CH2:39][CH2:38][N:37]([C:33]2[CH:32]=[N:31][C:30]3[C:35]([N:34]=2)=[CH:36][C:27]([C:9]2[CH:10]=[C:11]([NH:15][S:16]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)(=[O:17])=[O:18])[CH:12]=[N:13][CH:14]=2)=[CH:28][CH:29]=3)[CH2:42][CH2:41]1
Reactant: COc1ccccc1N1CCN(c2cnc3ccc(Br)cc3n2)CC1
Reactant: CC1(C)OB(c2cncc(NS(=O)(=O)c3ccccc3)c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COc1ccccc1N1CCN(c2cnc3ccc(-c4cncc(NS(=O)(=O)c5ccccc5)c4)cc3n2)CC1
Temperature: 25 °C
Yield: 48.4 %

Procedure:
A slurry of a boronate ester such as N-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]benzenesulfonamide (0.55 mmol), 7-bromo-2-{4-[2-(methyloxy)phenyl]-1-piperazinyl}quinoxaline (0.37 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (1:1) (0.03 mmol) in 1,4-dioxane (4 ml) and 2M potassium carbonate (aq) (2 ml) was stirred at 100° C. for 18 hours. The reaction was cooled to ambient temperature, the organic layer separated and purified directly on silica by column chromatography (80% ethyl acetate/hexanes). The desired fractions were combined and concentrated to give the title compound (99 mg, 48%) as a yellow solid. MS(ES)+ m/e 553.4 [M+H]+.
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH3:16])[C:11](=O)[CH:10]=[C:9]2[CH2:18][C:19]([OH:21])=[O:20].[CH3:22]O>ClCCl>[Cl:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH3:16])[CH2:11][CH:10]=[C:9]2[CH2:18][C:19]([O:21][CH3:22])=[O:20]
Reactant: CO
Reactant: Cn1c(=O)cc(CC(=O)O)c2cc(Cl)ccc21
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: COC(=O)CC1=CCN(C)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 17 h
Yield: 85 %

Procedure:
11 ml (147 mmol) of thionyl chloride are added dropwise over approximately 30 minutes to a stirred suspension of 12.5 g (49 mmol) of 6-chloro-1-methyl-2-oxo-1,2-dihydro-4-quinolineacetic acid in 150 ml of methanol. The mixture is stirred for 17 hours at room temperature and the solvent is driven off under vacuum. The residue is dissolved in 400 ml of dichloromethane, and then washed with saturated aqueous sodium bicarbonate solution and then with water. After drying over sodium sulphate, the organic phase is filtered and the filtrate is condensed. 11.16 g of expected product are obtained.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[CH:8][C:9]([NH:11]C(=O)C)=[CH:10][C:5]=2[O:4][C:3]=1[C:15](=[O:23])[C:16]1[CH:21]=[CH:20][C:19](C)=[CH:18][CH:17]=1.[ClH:24].C(OC(=O)C)C>CO>[NH2:11][C:9]1[CH:8]=[CH:7][C:6]2[C:2]([CH3:1])=[C:3]([C:15]([C:16]3[CH:21]=[CH:20][C:19]([Cl:24])=[CH:18][CH:17]=3)=[O:23])[O:4][C:5]=2[CH:10]=1
Reactant: CC(=O)Nc1ccc2c(C)c(C(=O)c3ccc(C)cc3)oc2c1
Reactant: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1c(C(=O)c2ccc(Cl)cc2)oc2cc(N)ccc12
Temperature: 25 °C

Procedure:
3.1 g (10 mmol) of N-[3-methyl-2-(4-methyl-benzoyl)benzofuran-6-yl]-acetamide were suspended in 40 ml methanol. 20 ml 2.6 N HCl were added with stirring. The reaction mixture was heated to reflux. After 1 hour a clear solution was obtained. After 3 hours reflux the solution was cooled to room temperature and ethylacetate was added. The organic layer was washed once with NaOH-solution, two times with water, dried over Na4SO4 and concentrated in vacuo. The residue was further purified by crystallisation.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH:8]=O)[CH:5]=[CH:4][CH:3]=1.[OH:10][CH:11]1[CH2:16][CH2:15][CH2:14][NH:13][CH2:12]1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([CH2:8][N:13]2[CH2:14][CH2:15][CH2:16][CH:11]([OH:10])[CH2:12]2)[N:7]=1
Reactant: OC1CCCNC1
Reactant: O=Cc1cccc(Br)n1
Solvent: ClCCl
Product: OC1CCCN(Cc2cccc(Br)n2)C1

Procedure:
8] To 6-bromo-2-pyridinecarboxaldehyde (400 mg, 2.15 mmol) was added 3-hydroxypiperidine (326 mg, 3.22 mmol) in dry CH2Cl2 (15 mL) to give 2-bromo-6-(3-hydroxypiperidinyl)methyl pyridine as pale yellow solid. MS m/z: 271.2 (M+H). Calc'd for C11H15BrN2O: 271.15.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([NH2:12])=[O:11])=[CH:4][C:3]=1Br.[CH3:14][C:15]1([CH3:24])[CH2:20][CH2:19][C:18](B(O)O)=[CH:17][CH2:16]1>CO.C(Cl)Cl>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([NH2:12])=[O:11])=[CH:4][C:3]=1[C:18]1[CH2:19][CH2:20][C:15]([CH3:24])([CH3:14])[CH2:16][CH:17]=1
Reactant: NC(=O)CCc1ccc(N)c(Br)c1
Reactant: CC1(C)CC=C(B(O)O)CC1
Solvent: CO
Solvent: ClCCl
Product: CC1(C)CC=C(c2cc(CCC(N)=O)ccc2N)CC1
Yield: 82.6 %

Procedure:
The title compound was prepared by the Suzuki coupling procedure of Example 7, step (d) using 3-(4-amino-3-bromo-phenyl)-propionamide (as prepared in Example 7, step (c), 76.0 mg, 0.351 mmol), and 4,4-dimethylcyclohexen-1-yl boronic acid (59.5 mg, 0.387 mmol). Silica gel chromatography (0-2% MeOH/DCM) afforded the title compound (79 mg, 92%) as a light brown oil. Mass spectrum (ESI, m/z): Calcd. for C17H24N2O, 273.2 (M+H). found 273.2.