Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].C[O:4][C:5]([C:7]1[CH:14]=[CH:13][C:10]([CH2:11]Br)=[CH:9][CH:8]=1)=[O:6].[F:15][C:16]1[C:17](=[O:50])[NH:18][C:19](=[O:49])[N:20]([CH:48]=1)[C@@H:21]1[O:47][C@H:25]([CH2:26][O:27]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[C@@H:23]([OH:24])[CH2:22]1>O1CCOCC1>[F:15][C:16]1[C:17](=[O:50])[NH:18][C:19](=[O:49])[N:20]([CH:48]=1)[C@@H:21]1[O:47][C@H:25]([CH2:26][OH:27])[C@@H:23]([O:24][CH2:11][C:10]2[CH:13]=[CH:14][C:7]([C:5]([OH:4])=[O:6])=[CH:8][CH:9]=2)[CH2:22]1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](COC(c3ccccc3)(c3ccccc3)c3ccccc3)O2)cc1F
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)c1ccc(CO[C@H]2C[C@H](n3cc(F)c(=O)[nH]c3=O)O[C@@H]2CO)cc1
Temperature: 25 °C
Yield: 27.8 %

Procedure:
Potassium hydroxide (4.30 g) and 1.70 g of 4-methoxycarbonylbenzyl bromide was added to a solution of 3.00 g of 2'-deoxy-5-fluoro-5'-O-trityluridine in 200 ml of dioxane. The mixture was stirred at room temperature for a day. The reaction mixture was concentrated under a reduced pressure. To the concentrate was added 200 ml of water and the mixture was stirred at room temperature for 15 minutes. The reaction mixture was rendered acidic with acetic acid, and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated under a reduced pressure. The concentrate was dissolved in 50 ml of a 80% aqueous solution of acetic acid. The solution was heated to 100° C. for 2 hours. The solvent was distilled off and the residue was applied to silica gel column chromatography using 3% methanol-chloroform as an eluent, affording 650 mg of the title compound in a yield of 28%.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.S(C)C.[O:12]=[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]1[C:19]1[CH:26]=[CH:25][C:22]([CH2:23]O)=[CH:21][CH:20]=1>C(Cl)Cl>[O:12]=[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]1[C:19]1[CH:26]=[CH:25][C:22]([CH2:23][Br:8])=[CH:21][CH:20]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=c1ccccn1-c1ccc(CO)cc1
Solvent: CSC
Solvent: ClCCl
Product: O=c1ccccn1-c1ccc(CBr)cc1
Temperature: 0 °C

Procedure:
A solution of NBS (1.59 g, 8.94 mmol) and CH2Cl2 was cooled to 0°. To this solution (under Ar) was added Me2S (10.72 mmol, 0.78 mL) via syringe. This mixture was then cooled to -20° and added to a solution of the benzyl alcohol from Step 2 (1.2 g, 5.96 mmol) in CH2Cl2 via pipette. The reaction mixture was warmed to 0° and stirred for several hours. The residue was poured into ice water and extracted with CH2Cl2 (3×). The organic layers were combined, washed with brine, dried (MgSO4), filtered and concentrated to give the title compound as a yellow solid, which will be used in the next step without further purification.
Reaction SMILES: [C:1]1([C:14]([OH:16])=[O:15])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]([OH:13])=O)=[CH:3][CH:2]=1.[NH2:17][CH2:18][C@@H:19]([OH:36])[CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([O:27][C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([Cl:35])[CH:29]=2)[CH2:23][CH2:22]1.C(N(CC)CC)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN1CCCC1=O>[Cl:35][C:30]1[CH:29]=[C:28]([CH:33]=[CH:32][C:31]=1[Cl:34])[O:27][CH:24]1[CH2:23][CH2:22][N:21]([CH2:20][C@H:19]([OH:36])[CH2:18][NH:17][C:11]([C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:1]([C:14]([OH:16])=[O:15])=[CH:2][CH:3]=2)=[O:13])[CH2:26][CH2:25]1
Reactant: NC[C@@H](O)CN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1
Reactant: O=C(O)c1ccc(C(=O)O)c2ccccc12
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: O=C(O)c1ccc(C(=O)NC[C@@H](O)CN2CCC(Oc3ccc(Cl)c(Cl)c3)CC2)c2ccccc12
Reaction time: 16 h
Yield: 21 %

Procedure:
To a solution of naphthalene-1,4-dicarboxylic acid (0.100 g), (2R)-1-amino-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]propan-2-ol (0.147 g) and triethylamine (0.193 mL) in N-methyl-2-pyrolidinone (20 mL) was added PyBrOP (0.258 g). The reaction mixture was stirred for 16 h and the solvent was removed in vacuo. The residue was purified by RPHPLC (Symmetry, 0.1% ammonium acetate/acetonitrile) to afford the title compound as a colourless solid (0.050 g, 20%).
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[F:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][C:30]=1[F:31])[CH2:26][NH2:27]>C(O)C>[F:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][C:30]=1[F:31])[CH2:26][NH:27][CH2:19][C@@H:17]([OH:18])[CH2:16][O:15][C:12]1[CH:11]=[CH:10][C:9]([C:6]2[C:5]3[CH:20]=[CH:21][C:2]([F:1])=[CH:3][C:4]=3[O:8][N:7]=2)=[CH:14][CH:13]=1
Reactant: Fc1ccc2c(-c3ccc(OC[C@H]4CO4)cc3)noc2c1
Reactant: NCc1ccc(F)c(F)c1
Solvent: CCO
Product: O[C@H](CNCc1ccc(F)c(F)c1)COc1ccc(-c2noc3cc(F)ccc23)cc1

Procedure:
The title compound is prepared from (R)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole, 3,4-difluorobenzylamine, and ethanol essentially as described above in Example 112. Purity by LC/MS=97%, [M+H]+=429.
Reaction SMILES: C[OH:2].O.[F:4][C:5]1[C:10]([O:11][CH2:12][CH2:13][O:14][CH3:15])=[CH:9][C:8]([O:16][CH3:17])=[CH:7][C:6]=1[CH:18]([NH:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]2[N:45]=[C:44]([C:46](F)(F)F)[O:43][N:42]=2)=[CH:37][CH:36]=1)[C:19]1[NH:20][C:21](=[O:33])[N:22]([C:24]2[C:29]([N+:30]([O-])=O)=[CH:28][CH:27]=[CH:26][N:25]=2)[N:23]=1>[Fe].C(O)(=O)C>[C:44]([OH:2])(=[O:43])[CH3:46].[NH2:30][C:29]1[C:24]([N:22]2[C:21](=[O:33])[NH:20][C:19]([CH:18]([NH:34][C:35]3[CH:36]=[CH:37][C:38]([C:41]([NH2:45])=[NH:42])=[CH:39][CH:40]=3)[C:6]3[CH:7]=[C:8]([O:16][CH3:17])[CH:9]=[C:10]([O:11][CH2:12][CH2:13][O:14][CH3:15])[C:5]=3[F:4])=[N:23]2)=[N:25][CH:26]=[CH:27][CH:28]=1
Reactant: CO
Reactant: COCCOc1cc(OC)cc(C(Nc2ccc(-c3noc(C(F)(F)F)n3)cc2)c2nn(-c3ncccc3[N+](=O)[O-])c(=O)[nH]2)c1F
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: COCCOc1cc(OC)cc(C(Nc2ccc(C(=N)N)cc2)c2nn(-c3ncccc3N)c(=O)[nH]2)c1F
Temperature: 65 °C
Reaction time: 24 h

Procedure:
Iron powder (55 mg) was added to 4.5 ml of a methanol:water:acetic acid=1:1:1 mixed solvent solution containing 38 mg of 5-{[2-fluoro-5-methoxy-3-(2-methoxyethoxy)phenyl]-[4-(5-trifluoromethyl-[1,2,4]oxadiazol-3-yl)phenylamino]methyl}-2-(3-nitropyridin-2-yl)-2,4-dihydro-[1,2,4]triazol-3-one. The mixture was stirred at 65° C. for 24 hours under a nitrogen atmosphere. The reaction mixture was filtered and then purified by reverse-phase high performance liquid chromatography (acetonitrile-water, 0.1% acetic acid) to give the title compound (25 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:28]([F:31])([F:30])[F:29])[O:14][N:13]=[C:12]([C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:24][CH:23]([C:25]([OH:27])=O)[CH2:22]4)=[CH:17][CH:16]=3)[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8].C1C=C[C:35]2N(O)N=[N:38][C:36]=2[CH:37]=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.Cl.Cl.C1(N)CC1>CN(C=O)C>[CH:36]1([NH:38][C:25]([CH:23]2[CH2:22][N:21]([C:18]3[CH:19]=[CH:20][C:15]([C:12]4[CH2:11][C:10]([C:4]5[CH:5]=[C:6]([Cl:9])[C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=5)([C:28]([F:30])([F:31])[F:29])[O:14][N:13]=4)=[CH:16][CH:17]=3)[CH2:24]2)=[O:27])[CH2:37][CH2:35]1
Reactant: O=C(O)C1CN(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2)C1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NC1CC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1CC1)C1CN(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 33.3 %

Procedure:
To a stirred solution of 1-{4-[5-(3,4,5-trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-phenyl}-azetidine-3-carboxylic acid (Preparation 12, 0.1 g, 0.203 mmol) in DMF (3 mL) was added HOBt (0.027 g, 0.203 mmol), DIPEA (0.052 g, 0.406 mmol), EDCl.HCl (0.058 g, 0.304 mmol) and cyclopropyl amine (0.011 g, 0.203 mmol) at 0° C. Resulting reaction mixture was stirred at room temperature for 16 hours under nitrogen atmosphere. After complete consumption of starting material, reaction mixture was quenched with water (20 mL) and extracted with EtOAc (3×20 mL). Combined organic layer was washed with saturated NaHCO3 (2×50 mL), water (2×50 mL), brine (50 mL), dried over sodium sulphate and evaporated in vacuo to crude. Crude was purified by column chromatography on silica gel (100-200 mesh size). Compound was eluted using 1.1% methanol in DCM to afford white solid (0.036 g, 33%). 1H-NMR (400 MHz, CDCl3) δ: 0.49-0.53 (m, 2H), 0.77-0.87 (m, 2H), 2.74-2.77 (m, 1H), 3.31-3.34 (m, 1H), 3.61 (d, 1H, J=16.88 Hz), 4.01-4.07 (m, 5H), 5.72 (bs, 1H), 6.40 (d, 2H, J=8.68 Hz), 7.47 (d, 2H, J=8.68 Hz), 7.63 (s, 2H). LC-MS (m/z): [M−H] 529.70.
Reaction SMILES: [C:1]([C:4]1[CH:13]([C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][C:15]=2[O:22][C:23]([F:26])([F:25])[F:24])[C:12]2[C:11](=[O:27])[NH:10][CH:9]=[CH:8][C:7]=2[NH:6][C:5]=1[CH3:28])(=[O:3])[CH3:2].FC(F)(F)S(O[CH2:35][CH3:36])(=O)=O.C(=O)(O)[O-].[Na+]>C1COCC1>[C:1]([C:4]1[CH:13]([C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][C:15]=2[O:22][C:23]([F:26])([F:25])[F:24])[C:12]2[C:7](=[CH:8][CH:9]=[N:10][C:11]=2[O:27][CH2:35][CH3:36])[NH:6][C:5]=1[CH3:28])(=[O:3])[CH3:2]
Reactant: CC(=O)C1=C(C)Nc2cc[nH]c(=O)c2C1c1ccc(C#N)cc1OC(F)(F)F
Reactant: CCOS(=O)(=O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOc1nccc2c1C(c1ccc(C#N)cc1OC(F)(F)F)C(C(C)=O)=C(C)N2
Reaction time: 0.08 h

Procedure:
2.40 g (6.16 mmol) of 4-(3-acetyl-2-methyl-5-oxo-1,4,5,6-tetrahydro-1,6-naphthyridin-4-yl)-3-(trifluoromethoxy)benzonitrile (example 10A) are suspended in 5 ml of abs. THF and, after addition of 6.78 ml (6.78 mmol) of N″′-(tert-butyl)-N,N′,N″-tris[tris(dimethylamino)-phosphoranylidene]phosphorimide triamide (phosphazene base P4-t-Bu; 1 M in hexane), stirred for 5 min. Then 1.32 g (7.40 mmol) of ethyl trifluoromethanesulfonate are added. After stirring for a further 5 min, the mixture is hydrolyzed with saturated sodium bicarbonate solution and extracted twice with ethyl acetate. The combined organic phases are washed with saturated sodium chloride solution, dried with sodium sulfate and then concentrated in a rotary evaporator. The residue is purified by column chromatography (silica gel, mobile phase: cyclohexane/ethyl acetate 3:7). Recrystallization from acetonitrile finally affords 745 mg (29% of theory) of the title compound.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.C(=O)=O.[NH2:31][C@@H:32]1[CH2:41][CH2:40][C:39]2[C:34](=[CH:35][CH:36]=[CH:37][C:38]=2[N:42]2[CH2:47][CH2:46][N:45]([CH3:48])[CH2:44][CH2:43]2)[CH2:33]1>CN(C)C=O.C(#N)C>[CH3:48][N:45]1[CH2:44][CH2:43][N:42]([C:38]2[CH:37]=[CH:36][CH:35]=[C:34]3[C:39]=2[CH2:40][CH2:41][C@@H:32]([NH:31][C:11](=[O:13])[C:10]2[CH:9]=[CH:8][C:7]([N:4]4[CH2:3][CH2:2][O:1][CH2:6][CH2:5]4)=[CH:15][CH:14]=2)[CH2:33]3)[CH2:47][CH2:46]1
Reactant: CN1CCN(c2cccc3c2CC[C@@H](N)C3)CC1
Reactant: O=C(O)c1ccc(N2CCOCC2)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: O=C=O
Solvent: CN(C)C=O
Solvent: CC#N
Product: CN1CCN(c2cccc3c2CC[C@@H](NC(=O)c2ccc(N4CCOCC4)cc2)C3)CC1
Temperature: 75 °C
Reaction time: 18 h
Yield: 30.5 %

Procedure:
To a solution of 4-morpholinobenzoic acid (110 mg, 0.51 mmol) in anhydrous N,N-dimethylformamide (10 mL) was added 1,1'-carbonyldiimidazole (87 mg, 0.54 mmol) and the reaction was heated at 75° C. When the carbon dioxide evolution had ceased (after 30 min), the reaction was cooled to room temperature and a solution of (R)-2-amino-5-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (120 mg, 0.49 mmol) in anhydrous N,N-dimethylformamide (5 mL) was added. The reaction was allowed to stir at 70° C. for 18 h and the solvent was evaporated in vacuo. The residue was purified on a silica gel column using chloroform/ethanol saturated with NH3 (100:3) as the eluent. This gave after crystallization from acetonitrile, 65 mg (30% yield) of the title compound as white crystals: mp 127-128° C.; [α]21D +51° (c 0.50, chloroform); EIMS (70 eV) m/z (relative intensity) 434 (14, M+).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:3]=1[C:4]([N:6]=[C:7]=[O:8])=[O:5].[Cl:14][C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][C:21]=1[Cl:22])[NH2:18]>C1C=CC=CC=1>[Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:3]=1[C:4]([NH:6][C:7]([NH:18][C:17]1[CH:19]=[CH:20][C:21]([Cl:22])=[C:15]([Cl:14])[CH:16]=1)=[O:8])=[O:5]
Reactant: O=C=NC(=O)c1c(Cl)cccc1Cl
Reactant: Nc1ccc(Cl)c(Cl)c1
Solvent: c1ccccc1
Product: O=C(NC(=O)c1c(Cl)cccc1Cl)Nc1ccc(Cl)c(Cl)c1

Procedure:
35 g of 2,6-dichlorobenzoylisocyanate in 100 ml of dry benzene are added drop by drop, with stirring and cooling, to a solution of 24.3 g of 3,4-dichloroaniline in 200 ml of dry benzene. Much heat is evolved and a precipitate is formed which is drawn off while hot and then is washed with hot benzene. The resulting N-(2,6-dichlorobenzoyl)-N'-(3,4-dichlorophenyl)-urea is pure, as is shown by thin layer chromatography (with ethylacetate as the solvent). If desired, the product may be recrystallized from acetonitrile. Melting point 238° K.
Reaction SMILES: [CH3:1][CH:2]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH2:13](Br)[C:14]#[CH:15].[Br-].[Na+]>>[CH3:1][C:2]([CH2:15][C:14]#[CH:13])([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C(C)C(=O)OCC
Reactant: C#CCBr
Agent: [Br-]
Agent: [Na+]
Product: C#CCC(C)(C(=O)OCC)C(=O)OCC

Procedure:
At 35° to 40° to C., with stirring, 174 g (1.0 ml) of diethyl methylmalonate are added dropwise to an alkoxide solution (prepared from 23 g of sodium and 800 ml of absolute ethanol), the mixture is stirred for a further hour and then at 45° C. 130.8 g (1.1 mol) of propargyl bromide are added dropwise. The mixture is refluxed for a further 2 hours. After cooling the precipitated sodium bromide is separated by suction filtering and the filtrate is substantially evaporated in vacuo. The residue is stirred into ice water and the aqueous solution is extracted several times with ether. The combined organic phases are dried and evaporated to dryness in vacuo. The resulting oil is used in the next stage without any further purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6]1[C:7]([CH2:13][CH3:14])=[N:8][NH:9][C:10]=1[CH2:11][CH3:12])[CH3:2].[N+:16]([C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[CH:21][CH:20]=1)([O-:18])=[O:17].C([O-])([O-])=O.[K+].[K+].O>C(#N)C>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6]1[C:7]([CH2:13][CH3:14])=[N:8][N:9]([CH2:23][C:22]2[CH:25]=[CH:26][C:19]([N+:16]([O-:18])=[O:17])=[CH:20][CH:21]=2)[C:10]=1[CH2:11][CH3:12])[CH3:2]
Reactant: CCOC(=O)Cc1c(CC)n[nH]c1CC
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)Cc1c(CC)nn(Cc2ccc([N+](=O)[O-])cc2)c1CC
Temperature: 25 °C
Reaction time: 48 h
Yield: 69.5 %

Procedure:
To a solution of (3,5-diethyl-1H-pyrazol-4-yl) acetic acid ethyl ester (10.95 g, 52.1 mmol) and 4-nitrobenzyl bromide (14.625 g, 68 mmol) in acetonitrile (110 mL) is added K2CO3 (10.80 g, 78.1 mmol) and the mixture is stirred for 48 hours at room temperature. The reaction mixture is poured into water and extracted twice with ethyl acetate. The organic phase is dried over MgSO4 and evaporated under reduced pressure. The residue is purified by MPLC with ethyl acetate/cyclohexane to yield 12.50 g [3,5-diethyl-1-(4-nitro-benzyl)-1H-pyrazol-4-yl]acetic acid ethyl ester (ESI mass spectrum: [M+H]+=346; Retention time HPLC: 1.42 min (method B)). b) To a solution of [3,5-diethyl-1-(4-nitro-benzyl)-1H-pyrazol-4-yl]acetic acid ethyl ester (6.66 g, 19.3 mmol) in methanol (500 mL) is added Raney nickel (500 mg) and the mixture is hydrogenated at 50 psi and room temperature. The catalyst is filtered off and the filtrate is concentrated under reduced pressure to yield 4.38 g of the title compound (ESI mass spectrum: [M+H]+=316; Retention time HPLC: 1.09 min (method B)).
Reaction SMILES: [CH2:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[C:5]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]=O)[C:13]=2[O:20][CH3:21])[N:4]=1)[CH3:2].CN.[C:24]([BH3-])#[N:25].[Na+].[C:28]([OH:35])(=[O:34])/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32]>C(O)(=O)C.CO>[C:28]([OH:35])(=[O:34])/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32].[C:28]([OH:35])(=[O:34])/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32].[CH2:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[C:5]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][NH:25][CH3:24])[C:13]=2[O:20][CH3:21])[N:4]=1)[CH3:2]
Reactant: CCc1ccc(C#N)c(Oc2cccc(C=O)c2OC)n1
Reactant: [BH3-]C#N
Agent: CN
Agent: O=C(O)/C=C/C(=O)O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCc1ccc(C#N)c(Oc2cccc(CNC)c2OC)n1
Yield: 62.7 %

Procedure:
6-Ethyl-2-(3-formyl-2-methoxy-phenoxy)-nicotinonitrile (0.28 g, 1.0 mmol), methylamine (33% in ethanol, 0.8 mL, 6.4 mmol) and sodium cyanoborohydride (80 mg, 1.3 mmol) were stirred at ambient temperature in a 1% acetic acid/methanol solution (60 mL) for 16 h. The solvent was removed in vacuo. The residue was treated with 10% sodium carbonate solution and extracted with ethyl acetate. The ethyl acetate layer was separated and fumaric acid (0.12 g, 1.0 mmol) was added. After the solvent was removed in vacuo, the residue was triturated with ethyl acetate overnight, collected by filtration, and dried to give 6-ethyl-2-(2-methoxy-3-methylaminomethyl-phenoxy)-nicotinonitrile difumarate (166 mg, 32%) as a beige solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH:8][CH2:9][CH2:10][N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[N:6][CH:7]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:24]=[CH:25][C:26]([C:29]#[CH:30])=[N:27][CH:28]=2)=[CH:19][CH:18]=1>>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[CH:24]=[CH:25][C:26]([C:29]#[C:30][C:2]3[CH:3]=[CH:4][C:5]([NH:8][CH2:9][CH2:10][N:11]4[CH2:15][CH2:14][CH2:13][CH2:12]4)=[N:6][CH:7]=3)=[N:27][CH:28]=2)=[CH:21][CH:22]=1
Reactant: Brc1ccc(NCCN2CCCC2)nc1
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Product: Clc1ccc(-c2ccc(C#Cc3ccc(NCCN4CCCC4)nc3)nc2)cc1

Procedure:
The product is obtained analogously to Example 3.16b is from 90 mg (0.33 mmol) (5-bromo-pyridin-2-yl)-(2-pyrrolidin-1-yl-ethyl)-amine and 88 mg (0.41 mmol) 5-(4-chloro-phenyl)-2-ethynyl-pyridine.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:28](=[CH:29][CH:30]=1)[C:8]1[NH:9][C:10]([C@@H:12]3[CH2:16][CH2:15][CH2:14][N:13]3[C:17](=[O:27])[C@@H:18]([NH:22][C:23](=[O:26])[O:24][CH3:25])[CH:19]([CH3:21])[CH3:20])=[N:11][C:7]=1[CH:6]=[CH:5]2.CC1(C)C(C)(C)OB([C:39]2[CH:40]=[C:41]3[C:63](=[CH:64][CH:65]=2)[C:45]2[NH:46][C:47]([C@@H:49]4[C@@H:54]5[CH2:55][C@@H:51]([CH2:52][CH2:53]5)[N:50]4[C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])=[N:48][C:44]=2[CH2:43][CH2:42]3)O1.C([O-])([O-])=O.[K+].[K+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:59]([O:58][C:56]([N:50]1[C@H:49]([C:47]2[NH:46][C:45]3[C:63]4[C:41]([CH2:42][CH2:43][C:44]=3[N:48]=2)=[CH:40][C:39]([C:2]2[CH:3]=[C:4]3[C:28](=[CH:29][CH:30]=2)[C:8]2[NH:9][C:10]([C@@H:12]5[CH2:16][CH2:15][CH2:14][N:13]5[C:17](=[O:27])[C@@H:18]([NH:22][C:23]([O:24][CH3:25])=[O:26])[CH:19]([CH3:21])[CH3:20])=[N:11][C:7]=2[CH:6]=[CH:5]3)=[CH:65][CH:64]=4)[C@@H:54]2[CH2:55][C@H:51]1[CH2:52][CH2:53]2)=[O:57])([CH3:62])([CH3:60])[CH3:61]
Reactant: CC(C)(C)OC(=O)N1[C@@H]2CC[C@@H](C2)[C@H]1c1nc2c([nH]1)-c1ccc(B3OC(C)(C)C(C)(C)O3)cc1CC2
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc2ccc3cc(Br)ccc3c2[nH]1)C(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc2ccc3cc(-c4ccc5c(c4)CCc4nc([C@@H]6[C@H]7CC[C@H](C7)N6C(=O)OC(C)(C)C)[nH]c4-5)ccc3c2[nH]1)C(C)C
Temperature: 85 °C
Yield: 39.7 %

Procedure:
Methyl (S)-1-((S)-2-(7-bromo-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate (482 mg, 1.02 mmol) and (1R,3S,4S)-tert-butyl 3-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4,5-dihydro-1H-naphtho[1,2-d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate (552 mg, 1.12 mmol) were combined in DME (12 mL). Pd(PPh3)4 (118 mg, 0.102 mmol) and K2CO3 (2M H2O, 1.68 mL, 3.36 mmol) were added, and the solution was degassed with N2 for 10 min. The solution was heated to 85° C. and stirred o/n. The following morning, the solution was cooled to rt. The solution was diluted with EtOAc, washed with sat. NaHCO3, brine, dried with MgSO4, and concentrated. The residue was purified by silica gel chromatography to yield product (307 mg).
Reaction SMILES: O[CH2:2][C:3]1[N:8]=[C:7]([NH:9][C:10]2[CH:14]=[C:13]([CH3:15])[NH:12][N:11]=2)[CH:6]=[CH:5][CH:4]=1.S(Cl)([Cl:18])=O>C(Cl)(Cl)Cl.CN(C)C=O>[Cl:18][CH2:2][C:3]1[N:8]=[C:7]([NH:9][C:10]2[CH:14]=[C:13]([CH3:15])[NH:12][N:11]=2)[CH:6]=[CH:5][CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1cc(Nc2cccc(CO)n2)n[nH]1
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: Cc1cc(Nc2cccc(CCl)n2)n[nH]1
Temperature: 25 °C
Reaction time: 18 h
Yield: 114.9 %

Procedure:
68 mg (340 μmol) of 3-(6-hydroxymethylpyridin-2-yl)amino-5-methyl-1H-pyrazole was dissolved in 4 mL of a 6:1 mixed solvent of chloroform and dimethylformamide. Under cooling on an ice bath, 250 μL (3.4 mmol) of thionyl chloride was added thereto. After stirring at room temperature for 18 hours, the reaction solution was concentrated. The resulting residue was purified by a silica gel thin-layer chromatography to give 87 mg of a brown oil. This oil was used as it was for the next reaction.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:31])[CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:19][CH:18]=3)=[O:15])=[CH:7][C:6]=2[CH:32]=1.B([O-])([O-])O[C:35]1[CH:40]=[CH:39][C:38]([O:41][CH2:42][CH2:43][O:44][CH2:45][CH3:46])=[C:37]([O:47][CH2:48][CH3:49])[CH:36]=1.C(=O)([O-])[O-].[K+].[K+].C(O)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[CH2:48]([O:47][C:37]1[CH:36]=[C:35]([C:2]2[CH:3]=[CH:4][C:5]3[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([CH2:23][N:24]([CH3:31])[CH:25]5[CH2:30][CH2:29][O:28][CH2:27][CH2:26]5)=[CH:21][CH:22]=4)=[O:15])=[CH:7][C:6]=3[CH:32]=2)[CH:40]=[CH:39][C:38]=1[O:41][CH2:42][CH2:43][O:44][CH2:45][CH3:46])[CH3:49]
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(Br)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
Reactant: CCOCCOc1ccc(OB([O-])[O-])cc1OCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCS3(=O)=O)cc1OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.4 %

Procedure:
A mixture of 7-bromo-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (0.3 g), 3-ethoxy-4-(2-ethoxyethoxy)phenyl borate (0.18 g), 1M potassium carbonate solution (1.3 ml), ethanol (1.3 ml) and toluene (25 ml) was stirred under argon atmosphere at room temperature for 30 minutes. To the mixture was added tetrakistriphenylphosphinepalladium (0.03 g), and the mixture was refluxed under argon atmosphere for 6 hours and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried with anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified with silica gel column chromatography (ethyl acetate/methanol/triethylamine) to give crude crystals, which were recrystallized from ethanol to give 7-[3-ethoxy-4-(2-ethoxyethoxy)phenyl]-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 126) (0.26 g) as colorless crystals.