Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:14])[S:8][C:7]2=[N:9][CH:10]=[CH:11][N:6]2[C:5]1=[N:12][OH:13].[CH3:15][N:16]([CH3:20])[C:17](Cl)=[O:18]>O1CCCC1>[CH3:3][C:4]1([CH3:14])[S:8][C:7]2=[N:9][CH:10]=[CH:11][N:6]2[C:5]1=[N:12][O:13][C:17](=[O:18])[N:16]([CH3:20])[CH3:15]
Reactant: CC1(C)Sc2nccn2C1=NO
Reactant: CN(C)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C)C(=O)ON=C1n2ccnc2SC1(C)C
Reaction time: 1 h
Yield: 85 %

Procedure:
To a solution of 330 mg (13.6 mmol) of sodium hydride in 150 ml of dry tetrahydrofuran was added 2.50 g (13.6 mmol) of 2,2-dimethyl-3-hydroxyimino-2,3-dihydroimidazo-[2,1-b]thiazole. The reaction mixture was stirred at 25° for 1 hour and cooled in an ice bath before 1.54 g (14.3 mmol) of dimethylcarbamoyl chloride was added. After stirring for 12 hours at 25°, the solvent was removed in vacuo and the residue washed with hexane, dissolved in methylene chloride. The methylene chloride solution was washed with water, dried (MgSO4), and concentrated in vacuo to give 2.94 g (85%) of desired product. m.p. 99°-102.5°.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:33]=[CH:32][C:15]([C:16]([NH:18][C@H:19]([C:27]([O:29]CC)=[O:28])[CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:17])=[CH:14][CH:13]=1)[CH:6]=[CH:5]2.[C:34]([C:38]1[CH:43]=[CH:42][C:41]([S:44](Cl)(=[O:46])=[O:45])=[CH:40][CH:39]=1)([CH3:37])([CH3:36])[CH3:35]>>[C:34]([C:38]1[CH:43]=[CH:42][C:41]([S:44]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[N:7]([CH2:11][C:12]2[CH:33]=[CH:32][C:15]([C:16]([NH:18][C@H:19]([C:27]([OH:29])=[O:28])[CH2:20][C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)=[O:17])=[CH:14][CH:13]=2)[CH:6]=[CH:5]3)(=[O:46])=[O:45])=[CH:40][CH:39]=1)([CH3:37])([CH3:35])[CH3:36]
Reactant: CCOC(=O)[C@H](Cc1ccccc1)NC(=O)c1ccc(Cn2ccc3cc(N)ccc32)cc1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc3c(ccn3Cc3ccc(C(=O)N[C@@H](Cc4ccccc4)C(=O)O)cc3)c2)cc1

Procedure:
The title compound was prepared from ethyl N-{4-[(5-amino-1H-indol-1-yl)methyl]benzoyl}phenylalaninate and 4-tert-butylphenyl sulfonyl chloride following the procedure of Example 10: MS (ESI) m/z 610; MS (ESI) m/z 608.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Br:12])[N:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[C:13](OC(=O)C)(=[O:15])[CH3:14]>N1C=CC=CC=1>[C:13]([NH:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Br:12])[N:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2)(=[O:15])[CH3:14]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cc2cccnc2c(Br)n1
Solvent: c1ccncc1
Product: CC(=O)Nc1cc2cccnc2c(Br)n1
Temperature: 0 °C

Procedure:
Suspended in 32 ml of pyridine was 4.84 g of 6-amino-8-bromo-1,7-naphthyridine, followed by an addition of 66 ml of acetic anhydride. The resultant mixture was stirred at room temperature for 4 hours. After the reaction, the reaction mixture was poured in 500 ml of ice water and crystals, which precipitated out, were collected by filtration and then washed thoroughly with water. They were recrystallized from methanol to obtain 5.37 g of 6-acetamido-8-bromo-1,7-naphthyridine as colorless needle-like crystals (yield: 93.4%).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][CH2:14][CH2:15][F:16])=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[CH:17]1([CH2:20][C:21]([NH2:29])([CH3:28])[C:22]2[N:26]=[C:25]([CH3:27])[O:24][N:23]=2)[CH2:19][CH2:18]1>>[CH:1]1([C:4]2[C:5]([O:13][CH2:14][CH2:15][F:16])=[CH:6][C:7]([C:10]([NH:29][C:21]([C:22]3[N:26]=[C:25]([CH3:27])[O:24][N:23]=3)([CH3:28])[CH2:20][CH:17]3[CH2:18][CH2:19]3)=[O:12])=[N:8][CH:9]=2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1cc(OCCF)c(C2CC2)cn1
Reactant: Cc1nc(C(C)(N)CC2CC2)no1
Product: Cc1nc(C(C)(CC2CC2)NC(=O)c2cc(OCCF)c(C3CC3)cn2)no1

Procedure:
The title compound was synthesized in analogy to Example 112e, using 5-cyclopropyl-4-(2-fluoroethoxy)pyridine-2-carboxylic acid (Example 146b) and 2-Cyclopropyl-1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethylamine (example 66e) as starting materials and isolated (90 mg, 93%); MS (ESI, m/z): 389.6 (M+H+).
Reaction SMILES: [N+:1]([C:4]1[CH:48]=[CH:47][C:7]([CH2:8][O:9][C:10]([N:12]=[C:13]([NH:33][C:34]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][C:41]([N+:44]([O-:46])=[O:45])=[CH:40][CH:39]=2)=[O:35])[NH:14][CH2:15][CH2:16][CH2:17][C:18]([NH:20][C@H:21]2[CH2:25]C[N:23](C(OC(C)(C)C)=O)[CH2:22]2)=[O:19])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[F:49][C:50]([F:55])([F:54])[C:51]([OH:53])=[O:52]>ClCCl.ClCCCl>[F:49][C:50]([F:55])([F:54])[C:51]([OH:53])=[O:52].[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10]([N:12]=[C:13]([NH:33][C:34]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][C:41]([N+:44]([O-:46])=[O:45])=[CH:40][CH:39]=2)=[O:35])[NH:14][CH2:15][CH2:16][CH2:17][C:18]([NH:20][CH:21]2[CH2:25][NH:23][CH2:22]2)=[O:19])=[O:11])=[CH:47][CH:48]=1)([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](NC(=O)CCCNC(=NC(=O)OCc2ccc([N+](=O)[O-])cc2)NC(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: O=C(CCCNC(=NC(=O)OCc1ccc([N+](=O)[O-])cc1)NC(=O)OCc1ccc([N+](=O)[O-])cc1)NC1CNC1
Reaction time: 0.17 h

Procedure:
To a solution of the compound (1.90 g), which had been obtained in (1), in anhydrous dichloromethane (20 ml), trifluoroacetic acid (10 ml) was added dropwise under ice cooling, followed by stirring at the same temperature for 10 minutes and then at room temperature for 10 minutes. The reaction mixture was diluted with 1,2-dichloroethane and concentrated by evaporation under reduced pressure. The residue was washed successively with hexane and diethyl ether by decantation and the solvent was distilled off, whereby a crude 3-[4-[2,3-di(4-nitrobenzyloxycarbonyl)guanidino]-butanoylamino]azetidine trifluoroacetate (1.93 g) was obtained. The product was provided for use in the subsequent reaction without isolation.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].FC(F)(F)C(O)=O.[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:45]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38]([C@@H:40]1[CH2:44][CH2:43][CH2:42][NH:41]1)=[O:39].[C:46]1([N:52]=[C:53]=[O:54])[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:45]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38]([C@@H:40]1[CH2:44][CH2:43][CH2:42][N:41]1[C:53]([NH:52][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:54])=[O:39]
Reactant: O=C=Nc1ccccc1
Reactant: O=C(Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2)[C@@H]1CCCN1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2)[C@@H]1CCCN1C(=O)Nc1ccccc1
Yield: 44 %

Procedure:
The desired compound was prepared according to the procedure of Example A9, step H using (2S)—N-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]pyrrolidine-2-carboxamide bis(trifluoroacetate) and phenyl isocyanate as starting materials in 44% yield. 1H NMR (300 MHz, DMSO-d6): δ 9.43 (s, 2H), 9.36 (s, 1H), 8.30 (s, 1H), 8.11 (s, 1H), 7.98 (s, 1H), 7.72 (s, 1H), 7.58 (d, 2H), 7.25 (m, 3H), 7.04 (m, 2H), 6.95 (m, 1H), 6.85 (d, 1H), 4.53 (m, 1H), 3.68 (m, 1H), 3.50 (m, 1H), 2.85 (m, 4H), 2.20 (m, 1H), 2.01 (m, 3H). LCMS for C30H29ClN7O2 (M+H)+: m/z=554.2.
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([F:19])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:20]([C:28]2[CH:33]=[CH:32][C:31]([S:34]([CH2:37][CH2:38][O:39][CH3:40])(=[O:36])=[O:35])=[CH:30][CH:29]=2)=[CH:21][CH:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)(=O)=O)C=CC=CC=1.[OH-].[Na+].[CH2:43](O)C>O1CCCC1.ClCCl>[CH2:40]([O:39][CH2:38][CH2:37][S:34]([C:31]1[CH:30]=[CH:29][C:28]([C:20]([C:11]2[NH:10][C:14]3=[N:15][CH:16]=[C:17]([F:19])[CH:18]=[C:13]3[CH:12]=2)=[CH:21][CH:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[CH:33][CH:32]=1)(=[O:35])=[O:36])[CH3:43]
Reactant: CCO
Reactant: COCCS(=O)(=O)c1ccc(C(=CC2CCOCC2)c2cc3cc(F)cnc3n2S(=O)(=O)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCOCCS(=O)(=O)c1ccc(C(=CC2CCOCC2)c2cc3cc(F)cnc3[nH]2)cc1
Yield: 99 %

Procedure:
A mixture of 1-benzenesulfonyl-5-fluoro-2-[1-[4-(2-methoxy-ethanesulfonyl)-phenyl]-2-(tetrahydro-pyran-4-yl)-vinyl]-1H-pyrrolo[2,3-b]pyridine (320 mg, 0.55 mmol) in ethanol (4 mL), tetrahydrofuran (8 mL) and an aqueous sodium hydroxide solution (10%, 2 mL) was heated at 50° C. for 5 h. The mixture diluted with dichloromethane (50 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 2-[1-[4-(2-ethoxy-ethanesulfonyl)-phenyl]-2-(tetrahydro-pyran-4-yl)-vinyl]-5-fluoro-1H-pyrrolo[2,3-b]pyridine (250 mg, 99%) which was used in the next step without further purification: LC/MS m/e calcd for C24H27FN2O4S [M+H]+ 459.56, observed 459.3.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([NH2:17])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[F:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[CH2:28][NH:27][CH2:26]2.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[F:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[CH2:28][N:27]([C:11]1[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5][N:4]3[CH:1]3[CH2:3][CH2:2]3)=[C:9]([NH2:17])[C:10]=1[F:16])[CH2:26]2
Reactant: Fc1ccc2c(c1)CNC2
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: Nc1c(F)c(N2Cc3ccc(F)cc3C2)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Yield: 71.3 %

Procedure:
268 mg of 1-cyclopropyl-5-amino-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 137 mg of 5-fluoroisoindoline, 274 mg of DBU, and 2 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 266 mg of the target compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:20](=[O:21])[NH:19][N:18]=[CH:17][C:6]3=[C:7]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[NH:8][C:9]([CH:10]=1)=[C:5]23.[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][N:32]([CH2:35][C:36](O)=[O:37])[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C(Cl)Cl.CO.CN(C)C=O>[C:22]([O:26][C:27]([N:29]1[CH2:30][CH2:31][N:32]([CH2:35][C:36](=[O:37])[NH:1][C:2]2[CH:3]=[C:4]3[C:20](=[O:21])[NH:19][N:18]=[CH:17][C:6]4=[C:7]([C:11]5[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=5)[NH:8][C:9]([CH:10]=2)=[C:5]34)[CH2:33][CH2:34]1)=[O:28])([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1CCN(CC(=O)O)CC1
Reactant: Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(CC(=O)Nc2cc3c4c(c(-c5ccccc5)[nH]c4c2)C=NNC3=O)CC1
Yield: 33.2 %

Procedure:
Preparation of example 27 from the title compound of Example 7 (0.025 g, 0.09 mmol), 4-carboxymethyl-piperazine-1-carboxylic acid tert-butyl ester (0.044 g, 0.18 mmol), triethylamine (0.05 mL, 0.4 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (38 mg, 0.1 mmol) and N,N-dimethylformamide (0.05 M, 1.8 mL) was carried out analogously to Example 11. Silica gel chromatography (95:5 CH2Cl2/methanol), also in an analogous manner, afforded the title compound (15 mg) as a yellow powder in 33% yield.
Reaction SMILES: C([N:8]1[CH:12]2[CH:13]3[N:17]([CH:18]([C:32]4[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[CH:33]=4)[C:19]4[CH:31]=[CH:30][C:22]([C:23]([N:25]([CH2:28][CH3:29])[CH2:26][CH3:27])=[O:24])=[CH:21][CH:20]=4)[CH:16]([CH:9]1[CH2:10][CH2:11]2)[CH2:15][CH2:14]3)C1C=CC=CC=1>C(O)C.[Pd]>[CH:13]12[N:17]([CH:18]([C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[CH:33]=3)[C:19]3[CH:31]=[CH:30][C:22]([C:23]([N:25]([CH2:28][CH3:29])[CH2:26][CH3:27])=[O:24])=[CH:21][CH:20]=3)[CH:16]([CH2:15][CH2:14]1)[CH:9]1[NH:8][CH:12]2[CH2:11][CH2:10]1
Reactant: CCN(CC)C(=O)c1ccc(C(c2cccc(OC)c2)N2C3CCC2C2CCC3N2Cc2ccccc2)cc1
Agent: [Pd]
Solvent: CCO
Product: CCN(CC)C(=O)c1ccc(C(c2cccc(OC)c2)N2C3CCC2C2CCC3N2)cc1
Reaction time: 6 h

Procedure:
0.38 mmoles of the compound 4-[(10-benzyl-9,10-diazatricyclo[4.2.1.12,5]-dec-9-yl)-(3-methoxyphenyl)methyl]-N,N-diethylbenzamide obtained in Example 4.1 were mixed with palladium at 10% by weight on carbon (0.1 equivalents) in ethanol (5 ml). The mixture was submitted to hydrogenation at a pressure of 45 psi of H2 and at a temperature of 60° C., for 6 hours. At the end of the reaction the catalyst was removed by filtration under vacuum. The solvent was then evaporated under vacuum obtaining the compound 4-[(9,10-diazatricyclo[4.2.1.12,5]dec-9-yl)-(3-methoxy phenyl)methyl]-N,N-diethylbenzamide. Yield: quantitative. IR (nujol) (λ=cm−1) 1630 (C═O), 3200 (NH); 1H-NMR (CDCl3) δ 1.00-1.45 (m, 6H); 1.90-2.43 (m, 10H); 2.90-3.10 (m, 2H); 3.10-3.30 (m, 2H); 3.40-3.60 (m, 2H); 3.66 (bs, 1H); 3.79 (s, 3H); 4.26 (s, 1H); 6.75-6.80 (m, 1H); 7.03-7.38 (m, 5H); 7.60 (d, 2H, J=8.0 Hz). Anal. calc. for C27H35N3O2: C, 74.79; H, 8.14; N, 9.69. Found: C, 75.04; H, 8.13; N, 9.67.
Reaction SMILES: [C:1]([O:13][CH3:14])(=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11].[C:15](#[N:18])[CH:16]=[CH2:17].[Na].C(C1C=CC=CC=1)(=O)C1C=CC=CC=1.CCCCCCCCCCCC.C(C=CCCCCCCCCC(OC)=O)#N>CC1C=C(C)C(N2C(=[Ru](Cl)(Cl)=CC3C=CC=CC=3OC(C)C)N(C3C(C)=CC(C)=CC=3C)CC2)=C(C)C=1.C1(C)C=CC=CC=1>[C:1]([O:13][CH3:14])(=[O:12])[CH:2]=[CH:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[C:15](#[N:18])[CH:16]=[CH2:17]
Reactant: C=CCCCCCCCCC(=O)OC
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)=Cc2ccccc2OC(C)C)c(C)c1
Agent: COC(=O)CCCCCCCCC=CC#N
Agent: O=C(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCCCCCCCCCCC
Solvent: C=CC#N
Product: CCCCCCCCC=CC(=O)OC
Reaction time: 0.67 h

Procedure:
100 mg of methyl 10-undecenoate (0.5 mmol), 53 mg of acrylonitrile (1 mmol) and 8 ml of toluene distilled over sodium-benzophenone are placed in a 50 ml second-generation Hoveyda-Grubbs catalyst dissolved in 2 ml of toluene is added, using a syringe and a syringe press, over a period of 2 hours 40 minutes, under nitrogen and with magnetic stirring. At the end of the addition, the mixture is left to react for 1 hour at 80° C. The reaction mixture is analyzed by gas chromatography (dodecane standard). The conversion of the methyl 10-undecenoate is 94%. The selectivity toward methyl 11-cyano-10-undecenoate (cis+trans mixture) is 100%. The TON is 940.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:13]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:12]2[OH:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:30][C:31]([F:37])([F:36])[CH2:32][CH2:33][CH2:34]O.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:13]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:12]2[O:29][CH2:34][CH2:33][CH2:32][C:31]([F:37])([F:36])[F:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCCC(F)(F)F
Reactant: CCOC(=O)c1c(O)c2cc(OCc3ccccc3)ccc2c(=O)n1CC(C)C
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCOC(=O)c1c(OCCCC(F)(F)F)c2cc(OCc3ccccc3)ccc2c(=O)n1CC(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.5 %

Procedure:
To a solution of ethyl 6-benzyloxy-4-hydroxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate (5.93 g, 15 mmol), 4,4,4-trifluorobutanol (2.31 g, 18 mmol) and tributylphosphine (7.5 ml, 30 mmol) in tetrahydrofuran (50 mL) was added 1,1′-(azodicarbonyl)dipiperidine (7.57 g, 30 mmol) and the mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to give ethyl 6-benzyloxy-2-isobutyl-1-oxo-4-(4,4,4-trifluorobutoxy)-1,2-dihydro-3-isoquinolinecarboxylate (6.71 g, 88.5%) as an oil.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]2[CH:12]2[CH2:14][CH2:13]2)=[CH:4][C:3]=1[F:19].[CH:20]1([NH:23][CH2:24][C@@H:25]2[C@H:29]([F:30])[CH2:28][NH:27][CH2:26]2)[CH2:22][CH2:21]1>>[CH:12]1([N:9]2[C:10]3[C:5](=[CH:4][C:3]([F:19])=[C:2]([N:27]4[CH2:28][C@@H:29]([F:30])[C@@H:25]([CH2:24][NH:23][CH:20]5[CH2:21][CH2:22]5)[CH2:26]4)[N:11]=3)[C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8]2)[CH2:14][CH2:13]1
Reactant: F[C@@H]1CNC[C@@H]1CNC1CC1
Reactant: O=C(O)c1cn(C2CC2)c2nc(Cl)c(F)cc2c1=O
Product: O=C(O)c1cn(C2CC2)c2nc(N3C[C@H](CNC4CC4)[C@H](F)C3)c(F)cc2c1=O
Yield: 19.6 %

Procedure:
Using 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid (283 mg) and (3R,4S)-3-cyclopropylaminomethyl-4-fluoropyrrolidine (190 mg), the same procedure was followed as in Example 23 to give 1-cyclopropyl-7-[(3S,4S)-3-cyclopropylaminomethyl-4-fluoro-1-pyrrolidinyl]-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid as a white powder (79.4 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[CH:5]=[C:4]([Br:19])[CH:3]=1.[CH2:20]([O:22][C:23](=[O:34])[CH2:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([SH:32])=[CH:28][C:27]=1[CH3:33])[CH3:21]>>[CH2:20]([O:22][C:23](=[O:34])[CH2:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([S:32][C:2]2[CH:7]=[C:6]([O:8][C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=3)[CH:5]=[C:4]([Br:19])[CH:3]=2)=[CH:28][C:27]=1[CH3:33])[CH3:21]
Reactant: FC(F)(F)c1cccc(Oc2cc(Br)cc(Br)c2)c1
Reactant: CCOC(=O)COc1ccc(S)cc1C
Product: CCOC(=O)COc1ccc(Sc2cc(Br)cc(Oc3cccc(C(F)(F)F)c3)c2)cc1C

Procedure:
1,3-Dibromo-5-(3-trifluoromethyl-phenoxy)-benzene (1.35 g; 3.4 mmol) and (4-Mercapto-2-methyl-phenoxy)-acetic acid ethyl ester (0.7 g; 3.1 mmol) was condensed to give the title product applying the procedure described for {4-[3-Bromo-5-cyclopentylmethoxyphenylsulfanyl)-2-methyl-phenoxy]-acetic acid ethyl ester. The crude product was purified by preparative HPLC (Method A) followed by flash chromatography (dichloromethane:heptane 3:7). Yield 0.5 g. HPLC-MS: m/z: 541.3 (M)+; Rt: 3.03 min.
Reaction SMILES: CS([C:4]1[C:9]([C:10]([NH2:12])=[O:11])=[CH:8][N:7]=[C:6]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N+:21]3([O-])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[CH:16][CH:15]=2)[N:5]=1)=O.[CH:28]([NH2:31])([CH3:30])[CH3:29].C(N(C(C)C)CC)(C)C.S([O-])(O)=O.[Na+].N>O.CC(N(C)C)=O>[O:24]1[CH2:25][CH2:26][N:21]([CH2:20][C:17]2[CH:18]=[CH:19][C:14]([NH:13][C:6]3[N:5]=[C:4]([NH:31][CH:28]([CH3:30])[CH3:29])[C:9]([C:10]([NH2:12])=[O:11])=[CH:8][N:7]=3)=[CH:15][CH:16]=2)[CH2:22][CH2:23]1
Reactant: CC(C)N
Reactant: CS(=O)c1nc(Nc2ccc(C[N+]3([O-])CCOCC3)cc2)ncc1C(N)=O
Agent: N
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Nc1nc(Nc2ccc(CN3CCOCC3)cc2)ncc1C(N)=O
Temperature: 80 °C
Reaction time: 3 h

Procedure:
A mixture of 450 mg of 4-methylsulfinyl-2-({4-[(N-oxidomorpholin-4-yl)methyl]phenyl}amino)pyrimidine-5-carboxamide, 0.29 ml of isopropylamine, 0.24 ml of diisopropylethylamine and 5 ml of DMA was stirred at 80° C. for 3 hours. The reaction mixture was cooled down to room temperature, mixed with 8 ml of 5% sodium hydrogen sulfite, followed by stirring for 1 hour. The reaction mixture was adjusted to pH 9 by adding 0.5 ml of concentrated aqueous ammonia, diluted with water and then extracted with chloroform. The organic layer was washed with saturated brine, and then the solvent was evaporated. The resulting residue was purified by a silica gel column chromatography (chloroform:methanol:aqueous ammonia), and the resulting pale brown oil was crystallized from ethyl acetate to obtain 50 mg of 2-{[4-(morpholinomethyl)phenyl]amino}-4-(2-propylamino)pyrimidine-5-carboxamide as colorless crystals.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:13]2[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:14]=2[O:20][C:21]2[C:30]3[C:25](=[CH:26][C:27]([O:33][CH3:34])=[C:28]([O:31][CH3:32])[CH:29]=3)[N:24]=[CH:23][CH:22]=2)=[O:12])=[CH:7][CH:6]=1.C(=O)([O-])[O-].[K+].[K+].[NH:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1.O>CN(C)C=O>[CH3:32][O:31][C:28]1[CH:29]=[C:30]2[C:25](=[CH:26][C:27]=1[O:33][CH3:34])[N:24]=[CH:23][CH:22]=[C:21]2[O:20][C:14]1[CH:15]=[CH:16][C:17]([CH3:19])=[CH:18][C:13]=1[C:11]([C:8]1[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][N:41]2[CH2:46][CH2:45][O:44][CH2:43][CH2:42]2)=[CH:6][CH:7]=1)=[O:12]
Reactant: COc1cc2nccc(Oc3ccc(C)cc3C(=O)c3ccc(OCCCl)cc3)c2cc1OC
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2nccc(Oc3ccc(C)cc3C(=O)c3ccc(OCCN4CCOCC4)cc3)c2cc1OC
Temperature: 80 °C
Reaction time: 8 h
Yield: 67.4 %

Procedure:
[4-(2-Chloro-ethoxy)-phenyl]-[2-(6,7-dimethoxy-quinolin-4-yloxy)-5-methyl-phenyl]-methanone (compound 189) (51 mg) was dissolved in N,N-dimethylformamide to prepare a solution. Potassium carbonate (84 mg) and morpholine (46 mg) were then added to the solution, and the mixture was stirred at 80° C. overnight. The reaction solution was cooled to room temperature, and water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using chloroform-methanol to give the title compound (38 mg, yield 68%).
Reaction SMILES: [F:1][CH:2]([F:39])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([C:20]3[CH2:21][CH2:22][CH2:23][N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH:25]=3)[N:9]=2)[C:6]2[CH:33]=[CH:34][CH:35]=[C:36]([O:37][CH3:38])[C:5]=2[N:4]=1>CO.C1COCC1.[Pd]>[F:39][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([CH:20]3[CH2:21][CH2:22][CH2:23][N:24]([C:26]([O:28][C:29]([CH3:31])([CH3:32])[CH3:30])=[O:27])[CH2:25]3)[N:9]=2)[C:6]2[CH:33]=[CH:34][CH:35]=[C:36]([O:37][CH3:38])[C:5]=2[N:4]=1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(C2=CN(C(=O)OC(C)(C)C)CCC2)nc(N2CCOCC2)n1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(C2CCCN(C(=O)OC(C)(C)C)C2)nc(N2CCOCC2)n1
Yield: 84.3 %

Procedure:
A solution of tert-butyl 5-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-3,4-dihydro-1(2H)-pyridinecarboxylate (272 mg, 0.50 mmol) in MeOH (20 mL) and THF (20 mL) was hydrogenated over 10% Pd on carbon (50 mg). After removal of the hydrogen, the mixture was refluxed in air for additional 2 hrs. The catalyst Pd/C was removed by filtration through celite, and the solvents were removed under vacuum. Recrystallization of the residue from methanol gave 0.23 g (81% yield) of tert-butyl 3-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1-piperidinecarboxylate: mp 200-202° C.; 1H NMR (CDCl3) δ 8.01 (dd, J=8.4, 0.6 Hz, 1H), 7.58 (t, JHF=53.6 Hz, 1H), 7.38 (t, J=8.2 Hz, 1H), 6.84 (d, J=8.1 Hz, 1H), 4.47-4.35 (m, 1H), 4.06 (s, 3H), 3.96 (m, 4H), 3.85-3.77 (m, 4H), 3.09 (dd, J=13.1, 10.7 Hz, 1H), 2.89-2.76 (m, 2H), 2.30-2.20 (m, 1H), 1.88-1.57 (m, 4H), 1.48 (s, 9H); Anal. Calcd. for C26H33F2N7O4: C, 57.2; H, 6.1; N, 18.0. Found: C, 57.1; H, 6.3; N, 17.8%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH:12]=O)[CH:11]=1)[O:8][C:7]([CH3:14])=[CH:6][C:5]2=[O:15].[C:16]([O:22][CH2:23][CH3:24])(=[O:21])[CH2:17][C:18]([CH3:20])=[O:19]>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH:12]=[C:17]([C:18](=[O:19])[CH3:20])[C:16]([O:22][CH2:23][CH3:24])=[O:21])[CH:11]=1)[O:8][C:7]([CH3:14])=[CH:6][C:5]2=[O:15]
Reactant: Cc1cc(=O)c2cc(F)cc(C=O)c2o1
Reactant: CCOC(=O)CC(C)=O
Product: CCOC(=O)C(=Cc1cc(F)cc2c(=O)cc(C)oc12)C(C)=O

Procedure:
The title compound is prepared in analogy to example 25 (stage 25a) starting from 6-fluoro-2-methyl-4-oxo-4H-chromene-8-carbaldehyde (2.18 g, 10.62 mmol) and ethyl acetoacetate (1.33 g, 10.62 mmol). 3.30 g (98% of theory) of the title compound are obtained as an E/Z isomer mixture.