Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:8][NH:9][C:10]2[N:18]=[C:17]([NH:19][NH2:20])[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][N:14]3[C@@H:21]2[CH2:25][C@H:24]([NH:26][C:27](=[O:30])[CH2:28][CH3:29])[C@@H:23]([OH:31])[C@H:22]2[OH:32])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:39]1([CH:45]=O)[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1>CO>[CH:39]1([CH:45]=[N:20][NH:19][C:17]2[N:16]=[C:15]3[C:11]([N:12]=[CH:13][N:14]3[C@@H:21]3[CH2:25][C@H:24]([NH:26][C:27](=[O:30])[CH2:28][CH3:29])[C@@H:23]([OH:31])[C@H:22]3[OH:32])=[C:10]([NH:9][CH2:8][CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:18]=2)[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(NN)nc32)[C@H](O)[C@@H]1O
Reactant: O=CC1CCCCC1
Solvent: CO
Product: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(NN=CC4CCCCC4)nc32)[C@H](O)[C@@H]1O

Procedure:
To a solution of N-{4-[6-(2,2-diphenyl-ethylamino)-2-hydrazino-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-propionamide (step 1) (0.1 g, 0.19 mmol) in dry methanol (5 ml) is added cyclohexane carboxaldehyde (0.026 g, 0.23 mmol). The reaction mixture is heated at reflux for 12 h. The reaction mixture is concentrated in vacuo purification by preparative TLC affords the title compound. LC-MS (0.1% formic acid, acetonitrile): (MH+ 611.45)
Reaction SMILES: [CH2:1]([N:8]([CH2:13][CH:14](S(C)(=O)=O)[CH2:15]S(C)(=O)=O)[CH2:9][CH2:10][C:11]#[N:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Na+]>C1C=CC=CC=1.O1CCCC1>[CH2:1]([N:8]1[CH2:13][CH:14]2[C:10]([C:11]#[N:12])([CH2:15]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)CC(CN(CCC#N)Cc1ccccc1)S(C)(=O)=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: c1ccccc1
Product: N#CC12CC1CN(Cc1ccccc1)C2
Reaction time: 2 h
Yield: 48.7 %

Procedure:
N-Benzyl-N-(2-cyanoethyl)-2,3-dimethanesulfonylpropylamine (32.25 g, 85.2 mmol) was dissolved in benzene (800 ml), cooled to -10°, and treated with sodium hexamethyldisilazide (170 ml of a 1M solution in tetrahydrofuran, 170 mmol). After 2 hours, the reaction mixture was quenched with saturated ammonium chloride solution, and the mixture was extracted three times with methylene chloride. The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo. Chromatographic purification (eluant: 4:1 hexane:ethyl acetate) gave the title product as a yellow oil (8.23 g, 41.5 mmol, 49% yield). 1H NMR (CDCl3): 7.26 (m, 5H), 3.59 (s, 2H), 3.11 (d, J=9 Hz, 1H), 2.94 (d, J=9 Hz, 1H), 2.54 (d, J=9 Hz, 1H), 2.47 (dd, J=10, 4 Hz, 1H), 2.03 (m, 1H), 1.57 (m, 1H), 1.10 (dd, J=8, 5 Hz, 1H).
Reaction SMILES: CC([NH:5][S:6]([C:9]1[CH:13]=[CH:12][NH:11][C:10]=1[CH:14]=[N:15][O:16][CH3:17])(=[O:8])=[O:7])(C)C.[C:18](O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:17][O:16][N:15]=[CH:14][C:10]1[N:11]([CH3:18])[CH:12]=[CH:13][C:9]=1[S:6]([NH2:5])(=[O:7])=[O:8]
Reactant: CON=Cc1[nH]ccc1S(=O)(=O)NC(C)(C)C
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CON=Cc1c(S(N)(=O)=O)ccn1C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 5.74 g (21.9 mmol) of N-(1,1-dimethylethyl)-2-[(methoxyimino)-methyl]-1H-pyrrole-3-sulfonamide in 75 mL methylene chloride under a nitrogen atmosphere was add 75 mL of TFA. The clear orange reaction mixture was allowed to stir at room temperature overnight ca. 16 hours. The orange reaction mixture was concentrated in vacuo. Three portions of diethyl ether were added to the residue and removed by evaporation to remove residual TFA, affording 3.49 g of the title compound as a gray solid, m.p. 120°-122° C. 1H NMR (CDCl3, 200 MHz.) δ: 8.43(s,1H), 6.66(d,1H), 6.54(d,1H), 6.1-6.7(bs,2H), 3.96(s,3H), 3.79(s,3H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=2[F:18])[N:3]=1.[H-].[Na+].[CH2:21]([OH:23])[CH3:22]>O>[Cl:8][C:6]1[CH:7]=[C:2]([O:23][CH2:21][CH3:22])[N:3]=[C:4]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=2[F:18])[N:5]=1
Reactant: CCO
Reactant: Fc1cccc(CSc2nc(Cl)cc(Cl)n2)c1F
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CCOc1cc(Cl)nc(SCc2cccc(F)c2F)n1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 4,6-Dichloro-2-[(2,3-difluorobenzyl)thio]pyrimidine (0.50 g) in ethanol (5 mL) was added 60% sodium hydride (72 mg) and the reaction mixture was stirred at ambient temperature for 6 h. The mixture was diluted with H2O and extracted with EtOAc (×2). The combined organic layers were dried (MgSO4), filtered and evaporated to give the subtitle compound as a clear, colourless oil. Yield: 0.53 g
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10](F)[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1)[CH3:2].Cl.Cl.[CH:22]12[NH:30][CH2:29][CH:26]([NH:27][CH2:28]1)[CH2:25][CH2:24][CH2:23]2.N12CCCN=C1CCCCC2>C(#N)C>[CH:22]12[NH:30][CH2:29][CH:26]([N:27]([C:10]3[C:11]([F:13])=[C:12]4[C:7]([C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4][N:3]4[CH2:1][CH3:2])=[CH:8][C:9]=3[F:15])[CH2:28]1)[CH2:25][CH2:24][CH2:23]2
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)c(F)c21
Reactant: C1CC2CNC(C1)CN2
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CC4CCCC3CN4)c(F)c21
Temperature: 25 °C
Yield: 45.9 %

Procedure:
A solution of 0.81 g (3.0 mmol) of 1-ethyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 0.66 g (3.3 mmol) of 6,8-diazabicyclo[3.2.2]nonane, dihydrochloride, 1.35 ml (9.0 mmol) of 1,8-diazabicyclo[5.4.0]undec-7-ene and 20 ml of acetonitrile was heated under reflux for 3 hr. After cooling to room temperature the solid was collected by filtration to give 0.52 g of the title compound, mp 245°-250°.
Reaction SMILES: [Br:1][C:2](Br)=[CH:3][C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][CH:5]=1.CC(C)([O-])C.[K+].C1(C)C=CC=CC=1>O>[Br:1][C:2]#[C:3][C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][CH:5]=1
Reactant: Fc1ccc(C=C(Br)Br)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: Fc1ccc(C#CBr)cc1
Temperature: 80 °C
Yield: 70.4 %

Procedure:
A mixture of 1-(2,2-dibromo-vinyl)-4-fluoro-benzene (0.6 g, 0.00214 mol), potassium tertbutoxide (0.48 g, 0.00428 mol) and toluene (6 mL) were heated at 80° C. for 4 h. After completion of reaction, the reaction mixture was cooled to RT, diluted with water (15 mL), and extracted with EtOAc (3×50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduce pressure to obtain product as a yellow oil (0.3 g, 70%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][C:11]([OH:13])=O.[Cl:14][C:15]1[CH:24]=[CH:23][C:18]([O:19][CH2:20][CH2:21][NH2:22])=[CH:17][CH:16]=1.CCN=C=NCCCN(C)C.Cl.Cl>O1CCCC1.C(Cl)Cl>[Cl:14][C:15]1[CH:24]=[CH:23][C:18]([O:19][CH2:20][CH2:21][NH:22][C:11](=[O:13])[CH2:10][CH2:9][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])=[CH:17][CH:16]=1
Reactant: COc1ccccc1CCC(=O)O
Reactant: NCCOc1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1ccccc1CCC(=O)NCCOc1ccc(Cl)cc1
Reaction time: 8 h

Procedure:
3-(2-Methoxyphenyl)propionic acid (8.3 g, 46.2 mmol) was dissolved in tetrahydrofuran (20 mL), and 4-chlorophenoxyethylamine (10.3 g, 60.0 mmol) was added dropwise thereto at room temperature. Subsequently, a solution (10 mL) of WSC.HCl (11.5 g, 60.0 mmol) in methylene chloride was slowly added dropwise thereto under ice-cooling, followed by stirring overnight. Under ice cooling, diluted hydrochloric acid was added dropwise thereto, followed by extraction with chloroform. The organic layer was washed with brine, and the resultant mixture was subjected to drying over anhydrous sodium sulfate, concentration under reduced pressure, and purification by silica gel chromatography (chloroform/methanol=20/1), whereby the target compound was obtained (12.8 g, 83%).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5](Cl)(=[O:7])=[O:6].[NH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]([CH3:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:12][C:11]=1[F:23].N1C=CC=CC=1>C(Cl)Cl>[Cl:1][CH2:2][CH2:3][CH2:4][S:5]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]([CH3:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:12][C:11]=1[F:23])(=[O:7])=[O:6]
Reactant: CCOC(=O)C(C)c1ccc(N)c(F)c1
Reactant: O=S(=O)(Cl)CCCCl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)C(C)c1ccc(NS(=O)(=O)CCCCl)c(F)c1
Reaction time: 1 h
Yield: 90.1 %

Procedure:
Chloropropanesulfonyl chloride (0.576 mL, 4.73 mmol) was added to a solution of ethyl 2-(4-amino-3-fluorophenyl)propanoate (1 g, 4.735 mmol) and pyridine (0.382 mL, 4.735 mmol) in DCM (18 mL) at 0° C. The reaction mixture was stirred for 1 h, after it was partitioned between DCM (10 mL) and 1N hydrochloric acid (10 mL). The organic phase was separated and dried over magnesium sulfate, filtered and concentrated in vacuo to afford ethyl 2-(4-(3-chloropropylsulfonamido)-3-fluorophenyl)propanoate as an oil (1.5 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[Cl:8].[C:12](OCC)(=[O:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14].[Na]>>[CH2:16]([O:15][C:13](=[O:14])/[C:12](/[OH:18])=[CH:10]/[C:9]([C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)=[O:11])[CH3:17]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)c1ccc(Cl)c(Cl)c1
Agent: [Na]
Product: CCOC(=O)/C(O)=C/C(=O)c1ccc(Cl)c(Cl)c1

Procedure:
In analogy to the procedure described for example 11 a], 1-(3,4-dichloro-phenyl)-ethanone was reacted with diethyl oxalate in the presence of metallic sodium to give (Z)-4-(3,4-dichloro-phenyl)-2-hydroxy-4-oxo-but-2-enoic acid ethyl ester as off-white solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]1([CH2:13][CH2:14][CH2:15][NH2:16])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][C:18]=1[O:27][CH2:28][CH2:29][CH2:30][CH2:31]Cl>CS(C)=O.O>[C:7]1([CH2:13][CH2:14][CH2:15][NH:16][CH2:31][CH2:30][CH2:29][CH2:28][O:27][C:18]2[CH:19]=[CH:20][C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:17]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: ClCCCCOc1ccc2ccccc2c1
Reactant: NCCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: c1ccc(CCCNCCCCOc2ccc3ccccc3c2)cc1
Temperature: 145 °C

Procedure:
A mixture of anhydrous potassium carbonate (10 gm, in excess) and 3-phenylpropylamine (0.42 ml, 0.003 mole) was taken in dry DMSO (40 ml). Now 4-(2-naphthyloxy)-1-chlorobutane (0.5 gm, 0.002 mole) was added in it. Reaction mixture was refluxed at 145° C. for 7 hrs and the reaction was completed as checked by TLC. Reaction mixture was poured in distilled water (60 ml) and extracted with ethyl acetate thrice. The organic layer was separated and concentrated to get oily compound which was later crystallized by benzene hexane to get N-(3-phenylpropyl)-(4-(naphthalen-2-yloxy)butyl)amine solid, m.p. 117° C., (yield 0.67 gm, 93.6%).
Reaction SMILES: Br[CH2:2][C:3]1[C:8](I)=[CH:7][N:6]=[C:5]([Cl:10])[CH:4]=1.[C:11]([N:14]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[CH:19]=[CH:18]C2N=C(Cl)C(F)=CC=2C1)(=[O:13])[CH3:12]>>[C:11]([N:14]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[CH:19]=[CH:18][C:8]2[CH:7]=[N:6][C:5]([Cl:10])=[CH:4][C:3]=2[CH2:2]1)(=[O:13])[CH3:12]
Reactant: Clc1cc(CBr)c(I)cn1
Reactant: CC(=O)N1Cc2cc(F)c(Cl)nc2C=Cc2ccccc21
Product: CC(=O)N1Cc2cc(Cl)ncc2C=Cc2ccccc21

Procedure:
Compound 25E was prepared from 25D and bb in two steps by a route analogous to that used for the preparation of 1D. HPLC Rt=2.506 min; LCMS Found: (M+H)+=285.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][CH:6]=1)=[O:4].[C:15]([O:21][CH3:22])(=[O:20])[CH2:16][C:17]([CH3:19])=O>>[CH3:19][C:17]1[O:4][C:3]([C:5]2[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][CH:6]=2)=[CH:2][C:16]=1[C:15]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)CC(C)=O
Reactant: O=C(CCl)c1ccc(C(F)(F)F)cc1
Product: COC(=O)c1cc(-c2ccc(C(F)(F)F)cc2)oc1C
Yield: 39.4 %

Procedure:
An operation similar to that in Example 1 (1) was performed using 2-chloro-4′-(trifluoromethyl)acetophenone (13.4 g) and methyl acetoacetate (5.8 g) to give the title compound (5.6 g, 39%) as a yellow crystal.
Reaction SMILES: C[Si]([N-:5][Si](C)(C)C)(C)C.[Li+].Cl[CH:12]([B:16]1[O:20][C:19]([CH3:22])([CH3:21])[C:18]([CH3:24])([CH3:23])[O:17]1)[CH2:13][CH:14]=[CH2:15].[F:25][C:26]([F:31])([F:30])[C:27]([OH:29])=[O:28]>O1CCCC1>[F:25][C:26]([F:31])([F:30])[C:27]([OH:29])=[O:28].[CH2:13]([CH:12]([B:16]1[O:20][C:19]([CH3:22])([CH3:21])[C:18]([CH3:24])([CH3:23])[O:17]1)[NH2:5])[CH:14]=[CH2:15]
Reactant: C=CCC(Cl)B1OC(C)(C)C(C)(C)O1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: C=CCC(N)B1OC(C)(C)C(C)(C)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.4 %

Procedure:
6.6 ml (6.6 mmol) of 1M lithium bis(trimethylsilyl)amide in tetrahydrofuran were added dropwise to a solution of 1.43 g (6.6 mmol) of 2-(1(RS)-chloro-3-butenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane in 20 ml of tetrahydrofuran under nitrogen at -78° C. The solution was then stirred overnight at room temperature. The solvent was removed by evaporation and the residue was taken up in diethyl ether. Insoluble material was removed by filtration and the filtrate was cooled to 0° C. 1.5 ml (19.8 mmol) of trifluoroacetic acid were added and thesolution was stirred at 0° C. for 30 minutes. The resulting precipitate was filtered off and dried to give 0.5 g of α-(RS)-allyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-methylamine trifluoroacetate which was used in the next step without further purification.
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]([CH3:15])[C:8]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[N:7][C:6]2=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:32])=CC=1>C1(C)C=CC=CC=1>[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]([CH3:15])[C:8]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[N:7][C:6]2=[S:32]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COc1cc2c(=O)nc(-c3ccccc3)n(C)c2cc1OC
Solvent: Cc1ccccc1
Product: COc1cc2c(=S)nc(-c3ccccc3)n(C)c2cc1OC
Reaction time: 2 h

Procedure:
1.50 g (5.06 mmol) 6,7-Dimethoxy-1-methyl-2-phenyl-1H-quinazolin-4-one and) 2.00 g (4.94 mmol) Lawesson's reagent (C14H14O2P2S4, Fluka) were dissolved in 20 ml toluene. The reaction mixture was boiled for 2 h. After evaporation the residue was further purified by column chromatography with silica, eluent dichloromethane/acetone 95/5.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:12][CH:13]=[CH:14][C:15]=1[NH:16][C:17]1[C:18]2[CH:25]=[CH:24][NH:23][C:19]=2[N:20]=[CH:21][N:22]=1)=[O:10])C1C=CC=CC=1.[F:26][C:27]1[CH:35]=[CH:34][C:30]([CH2:31]CN)=[CH:29][CH:28]=1>>[F:26][C:27]1[CH:35]=[CH:34][C:30]([CH2:31][CH2:1][NH:8][C:9]([C:11]2[S:12][CH:13]=[CH:14][C:15]=2[NH:16][C:17]2[C:18]3[CH:25]=[CH:24][NH:23][C:19]=3[N:20]=[CH:21][N:22]=2)=[O:10])=[CH:29][CH:28]=1
Reactant: NCCc1ccc(F)cc1
Reactant: O=C(NCc1ccccc1)c1sccc1Nc1ncnc2[nH]ccc12
Product: O=C(NCCc1ccc(F)cc1)c1sccc1Nc1ncnc2[nH]ccc12
Yield: 14 %

Procedure:
The title compound was prepared in an analogous manner as 3-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-thiophene-2-carboxylic acid benzylamide using 4-fluorophenethylamine instead of benzylamine and obtained in 14% yield (HPLC: 92%, RT: 6.36 min). 1H NMR (DMSO-d6) 11.97 (br s, 1H), 11.37 (s, 1H), 8.47 (d, J=5.4 Hz, 1H), 8.38 (s, 1H), 8.31 (t, J=5.7 Hz, 1H), 7.75 (d, J=5.4 Hz, 1H), 7.37 (dd, J=3.4, 2.4 Hz, 1H), 7.32-7.26 (m, 2H), 7.16-7.08 (m, 2H), 6.45 (dd, J=3.6, 1.9 Hz, 1H), 3.49 (dd, J=14.3, 6.4 Hz, 2H), 2.86 (t, J=7.6 Hz, 2H); MS (m/z) 382 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([Cl:9])[N:3]=1.[NH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>>[Cl:9][C:4]1[N:5]=[C:6]([Cl:8])[N:7]=[C:2]([NH:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[N:3]=1
Reactant: NCCN1CCCCC1
Reactant: Clc1nc(Cl)nc(Cl)n1
Product: Clc1nc(Cl)nc(NCCN2CCCCC2)n1

Procedure:
Following the general procedure A, 2,4,6-trichloro-1,3,5-triazine was coupled with 1-(2-Aminoethyl)piperidine with reaction time of 2 h. Purification by column chromatography gave the title compound.
Reaction SMILES: [CH2:1]1[C@@H:8]2[C@@H:4]([CH2:5][C:6](=[O:9])[CH2:7]2)[CH2:3][C:2]1=[O:10].[CH3:11][C:12]([CH3:17])([CH2:15]O)[CH2:13][OH:14].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1>[CH3:11][C:12]1([CH3:17])[CH2:13][O:14][C:6]2([CH2:7][CH:8]3[CH:4]([CH2:3][C:2](=[O:10])[CH2:1]3)[CH2:5]2)[O:9][CH2:15]1
Reactant: O=C1C[C@H]2CC(=O)C[C@H]2C1
Reactant: CC(C)(CO)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC1(C)COC2(CC3CC(=O)CC3C2)OC1
Temperature: 110 °C
Reaction time: 0.08 h
Yield: 45.9 %

Procedure:
To a of solution cis-tetrahydropentalene-2,5-(1H,3H)-dione (2.99 g, 21.6 mmol) and 2,2-dimethylpropane-1,3-diol (2.254 g, 21.6 mmol) in toluene (70 mL) was added p-toluenesulfonic acid monohydrate (0.206 g, 1.08 mmol) and the mixture was heated at 110° C. for 24 hrs with a Dean Stark apparatus. The reaction mixture was cooled to room temperature, poured over solid K2CO3, stirred 5 mins then filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (12 to 100% EtOAc in hexanes) to give 5,5-dimethyltetrahydro-1′H-spiro[1,3-dioxane-2,2′-pentalen]-5′(3′H)-one (2.224 g, 9.92 mmol, 45.8% yield) as a colorless oil which solidified upon standing. MS ESI: [M+Na]+ m/z 225.7.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:12]([CH2:17][CH:18]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:14][CH2:15][CH3:16])=[O:13].CCCCC>C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:11]=[CH:10][C:7](/[CH:8]=[C:17](\[CH3:18])/[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: CCOC(=O)CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCCCC
Solvent: Cc1ccccc1
Product: CCOC(=O)/C(C)=C/c1ccc([N+](=O)[O-])cc1
Reaction time: 8 h

Procedure:
4-Nitrobenzaldehyde (4.20 g) and (carbetoxyethylidene)triphenylphosphorane (10 g) were dissolved in toluene (36 ml), and the obtained mixture was stirred overnight under reflux conditions. After the obtained reaction mixture was allowed to cool, N-pentane (50 ml) was added thereto, and the produced white precipitate was filtered off. The filtrate was concentrated, and N-pentane (70 ml) was added to the residue. Then, ultrasonic waves were applied to the mixture. The produced precipitate was filtered off and dried under reduced pressure to obtain crude (E)-ethyl 3-(4-nitrophenyl)-2-methylacrylate as a yellow powder.
Reaction SMILES: [F:1][C:2]1([F:36])[CH2:8][N:7]([C@@H:9]2[CH2:11][C@H:10]2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:6]2[N:18]=[C:19]([NH:22][C:23]3[CH:31]=[CH:30][C:26]([C:27]([OH:29])=O)=[CH:25][C:24]=3[O:32][CH3:33])[N:20]=[CH:21][C:5]=2[N:4]([CH3:34])[C:3]1=[O:35].C(N(C(C)C)C(C)C)C.[CH3:46][N:47]([CH3:52])[CH2:48][CH2:49][CH2:50][NH2:51]>CN(C)C=O>[F:1][C:2]1([F:36])[CH2:8][N:7]([C@@H:9]2[CH2:11][C@H:10]2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:6]2[N:18]=[C:19]([NH:22][C:23]3[CH:31]=[CH:30][C:26]([C:27]([NH:51][CH2:50][CH2:49][CH2:48][N:47]([CH3:52])[CH3:46])=[O:29])=[CH:25][C:24]=3[O:32][CH3:33])[N:20]=[CH:21][C:5]=2[N:4]([CH3:34])[C:3]1=[O:35]
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N([C@@H]1C[C@H]1c1ccccc1)CC(F)(F)C(=O)N2C
Reactant: CN(C)CCCN
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)NCCCN(C)C)ccc1Nc1ncc2c(n1)N([C@@H]1C[C@H]1c1ccccc1)CC(F)(F)C(=O)N2C
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.5 %

Procedure:
To a mixture of 0.074 g (0.15 mmole) of 4-[7,7-difluoro-5-methyl-6-oxo-9-(trans-2-phenyl-cyclopropyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino]-3-methoxy-benzoic acid (I-287), 0.11 mL (0.6 mmole) of ethyldiisopropyl amine and 0.016 g (0.30 mmole) of N,N-dimethyl-propane-1,3-diamine in 2.0 mL of dimethylformamide was added 0.071 g (0.17 mmole) of 1-(di-1-pyrrolidinylmethylene)-1H-benzotriazolium 3-oxide hexafluorophosphate. The mixture was stirred at room temperature for 1 hour, then diluted with 10 mL of ice water. The mixture was extracted three times with dichloromethane. The combined organic layers were washed three times with sodium carbonate, three times with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 100:0-0:100) gave 0.063 g of 4-[7,7-difluoro-5-methyl-6-oxo-9-(trans-2-phenyl-cyclopropyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino]-N-(3-dimethylamino-propyl)-3-methoxy-benzamide (I-290) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][CH2:8][C@H:9]1[C@H:13]([C:14]([F:17])([F:16])[F:15])[CH2:12][NH:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].[N+](C1C=CC([O:28][C:29](=O)[NH:30][C:31]2[CH:36]=[CH:35][C:34]([N:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]3=[O:43])=[CH:33][C:32]=2[F:44])=CC=1)([O-])=O>>[C:1]([O:5][C:6](=[O:18])[NH:7][CH2:8][C@H:9]1[C@H:13]([C:14]([F:15])([F:16])[F:17])[CH2:12][N:11]([C:29](=[O:28])[NH:30][C:31]2[CH:36]=[CH:35][C:34]([N:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]3=[O:43])=[CH:33][C:32]=2[F:44])[CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC[C@@H]1CNC[C@H]1C(F)(F)F
Reactant: O=C(Nc1ccc(-n2ccccc2=O)cc1F)Oc1ccc([N+](=O)[O-])cc1
Product: CC(C)(C)OC(=O)NC[C@@H]1CN(C(=O)Nc2ccc(-n3ccccc3=O)cc2F)C[C@H]1C(F)(F)F

Procedure:
77.1 Using general procedure H, (3S,4S)-(4-trifluoromethyl-pyrrolidin-3-ylmethyl)-carbamic acid tert-butyl ester (H. Fukui et al., Bioorganic & Medicinal Chemistry Letters, 1998, 8, 2833) was coupled with [2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-carbamic acid 4-nitro-phenyl ester (prepared according to example 54.3) to give {(3R,4S)-1-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-4-trifluoromethyl-pyrrolidin-3-ylmethyl}-carbamic acid tert-butyl ester. Orange oil. MS 499.3 ([M+H]+)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH3:9].[C:10]([NH:17][CH:18](O)[CH3:19])([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>CCOCC.C1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:19][CH2:18][NH:17][C:10](=[O:11])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:4][C:3]=1[CH3:9]
Reactant: Cc1cc(O)ccc1Br
Reactant: CC(O)NC(=O)OC(C)(C)C
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: c1ccccc1
Product: Cc1cc(OCCNC(=O)OC(C)(C)C)ccc1Br
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 4-bromo-3-methylphenol (0.187 g; 1.00 mmol), N-Boc aminoethanol (0.39 mL; 2.5 mmol) and PPh3 (0.655 g; 2.5 mmol) in anhyd PhH (5 mL) at 0° C. was added DIAD (0.49 mL; 2.5 mmol), dropwise over 15 min. The mixture was stirred 16 h at room temperature, diluted with Et2O, washed (2×satd Na2CO3, 2×H2O, brine), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (EtOAc/hexanes), affording the title compound as a colorless gum, which solidified on standing. LC/MS (method A) tR 2.95 min, m/z 330, 332 (M+H, Br isotopes, 2%), 352, 354 (M+Na, Br isotopes, 40-43%), 230, 232 ([M−Boc]+H, Br isotopes, 100%).
Reaction SMILES: CO[C:3]([C:5]1[N:6]([CH3:26])[N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)=[N:14][O:15][C:16]=2[CH2:17][OH:18])[CH:9]=1)=[O:4].[F:27][C:28]([F:32])([F:31])[CH2:29][NH2:30]>>[F:27][C:28]([F:32])([F:31])[CH2:29][NH:30][C:3]([C:5]1[N:6]([CH3:26])[N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:19]3[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=3)=[N:14][O:15][C:16]=2[CH2:17][OH:18])[CH:9]=1)=[O:4]
Reactant: NCC(F)(F)F
Reactant: COC(=O)c1cc(OCc2c(-c3ccc(F)cc3)noc2CO)nn1C
Product: Cn1nc(OCc2c(-c3ccc(F)cc3)noc2CO)cc1C(=O)NCC(F)(F)F
Yield: 97 %

Procedure:
As described for example 91h, 5-[3-(4-fluoro-phenyl)-5-hydroxymethyl-isoxazol-4-ylmethoxy]-2-methyl-2H-pyrazole-3-carboxylic acid methyl ester (100 mg, 0.28 mmol) was converted, using 2,2,2-trifluoroethylamine instead of 4-aminotetrahydropyran, to the title compound (115 mg, 97%) which was obtained as a brown solid. MS: m/e=427.0 [M−]−.