Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([C:37]1[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][C:38]=1[CH3:44])=[O:36]>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([C:37]3[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][C:38]=3[CH3:44])=[O:36])[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: Cc1ccc(C(=O)CCCCCBr)c(C)c1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCC(=O)c2ccc(C)cc2C)CC1
Yield: 42.5 %

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride (1.1 g) as starting compound, potassium carbonate (2.0 g) and 6-bromo-1-(2,4-dimethylphenyl)-1-hexanone (0.94 g) were reacted and treated in the same manner as in Example 172 to give 0.63 g of 4-amino-5-chloro-N-((1-(6-(2,4-dimethylphenyl)-6-oxohexyl)piperidin-4-yl)methyl)-2-methoxybenzamide.
Reaction SMILES: [CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:6](=[O:13])[NH:5][CH2:4][C:3]1=[O:14].[N+:15]([O-])([O-:17])=[O:16].[K+]>S(=O)(=O)(O)O>[N+:15]([C:11]1[CH:10]=[CH:9][C:8]2[N:2]([CH3:1])[C:3](=[O:14])[CH2:4][NH:5][C:6](=[O:13])[C:7]=2[CH:12]=1)([O-:17])=[O:16]
Reactant: CN1C(=O)CNC(=O)c2ccccc21
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CN1C(=O)CNC(=O)c2cc([N+](=O)[O-])ccc21
Reaction time: 8 h

Procedure:
1-Methyl-3,4-dihydro-1H-benzo[e][1,4]diazapine-2,5-dione (3.4 g, 17.9 mmol) was dissolved in concentrated sulfuric acid (30 ml) and to this was added potassium nitrate (1.95 g, 19.3 mmol) at 0° C. The mixture was stirred overnight, dumped onto ice, and the solids filtered off (3.62 g, 86%), m.p. 274-276° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]([OH:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.N([C:16]1[NH:17][CH2:18][CH2:19][N:20]=1)[N+]([O-])=O.C1(C)C(C)=CC=CC=1>CC(C)CC(=O)C>[NH:20]1[CH2:19][CH2:18][N:17]=[C:16]1[NH:1][CH2:2][CH2:3][CH:4]([OH:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: NCCC(O)c1ccccc1
Reactant: O=[N+]([O-])NC1=NCCN1
Solvent: Cc1ccccc1C
Solvent: CC(=O)CC(C)C
Product: OC(CCNC1=NCCN1)c1ccccc1

Procedure:
A mixture of 8 parts of α-(2-aminoethyl)benzylalcohol, 6.5 parts of 2-(nitramino)-2-imidazoline and 40 parts of xylene is stirred and refluxed for 3 hours with waterseparator. The reaction mixture is cooled and the separated oily product is dissolved in 4-methyl-2-pentanone. The solvent is evaporated in vacuo, yielding α-{2-[N-(2-imidazolin-2-yl)amino]ethyl} benzylalcohol as a residue.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[C:22]([C:26](O)=[O:27])=[CH:21][CH:20]=[CH:19]2.[NH2:29][CH2:30][C:31]1[CH:50]=[CH:49][C:34]([C:35]([NH:37][C:38]2[CH:43]=[CH:42][C:41]([C:44]([F:47])([F:46])[F:45])=[CH:40][C:39]=2[NH2:48])=[O:36])=[CH:33][CH:32]=1>>[NH2:48][C:39]1[CH:40]=[C:41]([C:44]([F:46])([F:47])[F:45])[CH:42]=[CH:43][C:38]=1[NH:37][C:35]([C:34]1[CH:49]=[CH:50][C:31]([CH2:30][NH:29][C:26]([C:22]2[C:23]3[C:18](=[CH:17][C:16]([O:15][C:6]4[C:5]5[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=5)[N:9]=[CH:8][N:7]=4)=[CH:25][CH:24]=3)[CH:19]=[CH:20][CH:21]=2)=[O:27])=[CH:32][CH:33]=1)=[O:36]
Reactant: NCc1ccc(C(=O)Nc2ccc(C(F)(F)F)cc2N)cc1
Reactant: COc1cc2ncnc(Oc3ccc4c(C(=O)O)cccc4c3)c2cc1OC
Product: COc1cc2ncnc(Oc3ccc4c(C(=O)NCc5ccc(C(=O)Nc6ccc(C(F)(F)F)cc6N)cc5)cccc4c3)c2cc1OC
Yield: 69.9 %

Procedure:
The title compound (46.7 mg, 70% yield) was prepared as a brown solid from 6-(6,7-dimethoxyquinazolin-4-yloxy)-1-naphthoic acid (37.6 mg, 0.1 mmol) and 4-(aminomethyl)-N-(2-amino-4-trifluoromethylphenyl)benzamide (37.1 mg, 0.12 mmol) by an analogous procedure to that described in example 16. LC-MS (m/z) 668 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:10](Cl)=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])([O-:3])=[O:2].[CH2:14]([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(OCC)(=O)C>[N+:1]([C:4]1[CH:12]=[CH:11][C:10]([N:24]2[CH2:25][CH2:26][N:21]([CH2:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:22][CH2:23]2)=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])([O-:3])=[O:2]
Reactant: O=C(O)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: c1ccc(CN2CCNCC2)cc1
Solvent: CCOC(C)=O
Product: O=C(O)c1cc(N2CCN(Cc3ccccc3)CC2)ccc1[N+](=O)[O-]
Temperature: 120 °C
Reaction time: 6 h

Procedure:
The mixture of 20 g of 2-nitro-5-chlorobenzoic acid and 50 mL of N-benzylpiperazine is stirred at 120° C. for 6 hours. To the reaction mixture 250 mL of ethyl acetate is added. The precipitated yellow crystalline material is filtered off, dissolved in 200 mL of water. The pH of the mixture is adjusted to 6 with acetic acid. The precipitated material is filtered off, washed with water and dried, to obtain 30 g of the title compound. M.p.: 172° C.
Reaction SMILES: [Cl:1][C:2]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7]([CH3:16])=[CH:6][C:3]=1[CH:4]=[O:5].N1C=CN=C1.[C:22]1(=[O:27])[CH2:26][CH2:25][CH:24]=[CH:23]1>CO.O>[Cl:1][C:2]1[C:3]([CH:4]([OH:5])[C:23]2[C:22](=[O:27])[CH2:26][CH2:25][CH:24]=2)=[CH:6][C:7]([CH3:16])=[C:8]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:9]=1
Reactant: Cc1cc(C=O)c(Cl)nc1-c1ccccc1
Reactant: O=C1C=CCC1
Agent: c1c[nH]cn1
Solvent: CO
Solvent: O
Product: Cc1cc(C(O)C2=CCCC2=O)c(Cl)nc1-c1ccccc1
Yield: 93 %

Procedure:
The clear solution of 2-Chloro-5-methyl-6-phenylnicotinaldehyde (10 mmol, 2.31 g) and imidazole (10 mmol) in 50 ml. of MeOH was slowly charged with 50 ml. of deionized water. To a stirred homogeneous reaction mixture was added 2-cyclopenten-1-one (10.2 mmol., 0.88 g) at room temperature and reaction progress was monitored by TLC. Upon completion of the reaction, excess MeOH was removed under reduced pressure, washed with water and extracted with CHCl3 thrice. Combined organic layers were washed with brine solution twice. The organic layer was concentrated and column chromatography of the crude product on silica gel, using 30% EtOAC in hexane as eluent, gave pure Baylis-Hillman adduct in 93% yield (2.84 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Br:11])[C:9]=1[OH:10])[C:5]#[N:6].[Cl-].[Na+].O.[C:15](Cl)(=[O:23])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>[Cl-].C([N+](CCCC)(CCCC)CCCC)C1C=CC=CC=1.C1(C)C=CC=CC=1>[C:15]([O:10][C:9]1[C:2]([Br:1])=[CH:3][C:4]([C:5]#[N:6])=[CH:7][C:8]=1[Br:11])(=[O:23])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: N#Cc1cc(Br)c(O)c(Br)c1
Reactant: CCCCCCCC(=O)Cl
Agent: CCCC[N+](CCCC)(CCCC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCCCC(=O)Oc1c(Br)cc(C#N)cc1Br
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 99.4 %

Procedure:
A mixture of 3,5-dibromo-4-hydroxybenzonitrile (27.69 g) sodium hydroxide (4.08 g), sodium chloride (43.4 g) and water (125 ml) was stirred at room temperature for 15 minutes. Toluene (30 ml) and benzyltributyl ammonium chloride (1.57 g) was added, and a solution of octanoyl chloride (17.06 g) in toluene (30 ml) was slowly added to the stirred mixture over a half an hour while the temperature was maintained at 20° C. After addition was completed, the mixture was stirred for 1 hour and the phases allowed to separate. After removing the aqueous phase, the organic phase was washed with water, then with 5% aqueous Na2O3 and again with water. The solution was dried over Na2O3 and evaporated to dryness, yielding 2,6-dibromo-4-cyanophenyl octanoate (40.08 g, 99.5%) as a brown crystalline solid.
Reaction SMILES: [C:1]([C:3]1[C:4]([NH2:9])=[N:5][CH:6]=[CH:7][CH:8]=1)#[CH:2].[O:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24](Cl)=[N:25][OH:26])=[CH:19][CH:18]=1.C(N(CC)CC)C>O1CCCC1>[O:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24]2[CH:2]=[C:1]([C:3]3[C:4]([NH2:9])=[N:5][CH:6]=[CH:7][CH:8]=3)[O:26][N:25]=2)=[CH:19][CH:18]=1
Reactant: ON=C(Cl)Cc1ccc(CCc2ccco2)cc1
Reactant: C#Cc1cccnc1N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Nc1ncccc1-c1cc(Cc2ccc(CCc3ccco3)cc2)no1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 40.8 %

Procedure:
To an anhydrous tetrahydrofuran (5 mL) solution of 3-ethynyl-pyridin-2-ylamine (33.1 mg, 0.281 mmol) described in Manufacturing Example 1-2-3 was added (4-(2-furan-2-yl-ethyl) phenyl)-acetohydroximoyl chloride (224 mg, 0.85 mmol) described in Manufacturing Example 80-1-7 under nitrogen atmosphere at room temperature. Triethylamine (0.24 mL, 1.7 mmol) was then added dropwise, followed by 1.5 hours of stirring at 60° C. The reaction mixture was partitioned into water and ethyl acetate at room temperature. The organic layer was washed with water and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=1:9 then 3:7) to obtain the title compound (39.6 mg, 40.8%).
Reaction SMILES: [C:1]([S:4][CH:5]([CH:10]([C:15]([NH:17][C@H:18]([C:28]([NH:30][CH3:31])=[O:29])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])[CH2:6][C:7](O)=[O:8])(=[O:3])[CH3:2].ON1C2C=CC=CC=2N=N1.[CH3:42][N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1>ClCCl>[C:1]([S:4][CH:5]([CH:10]([C:15]([NH:17][C@H:18]([C:28]([NH:30][CH3:31])=[O:29])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)=[O:16])[CH2:11][CH:12]([CH3:13])[CH3:14])[CH2:6][C:7]([N:46]1[CH2:47][CH2:48][N:43]([CH3:42])[CH2:44][CH2:45]1)=[O:8])(=[O:3])[CH3:2]
Reactant: CNC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)C(CC(C)C)C(CC(=O)O)SC(C)=O
Reactant: CN1CCNCC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CNC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)C(CC(C)C)C(CC(=O)N1CCN(C)CC1)SC(C)=O
Temperature: 5 °C
Reaction time: 1 h

Procedure:
A mixture of 3-acetylmercapto-6-methyl-4-[[[1-(S)-[(methylamino)carbonyl]-2-(4-methoxyphenyl)ethyl]amino]-carbonyl]heptanoic acid (E5, Isomer A; 226 mg, 0.5 mmol), N,N1 -dicyclohexylcarbodiimide (103 mg, 0.5 mmol), 1-hydroxybenzotriazole (76 mg, 0.5 mmol) and N-methylpiperazine (0.05 ml, 0.5 mmol) in dichloromethane (8 ml) was stirred at 5° C. for 1 h, then at room temperature overnight. After cooling, the precipitated solid was filtered off. The solution was diluted with dichloromethane and extracted with 0.25 M citric acid. The extracts were washed with dichloromethane then basified with 10% sodium carbonate, and extracted with ether. The ether extracts were washed with brine, dried (Na2SO4) and evaporated in vacuo. Trituration of the oily residue with ether, followed by recrystallisation of the resulting solid from ethyl acetate/hexane gave the title compound as a single isomer (Isomer A), 98 mg (37%) mp 133°-138° C. (Found: C,60.48; H,8.15; N,10.40. C27H42N404S requires C,60.65; H,7.92; N,10.48%).
Reaction SMILES: [CH2:1]([C:3]1[N:12]([CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23](C(F)(F)F)[CH:22]=3)[CH2:17][CH2:16]2)[C:11](=[O:31])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1)[CH3:2].[CH3:32][O:33]C1C=CC=CC=1N1CCNCC1>>[CH2:1]([C:3]1[N:12]([CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[O:33][CH3:32])[CH2:17][CH2:16]2)[C:11](=[O:31])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1)[CH3:2]
Reactant: CCc1nc2ccccc2c(=O)n1CCN1CCN(c2cccc(C(F)(F)F)c2)CC1
Reactant: COc1ccccc1N1CCNCC1
Product: CCc1nc2ccccc2c(=O)n1CCN1CCN(c2ccccc2OC)CC1

Procedure:
This compound was prepared in compliance with the procedure described in 7d, using 1-(2-methoxyphenyl)piperazine instead of 1-(3-(trifluoromethyl)phenyl)piperazine.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][N:10]=[C:4]2[C:3]=1[C:17]#[N:18].C([O-])([O-])=O.[K+].[K+].C1([CH:31]([B-](F)(F)F)[N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)C=CC=CC=1.[K+]>O1CCOCC1.CN(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>[C:11]1([C:8]2[N:5]3[CH:6]=[CH:7][C:2]([CH2:31][N:32]4[CH2:33][CH2:34][CH:35]([C:11]5[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=5)[CH2:36][CH2:37]4)=[C:3]([C:17]#[N:18])[C:4]3=[N:10][CH:9]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: F[B-](F)(F)C(c1ccccc1)N1CCCCC1
Reactant: N#Cc1c(Cl)ccn2c(-c3ccccc3)cnc12
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: C1COCCO1
Solvent: CN(C)C=O
Product: N#Cc1c(CN2CCC(c3ccccc3)CC2)ccn2c(-c3ccccc3)cnc12
Temperature: 150 °C
Yield: 61.9 %

Procedure:
To a mixture of compound D6 (0.15 g, 0.593 mmol) and K2CO3 (0.35 g, 2.55 mmol) in 1,4-dioxane (4 ml) and DMF (1.5 ml) was added compound D7 (0.237 g, 0.85 mmol). The resulting mixture was degassed using a stream of nitrogen and to this was added Pd(PPh3)4 (0.098 g, 0.085 mmol). The reaction mixture was then subjected to microwave heating in a sealed tube at 150° C. for 10 min. The reaction mixture was cooled to room temperature and filtered through a pad of diatomaceous earth. The filtrate was concentrated in vacuo. The residue thus obtained was purified by preparative reverse phase HPLC to yield compound E1 (0.072 g, 31%).
Reaction SMILES: [N:1]1[N:12]2[C:4]([N:5]=[C:6]3[C:10](=[C:11]2[C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[C:15](I)[CH:14]=2)[CH2:9][CH2:8][CH2:7]3)=[CH:3][CH:2]=1.[CH:21]#[C:22][CH2:23][CH2:24][OH:25].C(N(CC)CC)C>CN(C=O)C.[Cu]I>[N:1]1[N:12]2[C:4]([N:5]=[C:6]3[C:10](=[C:11]2[C:13]2[CH:18]=[CH:17][C:16]4[O:19][C:22]([CH2:23][CH2:24][OH:25])=[CH:21][C:15]=4[CH:14]=2)[CH2:9][CH2:8][CH2:7]3)=[CH:3][CH:2]=1
Reactant: C#CCCO
Reactant: Oc1ccc(-c2c3c(nc4ccnn24)CCC3)cc1I
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: OCCc1cc2cc(-c3c4c(nc5ccnn35)CCC4)ccc2o1
Temperature: 65 °C

Procedure:
4-(6,7-Dihydro-5H-1,4,8a-triaza-s-indacen-8-yl)-2-iodo-phenol (440 mg, 1.17 mmol), homopropargyl alcohol (147.3 mg, 2.1 mmol) and triethyl amine (295 mg, 2.92 mmol) were dissolved in DMF (15 ml). To this solution was added copper (I) iodide (66.3 mg, 0.34 mmol) and bis-triphenylphosphine palladium (II) chloride (81.9 mg, 0.117 mmol). The reaction was flushed with nitrogen and heated at 65° C. for 12 hours. Solvent was removed under reduced pressure and the residue purified on silica gel (10%-75% EtOAc in hexane) to give 2-[5-(6,7-dihydro-5H-1,4,8a-triaza-s-indacen-8-yl)-benzofuran-2-yl]-ethanol.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][C:9]([OH:11])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.O=C1C=CC=CN1OC(N(C)C)=[N+](C)C.F[B-](F)(F)F.[NH2:41][CH2:42][C:43]1[CH:48]=[CH:47][C:46]([C:49]2[NH:66][C:52]3[N:53]=[CH:54][N:55]=[C:56]([NH:57][C@@H:58]([C:60]4[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=4)[CH3:59])[C:51]=3[CH:50]=2)=[CH:45][CH:44]=1>CN(C=O)C>[C:60]1([C@H:58]([NH:57][C:56]2[C:51]3[CH:50]=[C:49]([C:46]4[CH:45]=[CH:44][C:43]([CH2:42][NH:41][C:9](=[O:11])[CH2:8][CH2:7][N:1]5[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]5)=[CH:48][CH:47]=4)[NH:66][C:52]=3[N:53]=[CH:54][N:55]=2)[CH3:59])[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=1
Reactant: O=C(O)CCN1CCCCC1
Reactant: C[C@@H](Nc1ncnc2[nH]c(-c3ccc(CN)cc3)cc12)c1ccccc1
Agent: CN(C)C(On1ccccc1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H](Nc1ncnc2[nH]c(-c3ccc(CNC(=O)CCN4CCCCC4)cc3)cc12)c1ccccc1
Reaction time: 0.08 h

Procedure:
Under an atmosphere of nitrogen a mixture of 0.0865 g (0.55 mmol) 3-piperidin-1-yl-propionic acid and 0.117 ml (0.68 mmol) N,N-diisopropylethylamine in DMF (5 ml) is treated at RT and over a period of 5 min with a solution of 0.163 g (0.55 mmol) O-(1,2-dihydro-2-oxo-1-pyridyl)-N,N,N′,N′-tetramethyluronium-tetrafluoroborate (TPTU, Fluka, Buchs, Switzerland) in 2 ml DMF. After stirring for 5 min the resulting solution is added slowly (1.5 h) at RT to 0.172 g (0.5 mmol) [6-(4-aminomethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-((R)-1-phenyl-ethyl)-amine (step 40.5) in 3 ml DMF. The reaction mixture is allowed to stand over night after which the DMF is evaporated under reduced pressure. The residue is purified by flash chromatography using gradients of first dichloromethane/methanol 100:2.5 to 10:1 and then mixtures of dichloromethane/methanol/conc. ammonia 90:10:0.5 to 40:10:1. The title compound is obtained as yellowish solid; m.p. 140° C.; MS-ES+: (M+H)+=483.
Reaction SMILES: N1(CCC[O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([C:22]#[N:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)CCCC1.Cl[CH2:25][CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][CH:31]([CH2:34][CH2:35][OH:36])[CH2:30][CH2:29]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[OH:36][CH2:35][CH2:34][CH:31]1[CH2:32][CH2:33][N:28]([CH2:27][CH2:26][CH2:25][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([C:22]#[N:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:29][CH2:30]1
Reactant: N#CC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Reactant: OCCC1CCN(CCCCl)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CC1(c2ccc(OCCCN3CCC(CCO)CC3)cc2)CCOCC1
Yield: 64.9 %

Procedure:
4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-carbonitrile (185 mg, 0.91 mmol), 2-[1-(3-chloro-propyl)-piperidin-4-yl]-ethanol (300 mg, 1.46 mmol), DMF (4 ml) and K2CO3 (497 mg, 3.60 mmol) were reacted together according to general procedure E. Purification by chromatography on silica, eluant DCM:MeOH:NH3 (92:6:2) provided the title compound (220 mg, 65%) as a pale pink solid. 1H NMR (400 MHz, CDCl3) δ 7.37 (d, 2H), 6.93 (d, 2H), 4.11-4.04 (m, 2H), 4.01 (t, 2H), 3.89 (td, 2H), 3.70 (t, 2H), 2.97-2.87 (m, 2H), 2.48 (t, 2H), 2.15-1.88 (m, 8H), 1.77-1.57 (m, 3H), 1.57-1.38 (m, 3H), 1.35-1.21 (m, 2H).
Reaction SMILES: [C-:1]#[N:2].[K+].[CH3:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:13][O:12][C:11](=[O:21])[C:10]=2[CH:22]=1.C(O)(=O)C>O>[C:1]([CH2:13][N:14]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:8]=[CH:7][C:6]([O:5][CH3:4])=[CH:22][C:10]=1[C:11]([OH:12])=[O:21])#[N:2]
Reactant: [C-]#N
Reactant: COc1ccc2c(c1)C(=O)OCN2c1ccccc1
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(N(CC#N)c2ccccc2)c(C(=O)O)c1
Temperature: 0 °C
Yield: 96 %

Procedure:
To a solution of 268 g (4.1 mole) of potassium cyanide in 1.6 l of water was added 1021 g (4.0 mole) of 1,2-dihydro-6-methoxy-1-phenyl-4H-3,1-benzoxazine-4-one at a rate such that the reaction mixture temperature was 35°-40° C. The resulting solution was stirred and maintained at 35°-40° C. for two hours, and then added dropwise to a solution of 8.0 l of ice water and 800 ml of acetic acid. The resulting suspended solid was filtered and washed with water to yield 1084 g (96% yield) of the crude nitrile, mp 122°-130° C. This material was used for further synthesis without additional purification.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:11]([O-])=O)=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[H][H]>C(O)C.[Pd]>[NH2:11][C:3]1[C:2]([CH3:1])=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: [H][H]
Reactant: Cc1cccc(C(=O)O)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: Cc1cccc(C(=O)O)c1N

Procedure:
A solution of 3-methyl-2-nitrobenzoic acid (7 g) in ethanol (250 ml) was reduced with hydrogen gas at 2 psi over 5% palladium/carbon (0.7 g) catalyst. After hydrogen uptake ceased, the mixture was filtered and solvent removed by a rotary evaporator to give a white solid. Purification was by recrystallization from ethyl ether-hexane, m.p. ca. 170°-173° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])[CH:3]=1.[F:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([CH3:33])([CH3:32])[C:29]([OH:31])=[O:30])=[CH:24][C:23]=1B1OC(C)(C)C(C)(C)O1.C([O-])([O-])=O.[Cs+].[Cs+].COCCOC>O.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>[Cl:20][C:14]1[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=1[CH2:12][CH2:11][NH:10][C:4]1[N:5]=[C:6]([O:8][CH3:9])[N:7]=[C:2]([C:27]2[CH:26]=[C:25]([C:28]([CH3:33])([CH3:32])[C:29]([OH:31])=[O:30])[CH:24]=[CH:23][C:22]=2[F:21])[CH:3]=1
Reactant: CC(C)(C(=O)O)c1ccc(F)c(B2OC(C)(C)C(C)(C)O2)c1
Reactant: COc1nc(Cl)cc(NCCc2ccc(Cl)cc2Cl)n1
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: [Cs+]
Solvent: O
Solvent: COCCOC
Product: COc1nc(NCCc2ccc(Cl)cc2Cl)cc(-c2cc(C(C)(C)C(=O)O)ccc2F)n1
Yield: 29 %

Procedure:
A solution of (6-chloro-2-methoxy-pyrimidin-4-yl)-[2-(2,4-dichlorophenyl)-ethyl]amine (0.24 g), 2-[4-fluoro-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-2-methyl-propionic acid (0.4 g), Cs2CO3 (1.01 g) and tetrakis(triphenylphosphine)palladium (0) (100 mg) in water (20 mL)/DME (80 mL) is heated at 90° C. for 16 h. The solution is poured into water and extracted with EtOAc (2×200 mL). The organic layer is dried over sodium sulfate, filtered, evaporated in vacuo. The residue is chromatographed on silica gel eluting with EtOAc to afford 2-(3-{6-[2-(2,4-dichloro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-4-fluoro-phenyl)-2-methyl-propionic acid (100 mg), which is dissolved in THF (4 mL) and treated with 4 N HCl in 1,4-dioxane (1 mL). The mixture is concentrated in vacuo and the residue is suspended in ether (25 mL). The solid is formed and filtered under nitrogen to afford 2-(3-{6-[2-(2,4-Dichloro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-4-fluoro-phenyl)-2-methyl-propionic acid hydrochloride (67 mg, Example 99). MS: 478 (M+H); 1H NMR (300 MHz, NMR, CD3OD) □7.8, (d, 1H, J=0.3 Hz); 7.4 (m, 2H); 7.35 (s, 1H); 7-7.15 (m, 4H); 6.6 (s, 1H); 4.2 (s, 3H); 3.6 (m, 2H); 3.05 (t, 2H); 1.65 (s, 6H). IC50=0.5 nM
Reaction SMILES: [NH2:1][CH2:2][C:3]1[O:7][N:6]=[C:5]([CH2:8][CH3:9])[CH:4]=1.CO[CH:12](OC)[N:13]([CH3:15])[CH3:14]>>[CH2:8]([C:5]1[CH:4]=[C:3]([CH2:2][N:1]=[CH:12][N:13]([CH3:15])[CH3:14])[O:7][N:6]=1)[CH3:9]
Reactant: COC(OC)N(C)C
Reactant: CCc1cc(CN)on1
Product: CCc1cc(CN=CN(C)C)on1

Procedure:
9 g of 5-aminomethyl-3-ethyl-isoxazole is stirred in 12 ml of dimethylformamide-dimethylacetal with exclusion of moisture for 8 hours at 80° C. (bath temperature). After distillation on a bulb tube at 145° C. and 0.03 torr, 12.8 g (98% of theory) of the desired product is obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[CH2:17][CH2:16][C:15]3[C:14]([C:18]([O-:20])=O)=[CH:13][CH:12]=[CH:11][C:10]=3[CH2:9]2)=[CH:3][CH:2]=1.[Na+].[Cl:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[Cl:22][C:23]1[CH:29]=[CH:28][C:26]([NH:27][C:18]([C:14]2[C:15]3[CH2:16][CH2:17][N:8]([CH2:7][C:4]4[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=4)[CH2:9][C:10]=3[CH:11]=[CH:12][CH:13]=2)=[O:20])=[CH:25][CH:24]=1
Reactant: O=C([O-])c1cccc2c1CCN(Cc1ccncc1)C2
Reactant: Nc1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(Cl)cc1)c1cccc2c1CCN(Cc1ccncc1)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.3 %

Procedure:
Sodium 2-(pyridin-4-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxylate (80 mg, 0.276 mmol) was dissolved in N,N-dimethylformamide (1 mL) then added 4-chloroaniline (42 mg, 0.331 mmol), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (133 mg, 0.414 mmol), and N,N-diisopropylethylamine (56 mg, 0.552 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was concentrated under vacuum. The remaining orange oil was purified by silica gel chromatography (1% to 3% 7N ammonia in methanol/dichloromethane) to afford N-(4-chlorophenyl)-2-(pyridin-4-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxamide (89 mg) as a light yellow solid. MS (ESI, pos. ion) m/z: 378.0 (M+1).