Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.CCCCCC.[CH:12]([NH:14][CH2:15][CH2:16][S:17][C:18]1[N:19]=[CH:20][N:21]2[CH:25]=[CH:24][S:23][C:22]=12)=[O:13].[CH2:26]([Sn:30](Cl)([CH2:35][CH2:36][CH2:37][CH3:38])[CH2:31][CH2:32][CH2:33][CH3:34])[CH2:27][CH2:28][CH3:29].[Cl-].[NH4+]>C1COCC1>[CH:12]([NH:14][CH2:15][CH2:16][S:17][C:18]1[N:19]=[CH:20][N:21]2[CH:25]=[C:24]([Sn:30]([CH2:31][CH2:32][CH2:33][CH3:34])([CH2:35][CH2:36][CH2:37][CH3:38])[CH2:26][CH2:27][CH2:28][CH3:29])[S:23][C:22]=12)=[O:13]
Reactant: O=CNCCSc1ncn2ccsc12
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCC[Sn](CCCC)(CCCC)c1cn2cnc(SCCNC=O)c2s1
Reaction time: 0.17 h

Procedure:
A 1.6 N n-butyllithium/n-hexane solution (11.7 ml) was added to a solution of 1.19 g of 7-(2-formylaminoethyl)thioimidazo[5,1-b]thiazole in 50 ml of THF at −55° C. under an argon atmosphere. The mixture was stirred at that temperature for 10 min. Tri-n-butylstannyl chloride (2.24 ml) was added thereto, and the mixture was stirred for 20 min. The temperature of the reaction solution was raised to −30° C. over a period of one hr, during which time 3.34 ml of a 1.6 N n-butyllithium/n-hexane solution and 2.4 ml of tri-n-butylstannyl chloride were added. An aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate, followed by washing with brine. The organic layer was dried over anhydrous magnesium sulfate. The solvent was removed by distillation, and the residue was purified by column chromatography on silica gel (ethyl acetate only to dichloromethane:methanol=20:1) to prepare 1.615 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[CH3:27][C:28]([CH3:41])([CH3:40])[CH2:29][CH2:30][O:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36][NH2:37])=[CH:34][CH:33]=1>>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:37][CH2:36][C:35]1[CH:38]=[CH:39][C:32]([O:31][CH2:30][CH2:29][C:28]([CH3:41])([CH3:40])[CH3:27])=[CH:33][CH:34]=1
Reactant: CC(C)(C)CCOc1ccc(CN)cc1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Product: CC(C)(C)CCOc1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)C(F)(F)F)CC3)cc1

Procedure:
Use a method similar to the General Procedure 5-3 to couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (426 mg, 1.0 mmol) and 4-(3,3-dimethylbutoxy)-benzylamine (325 mg, 1.5 mmol). Purify by chromatography on silica gel eluting with hexane/EtOAc (1:0 and 9:1) and then SCX chromatography to obtain 7-chloro-6-[4-(3,3-dimethylbutoxy)-benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine. MS (ES+) m/z: 483 (M+H)+.
Reaction SMILES: [CH3:1][Si:2]([CH3:7])([CH3:6])[CH2:3][CH2:4][OH:5].C(N(CC)CC)C.[CH2:15]=[C:16]1[O:19][C:18](=[O:20])[CH2:17]1>>[O:19]=[C:16]([CH3:15])[CH2:17][C:18]([O:5][CH2:4][CH2:3][Si:2]([CH3:7])([CH3:6])[CH3:1])=[O:20]
Reactant: C[Si](C)(C)CCO
Reactant: C=C1CC(=O)O1
Solvent: CCN(CC)CC
Product: CC(=O)CC(=O)OCC[Si](C)(C)C
Temperature: 95 °C
Reaction time: 3 h

Procedure:
To a mixture of 5.0 g (42.28 mmol) 2-(trimethylsilyl)ethanol and 0.20 g (1.99 mmol) triethylamine are added dropwise 3.55 g (42.28 mmol) 4-methylene-2-oxetanone at 50-60° C. The mixture is stirred at 95° C. for 3 hours and then allowed to stand at ca 5° C. overnight. The reaction mixture is purified by distillation
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C([Cl:15])=O>C(Cl)Cl>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([Cl:15])=[O:5]
Reactant: Cc1cccc(C)c1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: Cc1cccc(C)c1C(=O)Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2,6-Dimethylbenzoic acid (15 g, 99.88 mmol) was added to anhydrous CH2Cl2 (20 ml) at 0° C. followed by drop wise addition of oxalyl chloride (2M in CH2Cl2, 14.14 g) under argon. The reaction mixture was stirred at the same temperature for 30 minutes and then warmed to the room temperature for 1 hour, concentrated and used without purification.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([N:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]([C:28]2[C:36]([OH:37])=[CH:35][C:31]3[O:32][CH2:33][O:34][C:30]=3[CH:29]=2)[C:20]1=[O:38])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].Br[CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42]>C1COCC1>[CH2:44]([O:43][C:41](=[O:42])[CH2:40][C:21]1([C:28]2[C:36]([OH:37])=[CH:35][C:31]3[O:32][CH2:33][O:34][C:30]=3[CH:29]=2)[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:19]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:20]1=[O:38])[CH3:45]
Reactant: CCCCCCN1C(=O)C(c2cc3c(cc2O)OCO3)c2ccccc21
Reactant: CCOC(=O)CBr
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCCCCCN1C(=O)C(CC(=O)OCC)(c2cc3c(cc2O)OCO3)c2ccccc21
Temperature: -75 °C
Yield: 8 %

Procedure:
To a solution of diisopropylamine (1.14 g, 11.0 mmol) in THF (10.0 mL) was added n-butyl lithium (7.00 mL, 11.0 mmol, 1.6 M solution in hexane) at −75° C. The resulting mixture was stirred at −75° C. for half an hour and added slowly to a solution of 1-hexyl-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-one in THF (20.0 mL) at −75° C. After stirring at −75° C. for another half an hour, ethyl bromoacetate was added. The mixture was stirred at ambient temperature for 18 hrs and quenched with saturated ammonim chloride solution. The organic solvent was removed in vacuo and the aqueous residue was diluted with ethyl acetate (100 mL). The orgnic layer was washed with saturated ammonium chloride (25.0 mL), brine (50.0 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The residue was subjected to column chromatography eluting with 40% EtOAc/Hexanes to yield the title compound (0.19 g, 8%) as an oil: MS (ES+) m/z 440.5 (M+1).
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[C:10]([CH2:24][O:25][CH3:26])=[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.[NH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([N:36]([CH3:44])[CH2:37][CH2:38][C:39]([O:41]CC)=[O:40])=[O:35])=[CH:30][CH:29]=1>>[CH:1]1([CH:7]([NH:27][C:28]2[CH:29]=[CH:30][C:31]([C:34]([N:36]([CH3:44])[CH2:37][CH2:38][C:39]([OH:41])=[O:40])=[O:35])=[CH:32][CH:33]=2)[C:9]2[C:10]([CH2:24][O:25][CH3:26])=[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)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(N)cc1
Reactant: COCc1nn(-c2ccc(C(F)(F)F)cn2)cc1C(O)C1CCCCC1
Product: COCc1nn(-c2ccc(C(F)(F)F)cn2)cc1C(Nc1ccc(C(=O)N(C)CCC(=O)O)cc1)C1CCCCC1
Yield: 9.1 %

Procedure:
Using cyclohexyl{3-(methoxymethyl)-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazol-4-yl}methanol (1.2 g) synthesized in Example 29(4) and ethyl 3-{[(4-aminophenyl)carbonyl](methyl)amino}propanoate (1.0 g) synthesized in Example 2(2) and in the same manner as in Example 1(7), the title object compound (0.17 g, 8%) was obtained as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]([CH3:16])[CH2:9][CH2:10][NH:11][C:12](=[O:15])[CH:13]=[CH2:14])[CH:5]=[CH:4][CH:3]=1.Br[C:18]1[C:19](=[O:26])[N:20]([CH3:25])[CH:21]=[C:22]([Br:24])[CH:23]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CC(=O)OCC.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Br:24][C:22]1[CH:23]=[C:18]([NH:1][C:2]2[N:7]=[C:6]([N:8]([CH3:16])[CH2:9][CH2:10][NH:11][C:12](=[O:15])[CH:13]=[CH2:14])[CH:5]=[CH:4][CH:3]=2)[C:19](=[O:26])[N:20]([CH3:25])[CH:21]=1
Reactant: C=CC(=O)NCCN(C)c1cccc(N)n1
Reactant: Cn1cc(Br)cc(Br)c1=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CC(=O)NCCN(C)c1cccc(Nc2cc(Br)cn(C)c2=O)n1
Temperature: 95 °C
Reaction time: 7 h
Yield: 21.6 %

Procedure:
A mixture of 110e (400 mg, 1.82 mmol), 3,5-dibromo-1-methylpyridin-2(1H)-one (534 mg, 2.0 mmol), Pd2(dba)3 (83 mg, 0.091 mmol), Xantphos (105 mg, 0.182 mmol) and Cs2CO3 (1.48 g, 4.55 mmol) in DMF (10 mL) was stirred at 95° C. under N2 for 7 h. The mixture was diluted with EA (50 mL) and filtered. The filtrate was washed with water, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography (PE/EA=1/2) to give N-(2-((6-(5-bromo-1-methyl-2-oxo-1,2-dihydropyridin-3-ylamino)pyridin-2-yl)(methyl)amino)ethyl)acrylamide 110f (160 mg, 22%) as a yellow solid. ESI-LCMS: m/z=408.0
Reaction SMILES: C[O-].[Na+:3].[CH3:4][C:5]1[CH:29]=[CH:28][C:8]([O:9][CH2:10][C:11]#[C:12][CH2:13][C:14]#[C:15][CH2:16][C:17]#[C:18][CH2:19][C:20]#[C:21][CH2:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26])=[CH:7][CH:6]=1>CO>[Na+:3].[CH3:4][C:5]1[CH:29]=[CH:28][C:8]([O:9][CH2:10][C:11]#[C:12][CH2:13][C:14]#[C:15][CH2:16][C:17]#[C:18][CH2:19][C:20]#[C:21][CH2:22][CH2:23][CH2:24][C:25]([O-:27])=[O:26])=[CH:7][CH:6]=1
Reactant: Cc1ccc(OCC#CCC#CCC#CCC#CCCCC(=O)O)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1ccc(OCC#CCC#CCC#CCC#CCCCC(=O)[O-])cc1

Procedure:
Sodium methoxide (82 mg) is added to a solution of 16-(p-methylphenoxy)-hexadeca-5,8,11,14-tetraynoic acid (500 mg) in methanol (5 ml). The solution is then evaporated to dryness to afford 16-(p-methylphenoxy)-hexadeca-5,8,11,14-tetraynoic acid sodium salt.
Reaction SMILES: [Cl:1][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([N:11]2[CH:15]=[C:14]([CH3:16])[N:13]=[CH:12]2)[C:3]=1[C:4]#[N:5].[CH3:17][N+:18]([CH3:20])=[CH2:19].[I-]>CN(C=O)C>[Cl:1][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([N:11]2[C:15]([CH2:17][N:18]([CH3:20])[CH3:19])=[C:14]([CH3:16])[N:13]=[CH:12]2)[C:3]=1[C:4]#[N:5]
Reactant: C=[N+](C)C
Reactant: Cc1cn(-c2ccc(F)c(Cl)c2C#N)cn1
Agent: [I-]
Solvent: CN(C)C=O
Product: Cc1ncn(-c2ccc(F)c(Cl)c2C#N)c1CN(C)C
Yield: 52 %

Procedure:
In analogy to example 5b, 2-chloro-3-fluoro-6-(4-methyl-imidazol-1-yl)-benzonitrile was reacted with Eschenmoser's salt in DMF for 16 h at 90° C. Evaporation of the solvent, aqueous workup and chromatography (SiO2, dichloromethane:methanol=100:0 to 97:3) afforded the title compound as a light yellow oil (yield: 52%). MS: m/e=293.1 [M+H]+.
Reaction SMILES: [CH2:1]([N:3]([CH2:32][CH3:33])[C:4](=[O:31])[CH:5]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)[C:6]([NH:8][S:9]([C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=1)(=[O:11])=[O:10])=[O:7])[CH3:2].[C:34]([C:36]1[CH:37]=[C:38]([N:44]2CCNCC2)[CH:39]=[CH:40][C:41]=1[C:42]#[N:43])#[N:35]>>[C:34]([C:36]1[CH:37]=[C:38]([N:44]2[CH2:2][CH2:1][N:3]([C:4](=[O:31])[CH:5]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)[C:6]([NH:8][S:9]([C:12]3[CH:21]=[CH:20][C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH:13]=3)(=[O:10])=[O:11])=[O:7])[CH2:32][CH2:33]2)[CH:39]=[CH:40][C:41]=1[C:42]#[N:43])#[N:35]
Reactant: CCN(CC)C(=O)C(Cc1ccc(OC)cc1)C(=O)NS(=O)(=O)c1ccc2ccccc2c1
Reactant: N#Cc1ccc(N2CCNCC2)cc1C#N
Product: COc1ccc(CC(C(=O)NS(=O)(=O)c2ccc3ccccc3c2)C(=O)N2CCN(c3ccc(C#N)c(C#N)c3)CC2)cc1
Yield: 67.3 %

Procedure:
In the same manner as in Example 1 (4), a crude product was obtained using the compound (550 mg) obtained in Example 112 (4) and N-(3,4-dicyanophenyl)piperazine (282 mg). This was purified by silica gel column chromatography to give the title compound (480 mg) as a yellow powder.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:11]#[C:12][C:13]2[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][N:16]=[C:15]([NH:23][C:24]3[CH:29]=[CH:28][C:27]([N:30]4[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH2:31]4)=[CH:26][CH:25]=3)[N:14]=2)[CH2:4][NH:3]1.[H][H].CO>CN(C=O)C.[OH-].[OH-].[Pd+2].CCOC(C)=O>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH2:11][CH2:12][C:13]2[C:18]([C:19]([F:20])([F:21])[F:22])=[CH:17][N:16]=[C:15]([NH:23][C:24]3[CH:25]=[CH:26][C:27]([N:30]4[CH2:31][CH2:32][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:34][CH2:35]4)=[CH:28][CH:29]=3)[N:14]=2)[CH2:4][NH:3]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3ncc(C(F)(F)F)c(C#Cc4cccc5c4C(=O)NC5)n3)cc2)CC1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4cccc5c4C(=O)NC5)n3)cc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 55.9 %

Procedure:
tert-Butyl 4-(4-((4-((3-oxoisoindolin-4-yl)ethynyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperazine-1-carboxylate (I62) (0.149 g, 0.258 mmol) was dissolved in dry DMF (6 mL) under an atmosphere of nitrogen. 20% Pearlman's catalyst (0.090 g) in EtOAc (6 mL) was added to the solution and the atmosphere was changed to hydrogen gas (balloon). The reaction was sealed with a balloon and stirred at room temperature for 18 hours at room temperature. The catalyst was removed by filtration through Celite, which was washed with EtOAc (5×10 mL). The solvent was removed in vacuo to give a yellow solid which was purified by silica gel chromatography (Biotage Isolera, 40 g Si Cartridge, 0-100% EtOAc in petroleum benzine 40-60° C., then 0-5% methanol in EtOAc) to give the title compound (I63) (0.084 g, 56% yield) as an off-white solid; 1H NMR (400 MHz, d6-DMSO) δ 9.98 (s, 1H), 8.57 (s, 1H), 8.48 (s, 1H), 7.62-7.55 (m, 2H), 7.44 (t, J=7.4 Hz, 1H), 7.38 (d, J=7.3 Hz, 1H), 7.17 (br d, J=6.0 Hz, 1H), 6.92 (d, J=9.0 Hz, 2H), 4.31 (s, 2H), 3.56 (t, J=7.6 Hz, 2H), 3.51-3.41 (m, 4H), 3.12 (t, J=7.5 Hz, 2H), 3.08-2.98 (m, 4H), 1.42 (s, 9H). LCMS Method A: rt 5.86 min; m/z 583.5 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=[CH:10][N+:9]=2[O-])=[CH:4][CH:3]=1.C(=O)([O-])[O-:20].[K+].[K+]>C(OC(=O)C)(=O)C.CO.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=[C:10]([OH:20])[N:9]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc[n+]([O-])c1-c1ccc(F)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Solvent: CO
Solvent: O
Product: COC(=O)c1ccc(O)nc1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.2 %

Procedure:
A solution of 2-(4-fluorophenyl)-3-(methoxycarbonyl)pyridine-1-oxide (10.5 g.) in acetic anhydride (500 ml.) was stirred at reflux for 17 hr., cooled, evaporated to dryness and the residue partitioned between saturated sodium bicarbonate solution and ethyl acetate. The organic layer was separated, dried and evaporated to dryness. The gum obtained was dissolved in methanol (400 ml.), treated with a solution of potassium carbonate (11.7 g.) in water (100 ml) and stirred at ambient temperature for 2 hours. The methanol was evaporated off, the aqueous residue diluted with more water (200 ml.) and the mixture filtered to give methyl 2-(4-fluorophenyl)-6-hydroxypyridin-3-carboxylate (8.0 g.) as a brown solid.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]2[N:5]=[CH:4][C:3]=1[C:16]([N:18]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:20][CH2:19]1)=[O:17].[F:30][C:31]1[CH:37]=[CH:36][C:34]([NH2:35])=[CH:33][C:32]=1[CH3:38]>>[CH2:14]([O:13][C:11]([C:10]1[CH:9]=[N:8][N:7]2[C:2]([NH:35][C:34]3[CH:36]=[CH:37][C:31]([F:30])=[C:32]([CH3:38])[CH:33]=3)=[C:3]([C:16]([N:18]3[CH2:23][CH2:22][CH:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH2:20][CH2:19]3)=[O:17])[CH:4]=[N:5][C:6]=12)=[O:12])[CH3:15]
Reactant: Cc1cc(N)ccc1F
Reactant: CCOC(=O)c1cnn2c(Cl)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Product: CCOC(=O)c1cnn2c(Nc3ccc(F)c(C)c3)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Yield: 99.7 %

Procedure:
In the same manner as in Example 19, step 5 and using 7-chloro-3-ethoxycarbonyl-6-(4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine (100 mg, 0.24 mmol) obtained in Example 19, step 4 and 4-fluoro-3-methylaniline (46 mg, 0.36 mmol), the title compound (120 mg, 99%) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][C:8]([NH2:10])=[NH:9])=[CH:4][CH:3]=1.[Cl:13][C:14]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:15]=1[CH:16]=[C:17]([C:20]#[N:21])[C:18]#[N:19]>>[NH2:21][CH2:20][C:17]1[C:18]([NH2:19])=[N:9][C:8]([CH2:7][O:6][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:12][CH:11]=2)=[N:10][C:16]=1[C:15]1[CH:22]=[CH:23][C:24]([Cl:26])=[CH:25][C:14]=1[Cl:13]
Reactant: N=C(N)COc1ccc(F)cc1
Reactant: N#CC(C#N)=Cc1ccc(Cl)cc1Cl
Product: NCc1c(N)nc(COc2ccc(F)cc2)nc1-c1ccc(Cl)cc1Cl

Procedure:
The title compound, MS: m/e=392.8 (M+H+), was prepared from 2-(4-fluoro-phenoxy)-acetamidine and 2-(2,4-dichloro-benzylidene)-malononitrile in analogy to the process described in Example 11 as a solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:12]([C:13]([OH:15])=O)[CH2:11][S:10][CH:9]1[C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:22][CH2:23][CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][N:29]([CH:32]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:28][CH2:27]1.C(P(C#N)(CC)=O)C.C(N(CC)CC)C>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[C@H:12]([C:13](=[O:15])[NH:22][CH2:23][CH2:24][CH2:25][N:26]2[CH2:27][CH2:28][N:29]([CH:32]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH2:30][CH2:31]2)[CH2:11][S:10][CH:9]1[C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: NCCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Reactant: CC(C)(C)OC(=O)N1C(c2cccnc2)SC[C@H]1C(=O)O
Agent: CCP(=O)(C#N)CC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C(c2cccnc2)SC[C@H]1C(=O)NCCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.7 %

Procedure:
A mixture of 500 mg (1.61 mmole) of 3-t-butoxycarbonyl-2-(3-pyridyl)thiazolidine-4(R)-carboxylic acid, 500 mg (1.61 mmole) of 1-(3-aminopropyl)-4-(diphenylmethyl) piperazine (prepared as described in Preparation 16'), 263 mg (1.61 mmole) of diethylphosphoryl cyanide, 163 mg (1.61 mmole) of triethylamine and 10 ml of tetrahydrofuran was stirred at room temperature overnight. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, diluted with water and extracted with methylene chloride. The solvent was then removed by evaporation under reduced pressure, and the resulting residue was subjected to column chromatography through alumina, using ethyl acetate as the eluent, to afford 840 mg (yield 89%) of the title compound as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6]2.[CH2:13]([O:15][C:16](=[O:24])[N:17]([CH2:21][CH2:22]Br)[CH2:18][CH2:19]Br)[CH3:14].[H-].[Na+]>CN(C=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[C:7]1([CH2:22][CH2:21][N:17]([C:16]([O:15][CH2:13][CH3:14])=[O:24])[CH2:18][CH2:19]1)[CH2:6]2
Reactant: COc1ccc2c(c1)CCC2=O
Reactant: CCOC(=O)N(CCBr)CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)N1CCC2(CC1)Cc1cc(OC)ccc1C2=O
Temperature: 50 °C
Reaction time: 16 h
Yield: 31.5 %

Procedure:
To a stirred solution of 5-methoxy-1-indanone (1.0 g, 6.17 mmol) and bis-(2-bromo-ethyl)-carbamic acid ethyl ester (1.87 g, 6.17) in DMF (10 mL) at 50° C. was added NaH (0.370 g, 15.4 mmol) by small portions. After being stirred at 50° C. for 16 hr, the reaction was cooled to ambient temperature. The reaction was diluted with 15 mL of ethyl acetate and washed twice with 10 mL of water, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by flash column (gradient of 85:15 to 60:40 heptane/ethyl acetate over 30 min) to give the title compound (590 mg, 1.945 mmol). MS calculated for C17H22NO4 304.4. found (ESI) m/z 304.2 (M+H)+, retention time 1.56 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].[CH2:11]([O:18][NH:19][C:20]([C:22]1[C:27]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[C:26]([CH2:36][OH:37])[C:25]([C:38](NCC2C=CC(F)=CC=2)=[O:39])=[CH:24][N:23]=1)=[O:21])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CN(C=O)C>[CH2:11]([O:18][NH:19][C:20]([C:22]1[C:27]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[C:26]([CH2:36][OH:37])[C:25]([C:38]([NH:6][CH2:5][C:4]2[CH:7]=[CH:8][C:9]([Cl:10])=[C:2]([Cl:1])[CH:3]=2)=[O:39])=[CH:24][N:23]=1)=[O:21])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(NCc1ccc(F)cc1)c1cnc(C(=O)NOCc2ccccc2)c(OCc2ccccc2)c1CO
Reactant: NCc1ccc(Cl)c(Cl)c1
Solvent: CN(C)C=O
Product: O=C(NCc1ccc(Cl)c(Cl)c1)c1cnc(C(=O)NOCc2ccccc2)c(OCc2ccccc2)c1CO
Yield: 37.6 %

Procedure:
3,4 diChloro benzylamine (0.060 g, 1.29 mmol, 2 eq) and N,7-bis(benzyloxy)-3-oxo-1,3-dihydrofuro[3,4-c]pyridine-6-carboxamide (0.050 g, 0.141 mmol, 1 eq) (compound 1c of example 1) were heated in DMF at 90° C. for 120 min. The crude product was purified by silica gel (100% ethyl acetate) yielding 0.03 g of N2,3-bis(benzyloxy)-N5-(3,4-dichlorobenzyl)-4-(hydroxymethyl)pyridine-2,5-dicarboxamide (29%) as a white solid; MS-ESI m/z 589 [MH]+.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]([C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]([NH2:19])=[NH:18])=[CH:12][CH:11]=1)=[O:4].CN(C)/[CH:23]=[C:24](\[F:36])/[C:25]([C:27]1[N:31]([CH:32]([CH3:34])[CH3:33])[C:30]([CH3:35])=[N:29][CH:28]=1)=O>C(O)CCC>[CH3:1][N:2]([CH3:20])[C:3]([C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[N:19]=[C:25]([C:27]3[N:31]([CH:32]([CH3:33])[CH3:34])[C:30]([CH3:35])=[N:29][CH:28]=3)[C:24]([F:36])=[CH:23][N:18]=2)=[CH:12][CH:11]=1)=[O:4]
Reactant: Cc1ncc(C(=O)/C(F)=C/N(C)C)n1C(C)C
Reactant: CN(C)C(=O)[C@@H]1CCCN1c1ccc(NC(=N)N)cc1
Solvent: CCCCO
Product: Cc1ncc(-c2nc(Nc3ccc(N4CCC[C@H]4C(=O)N(C)C)cc3)ncc2F)n1C(C)C
Temperature: 200 °C
Yield: 26.9 %

Procedure:
(S)-1-(4-Guanidino-phenyl)-pyrrolidine-2-carboxylic acid dimethylamide (Method 54; 0.5 g, 1.82 mmol) and (2Z)-3-(dimethylamino)-2-fluoro-1-(1-isopropyl-2-methyl-1H-imidazol-5-yl)prop-2-en-1-one (Method 14; 0.2 g, 0.83 mmol) were heated at reflux in butanol (7 ml) overnight. LCMS indicated only 7% product. The reaction was transferred to a microwave tube and heated at 200° C. for 2 hours. LCMS indicated 15% starting material and mainly product. The solvent was removed in vacuo and chromatographed. The product was purified by HPLC and the required fractions were combined and basified with K2CO3 (0.5 g), extracted with DCM (2×50 ml), dried and the solvent removed in vacuo to yield a yellow solid (101 mg, 31%). NMR (400.132 MHz, CDCl3) 8.18 (d, 1H), 7.56 (d, 1H), 7.24 (d, 2H), 6.69 (s, 1H), 6.42 (d, 2H), 5.59 (septet, 1H), 4.51 (dd, 1H), 3.64 (dt, 1H), 3.41 (q, 1H), 3.16 (s, 3H), 2.98 (s, 3H), 2.56 (s, 3H), 2.38-2.28 (m, 1H), 2.25-2.14 (m, 1H), 2.08-1.98 (m, 2H), 1.39 (t, 6H); m/z 452.
Reaction SMILES: CC1(C)C2C=C(C#CC3C=CC(C(O)=O)=CC=3)C=CC=2C(C2C=CC=CC=2)=CC1.[CH3:30][C:31]1([CH3:58])[C:40]2[CH:39]=[C:38]([C:41]#[C:42][C:43]3[CH:53]=[CH:52][C:46]([C:47]([O:49]CC)=[O:48])=[CH:45][CH:44]=3)[CH:37]=[CH:36][C:35]=2[C:34]([C:54]([CH3:57])([CH3:56])[CH3:55])=[CH:33][CH2:32]1>>[CH3:30][C:31]1([CH3:58])[C:40]2[CH:39]=[C:38]([C:41]#[C:42][C:43]3[CH:44]=[CH:45][C:46]([C:47]([OH:49])=[O:48])=[CH:52][CH:53]=3)[CH:37]=[CH:36][C:35]=2[C:34]([C:54]([CH3:57])([CH3:56])[CH3:55])=[CH:33][CH2:32]1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CC=C3C(C)(C)C)cc1
Agent: CC1(C)CC=C(c2ccccc2)c2ccc(C#Cc3ccc(C(=O)O)cc3)cc21
Product: CC(C)(C)C1=CCC(C)(C)c2cc(C#Cc3ccc(C(=O)O)cc3)ccc21

Procedure:
Employing the same general procedure as for the preparation of 4-[(7,8-dihydro-8,8-dimethyl-5-phenylnaphth-2-yl)ethynyl]benzoic acid (Compound 97), 51 mg (0.13 mmol) of ethyl 4-[(7,8-dihydro-8,8-dimethyl-5-(1,1-dimethylethyl)naphth-2-yl)ethynyl]benzoate (Compound 96) was converted to the title compound (white solid) using 28 mg (1.3 ml, 0.66 mmol) of LiOH (0.5M aqueous solution).