Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([CH2:23][O:24]C(=O)C)[C@@H:12]([CH2:28][O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[O:11][C@@H:10]1[O:37][C@@H:38]1[C@@H:45]([CH2:46][O:47][CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[O:44][C@H:41]([O:42][CH3:43])[C@H:40]([O:55][CH2:56][C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[C@H:39]1[O:63][CH2:64][C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.C[O-].[Na+]>C1(C)C=CC=CC=1>[CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C@H:13]([CH2:23][OH:24])[C@@H:12]([CH2:28][O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[O:11][C@@H:10]1[O:37][C@@H:38]1[C@@H:45]([CH2:46][O:47][CH2:48][C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=2)[O:44][C@H:41]([O:42][CH3:43])[C@H:40]([O:55][CH2:56][C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[C@H:39]1[O:63][CH2:64][C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CO[C@H]1O[C@H](COCc2ccccc2)[C@@H](O[C@H]2O[C@H](COCc3ccccc3)[C@@H](COC(C)=O)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: CO[C@H]1O[C@H](COCc2ccccc2)[C@@H](O[C@H]2O[C@H](COCc3ccccc3)[C@@H](CO)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methyl 4-O-(2,3,6-tri-O-benzyl-4-deoxy-4-acetyloxymethy-α-D-glucopyranosyl)-2,3,6-tri-O-benzyl-α-D-glucopyranoside (3.19 g, 3.35 mmol) is dissolved in hot toluene (20 mL) and methanol (80 mL) is added, followed by a few drops of 1 M. methanolic sodium methoxide. The mixture is stirred at room temperature during 2 h. The reaction mixture is made neutral with Amberlite IR 120 (H+) resin, filtered and concentrated under reduced pressure so as to afford methyl 4-O-(2,3,6-tri-O-benzyl-4-deoxy-4-hydroxymethyl-α-D-glucopyranosyl)-2,3,6-tri-O-benzyl-α-D-glucopyranoside as an amorphous solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:15][CH3:16])=[C:6]([CH:14]=1)[O:7][C@@H:8]1[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9]1.C(OC([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][C@@H:25]1[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=O)(C)(C)C>>[CH2:30]([C@@H:25]1[NH:24][CH2:29][CH2:28][N:27]([C:2]2[CH:3]=[CH:4][C:5]([O:15][CH3:16])=[C:6]([O:7][C@@H:8]3[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9]3)[CH:14]=2)[CH2:26]1)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: COc1ccc(Br)cc1O[C@@H]1CCN(C)C1
Reactant: CC(C)(C)OC(=O)N1CCNC[C@@H]1Cc1ccccc1
Product: COc1ccc(N2CCN[C@@H](Cc3ccccc3)C2)cc1O[C@@H]1CCN(C)C1

Procedure:
The title compound was prepared by the method outlined for Example 1 using (3R)-3-(5-Bromo-2-methoxyphenoxy)-1-methylpyrrolidine as the aryl halide and 2(S)-benzyl-piperazine-1-carboxylic acid tert-butyl ester as the amine component. The title compound was isolated as an orange oil. LC/MS (Method B) 0.87 min, [M+1]+ 382.
Reaction SMILES: [F:1][C:2]1[CH:27]=[C:26]([N+:28]([O-])=O)[CH:25]=[CH:24][C:3]=1[O:4][C:5]1[N:10]=[CH:9][N:8]=[C:7]([NH:11][C:12](=[O:23])[N:13]([CH2:15][CH2:16][CH2:17][N:18]([CH2:21][CH3:22])[CH2:19][CH3:20])[CH3:14])[CH:6]=1.[H][H]>O1CCCC1.CO.[C].[Pd]>[NH2:28][C:26]1[CH:25]=[CH:24][C:3]([O:4][C:5]2[N:10]=[CH:9][N:8]=[C:7]([NH:11][C:12](=[O:23])[N:13]([CH2:15][CH2:16][CH2:17][N:18]([CH2:19][CH3:20])[CH2:21][CH3:22])[CH3:14])[CH:6]=2)=[C:2]([F:1])[CH:27]=1
Reactant: [H][H]
Reactant: CCN(CC)CCCN(C)C(=O)Nc1cc(Oc2ccc([N+](=O)[O-])cc2F)ncn1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CCN(CC)CCCN(C)C(=O)Nc1cc(Oc2ccc(N)cc2F)ncn1
Reaction time: 8 h
Yield: 68.4 %

Procedure:
3-[6-(2-Fluoro-4-nitrophenoxy)pyrimidin-4-yl]-1-(3-diethylaminopropyl)-1-methylurea (54.0 mg) was dissolved in tetrahydrofuran (2 ml)-methanol (2 ml), and then 10% palladium carbon (27.2 mg) was added thereto, followed by replacing with hydrogen inside the system and stirring overnight. After replacing with nitrogen inside the system, the reaction mixture was filtered to remove the catalyst, which was washed with methanol. The filtrate was concentrated under a reduced pressure to give a residue, which was then purified by silica gel column chromatography (Fuji Silysia NH, eluent; hexane:ethyl acetate=1:1, then ethyl acetate). Fractions containing the target compound were concentrated under a reduced pressure to provide the titled compound (34.3 mg, 68.6%) as a pale yellow solid.
Reaction SMILES: CC1(C)[O:6][CH:5]([CH2:7][O:8][NH:9][C:10]([C:12]2[N:20]([CH:21]3[CH2:23][CH2:22]3)[C:19]3[CH:18]=[CH:17][N:16]=[CH:15][C:14]=3[C:13]=2[NH:24][C:25]2[CH:30]=[CH:29][C:28]([I:31])=[CH:27][C:26]=2[F:32])=[O:11])[CH2:4][O:3]1.Cl>CO.O1CCOCC1>[OH:6][CH:5]([CH2:4][OH:3])[CH2:7][O:8][NH:9][C:10]([C:12]1[N:20]([CH:21]2[CH2:22][CH2:23]2)[C:19]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[C:13]=1[NH:24][C:25]1[CH:30]=[CH:29][C:28]([I:31])=[CH:27][C:26]=1[F:32])=[O:11]
Reactant: CC1(C)OCC(CONC(=O)c2c(Nc3ccc(I)cc3F)c3cnccc3n2C2CC2)O1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: O=C(NOCC(O)CO)c1c(Nc2ccc(I)cc2F)c2cnccc2n1C1CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 5.2 %

Procedure:
To 1-cyclopropyl-3-(2-fluoro-4-iodo-phenylamino)-1H-pyrrolo[3,2-c]-pyridine-2-carboxylic acid (2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-amide (65.0 mg, 0.12 mmol) in anhydrous methanol (1.8 mL) was added 4 M Hydrogen chloride in 1,4-Dioxane (1.0 mL), and the reaction mixture was stirred at ambient temperature for 17 h. The solvent was removed in vacuo and the residue was redissolved in acetonitrile (2.0 mL) and loaded onto a Phenomenex Strata-X cartridge (5 g). The cartridge was washed with water (10 mL) and methanol (15 ml). The desired product was then eluted using 2M ammonia in MeOH. Methanol was removed in vacuo to give a brown oil, which was purified by HPLC to obtain 3.3 mg (5.5%) of the desired product as the TFA salt. 1H-NMR (500 MHz, MeOD.) δ ppm 8.96 (s, 1H), 8.45 (d, J=6.81 Hz, 1H), 8.18 (d, J=6.77 Hz, 1H), 7.48 (dd, J=10.76 Hz, 1H), 7.28 (d, J=8.50 Hz, 1H), 6.56 (t, J=9.6, 1H), 4.01-3.86 (m, 1H), 3.85-3.75 (m, 2H), 3.75-3.64 (m, 1H), 3.63-3.47 (m, 2H), 1.34-1.29 (m, 2H), 1.09-1.04 (m, 2H); LC-MS (method D): [M+H]+=527.0, RT=3.33 min.
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=O)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:17][NH2:18]>[Ti](Cl)(Cl)(Cl)Cl.C1C=CC=CC=1>[CH3:17][N:18]=[C:6]1[C:5]2[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=2[CH:10]=[CH:9][C:8]2[CH:12]=[CH:13][CH:14]=[CH:15][C:7]1=2
Reactant: O=c1c2ccccc2ccc2ccccc12
Reactant: CN
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: c1ccccc1
Product: CN=c1c2ccccc2ccc2ccccc12
Temperature: 25 °C
Reaction time: 144 h
Yield: 95 %

Procedure:
Using the procedure following Example 1, a mixture of 100 g 0f 5H-dibenzo[a,d]-cyclohepten-5-one, 98 g of methylamine and 1000 ml of benzene is treated with 53 g of titanium tetrachloride. The mixture is worked up after stirring at room temperature for 6 days. Short-path distillation of the crude product at 120° bath temperature and 0.1 micron pressure gives 101.2 g (95% yield) of N-methyl-5H-dibenzo[a,d]cyclohepten-5-imine as a viscous oil that solidifies slowly on standing. Nmr spectrum (in CDCl3): multiplet at τ 2.3-2.9 (8H) and singlets at 3.2 (2H) and 6.7 (3H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][C:11]2[O:12][C:13]3[C:22]4[C:21](=[CH:23][CH2:24][NH:25][C:26](=[O:28])[CH3:27])[CH2:20][CH2:19][C:18]=4[CH:17]=[CH:16][C:14]=3[N:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CO.[C].[Pd]>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][C:11]2[O:12][C:13]3[C:22]4[CH:21]([CH2:23][CH2:24][NH:25][C:26](=[O:28])[CH3:27])[CH2:20][CH2:19][C:18]=4[CH:17]=[CH:16][C:14]=3[N:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)NCC=C1CCc2ccc3nc(CCCCc4ccccc4)oc3c21
Agent: [Pd]
Solvent: CO
Product: CC(=O)NCCC1CCc2ccc3nc(CCCCc4ccccc4)oc3c21
Temperature: 25 °C
Reaction time: 24 h
Yield: 91.2 %

Procedure:
N-{2-[2-(4-Phenylbutyl)-6,7-dihydro-8H-indeno[5,4-d][1,3]oxazol-8-ylidene]ethyl}acetamide (32.5 mg, 0.0868 mmol) was dissolved in methanol (0.87 mL), a 10% palladium-carbon powder (6 mg) was added, and the mixture was stirred at room temperature for 24 hr under a hydrogen atmosphere. The catalyst was filtered off using celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to give the title compound (29.8 mg, yield 91%).
Reaction SMILES: [C:1]([O:4][CH:5]=[CH:6][C:7]([F:10])([F:9])[F:8])(=[O:3])[CH3:2]>[Pd]>[C:7]([CH2:6][CH2:5][O:4][C:1]([CH3:2])=[O:3])([F:10])([F:9])[F:8]
Reactant: CC(=O)OC=CC(F)(F)F
Agent: [Pd]
Product: CC(=O)OCCC(F)(F)F
Yield: 93 %

Procedure:
3,3,3-Trifluoropropenyl acetate (7.1. g) was hydrogenated in a glass pressure bottle overnight at 65°-70° C. using 0.1 g 10% Pd/C as catalyst and a maximum H2 pressure of 35 psi. The catalyst was separated by centrifugation, providing 6.7 g of 97% pure CF3CH2CH2OAc (93% yield). Bp 112°-113° C. [lit. 112° C.; B. T. Golding, P. J. Sellars, and W. P. Watson, J. Fluorine Chem., 30 (1985) 153]. 1H NMR: δ4.29 (t, 2 H, J=6.4 Hz), 2.4 (m, 2 H), 2.07 (s, 3H). 19F NMR: δ-65.8 (t, J=10.4 Hz).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].[CH:29]([C:31]1[CH:51]=[CH:50][C:34]([O:35][CH2:36][C:37]2([NH:42]C(=O)OC(C)(C)C)[CH2:41][CH2:40][CH2:39][CH2:38]2)=[CH:33][CH:32]=1)=O>>[NH2:42][C:37]1([CH2:36][O:35][C:34]2[CH:33]=[CH:32][C:31]([CH2:29][CH2:2][CH2:1][NH:3][C:4]3[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=3[C@@H:12]3[CH2:21][CH2:20][C:19]4[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=4[CH2:13]3)=[CH:51][CH:50]=2)[CH2:38][CH2:39][CH2:40][CH2:41]1
Reactant: CCNc1cc(OC)ccc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: CC(C)(C)OC(=O)NC1(COc2ccc(C=O)cc2)CCCC1
Product: COc1ccc([C@@H]2CCc3cc(O)ccc3C2)c(NCCCc2ccc(OCC3(N)CCCC3)cc2)c1
Yield: 61 %

Procedure:
Synthesized from pivalic acid (R)-6-(2-ethylamino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-yl ester (20 mg) and tert-butyl [1-(4-formylphenoxymethyl)cyclopentyl]carbamate (74 mg) according to an analogous synthetic method to Example 238 and purified by LC-MS, the title compound (16 mg) was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[C:16]([OH:17])=[CH:15][CH:14]=[CH:13][C:12]=2[OH:18])[CH:10]=1)=[O:5])[CH3:2].[CH2:19](Cl)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(O)(C)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[C:16]([O:17][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:15][CH:14]=[CH:13][C:12]=2[O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn(-c2c(O)cccc2O)cn1
Reactant: ClCc1ccccc1
Solvent: CC(C)O
Product: CCOC(=O)c1cn(-c2c(OCc3ccccc3)cccc2OCc2ccccc2)cn1

Procedure:
by reaction of the compound produced in Example 2 with benzyl chloride; mp: 125°-126° C. (isopropanol).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:17]2[CH:39]=[CH:38][C:20]([C:21]([NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[NH:30]C(=O)OC(C)(C)C)=[O:22])=[CH:19][CH:18]=2)=[N:5][CH:6]=[C:7]([CH2:9][O:10][CH2:11][CH2:12][NH:13][CH:14]([CH3:16])[CH3:15])[CH:8]=1)#[N:2].Cl>O1CCOCC1>[NH2:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[NH:23][C:21](=[O:22])[C:20]1[CH:38]=[CH:39][C:17]([C:4]2[C:3]([C:1]#[N:2])=[CH:8][C:7]([CH2:9][O:10][CH2:11][CH2:12][NH:13][CH:14]([CH3:15])[CH3:16])=[CH:6][N:5]=2)=[CH:18][CH:19]=1
Reactant: CC(C)NCCOCc1cnc(-c2ccc(C(=O)Nc3ccccc3NC(=O)OC(C)(C)C)cc2)c(C#N)c1
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)NCCOCc1cnc(-c2ccc(C(=O)Nc3ccccc3N)cc2)c(C#N)c1

Procedure:
t-Butyl (2-{[4-(3-cyano-5-{[2-(isopropylamino)ethoxy]methyl}pyridin-2-yl)benzoyl]amino}phenyl)carbamate (170 mg, 0.32 mmol, prepared as described in Method 31), 1,4-dioxane (1.5 ml) and a 4M solution of hydrogen chloride in 1,4-dioxane (1.2 ml) were stirred at ambient temperature for 21 hours.
Reaction SMILES: [CH:1]([C:3]1[CH:15]=[CH:14][C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH2:6][C:5]=2[CH:4]=1)=[CH2:2].C([Li])CCC.Br[CH2:22][CH2:23][CH:24]1[C:36]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:30]2[C:25]1=[CH:26][CH:27]=[CH:28][CH:29]=2>C(OCC)C>[CH:1]([C:3]1[CH:15]=[CH:14][C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH2:6][C:5]=2[C:4]=1[C:24]1([CH2:23][CH3:22])[C:36]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:30]2[C:25]1=[CH:26][CH:27]=[CH:28][CH:29]=2)=[CH2:2]
Reactant: BrCCC1c2ccccc2-c2ccccc21
Reactant: C=Cc1ccc2c(c1)Cc1ccccc1-2
Agent: [Li]CCCC
Solvent: CCOCC
Product: C=Cc1ccc2c(c1C1(CC)c3ccccc3-c3ccccc31)Cc1ccccc1-2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To 1.15 g (6.0 mmol) 2-vinylfluorene in 100 mL diethyl ether was added 3.75 mL (6.0 mmol) n-butyllithium (1.6M in hexane). The reaction mixture was stirred for 4 hours at room temperature. Then 1.64 g (6.0 mmol) 1-bromo-2-(9-fluorenyl)ethane was added and the mixture was stirred for 14 hours at room temperature. The precipitate was removed by filtration, washed with methanol, filtered with pentane using silica gel 60, and concentrated by evaporation under vacuum. The yield was 1.69 g (73%) 1-(9-(2-vinyl)fluorenyl)-2-(9-fluorenyl)ethane as a colorless solid.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH2:6]([OH:9])[C:7]#[CH:8].[O:10]1[CH:15]=[CH:14][CH2:13][CH2:12][CH2:11]1>ClCCl>[CH2:6]([O:9][CH:11]1[CH2:12][CH2:13][CH2:14][CH2:15][O:10]1)[C:7]#[CH:8]
Reactant: C1=COCCC1
Reactant: C#CCO
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: C#CCOC1CCCCO1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of phosphoryl chloride (0.5 ml in 10 ml of dichloromethane [DCM])) was added with care to a solution of prop-2-yn-1-ol (7.00 g, 125 mmol) and dihydropyran (10.50 g, 125 mmol) in DCM (80 ml). The reaction mixture was stirred at room temperature for 16 h, washed with sodium hydrogen carbonate solution (3 times), dried (MgSO4) and the solvent removed in vacuo to yield a colorless oil. The crude product was purified by column chromatography [silica gel, eluted with hexane/ethyl acetate (4:1), Rf: 0.43] to yield a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]4[CH2:21][CH2:20][N:19]([C:22]5[CH:27]=CC=C[CH:23]=5)[C:18]4=[O:28])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.[C:31](N=C=O)(C)(C)C.Cl>>[F:1][C:2]1[CH:30]=[CH:29][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][N:17]4[CH2:21][CH2:20][N:19]([C:22]([CH3:31])([CH3:23])[CH3:27])[C:18]4=[O:28])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: CC(C)(C)N=C=O
Reactant: O=C1N(CCN2CCC(c3noc4cc(F)ccc34)CC2)CCN1c1ccccc1
Agent: Cl
Product: CC(C)(C)N1CCN(CCN2CCC(c3noc4cc(F)ccc34)CC2)C1=O

Procedure:
This product is obtained in the same manner as the compound of Example 5, but with replacement of the phenyl isocyanate by tert-butyl isocyanate in Step 1 of the synthesis. The hydrochloride of the title compound melts at 205°-208° C.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:36]=[CH:35][C:25]([C:26]([NH:28][CH:29]5[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]5)=[O:27])=[CH:24][C:23]=4[O:37][CH3:38])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:39][N:40]([CH3:45])[CH2:41][C:42](Cl)=[O:43]>>[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([F:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:36]=[CH:35][C:25]([C:26]([NH:28][CH:29]5[CH2:34][CH2:33][N:32]([C:42](=[O:43])[CH2:41][N:40]([CH3:45])[CH3:39])[CH2:31][CH2:30]5)=[O:27])=[CH:24][C:23]=4[O:37][CH3:38])=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CN(C)CC(=O)Cl
Reactant: COc1cc(C(=O)NC2CCNCC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Product: COc1cc(C(=O)NC2CCN(C(=O)CN(C)C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(piperidin-4-yl)benzamide in accordance with scheme 6 using 2-(dimethylamino)acetyl chloride. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.38 (dd, J=13.1, 4.0 Hz, 1 H) 1.58 (m, 5 H) 1.71 (m, 2 H) 1.83 (m, 2 H) 1.93 (m, 2 H) 2.21 (s, 5 H) 2.52 (d, J=1.8 Hz, 1 H) 2.63-2.73 (m, 1 H) 3.05 (t, J=12.1 Hz, 2 H) 3.17-3.24 (m, 1 H) 3.32 (s, 5 H) 3.93 (s, 3 H) 4.05 (t, J=14.2 Hz, 3 H) 4.36 (d, J=12.6 Hz, 1 H) 4.77 (q, J=8.3 Hz, 1 H) 7.48 (dd, 1 H) 7.50 (s, 1 H) 7.97 (s, 1 H) 8.17 (d, J=7.8 Hz, 1 H) 8.26 (s, 1 H) 8.29 (d, 1H). [M+H] calc'd for C30H40F2N8O4, 615; found 615.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](=[O:43])[NH:17][CH2:18][C:19]3[N:20]([CH2:39][CH:40]([CH3:42])[CH3:41])[C:21](=[O:38])[C:22]4[C:27]([C:28]=3[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:26][C:25]([C:35]([NH2:37])=[S:36])=[CH:24][CH:23]=4)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Br[CH2:45][C:46](=O)[C:47]([O:49][CH2:50][CH3:51])=[O:48].O>C(O)C>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:17][CH2:18][C:19]3[N:20]([CH2:39][CH:40]([CH3:41])[CH3:42])[C:21](=[O:38])[C:22]4[C:27]([C:28]=3[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[CH:26][C:25]([C:35]3[S:36][CH:45]=[C:46]([C:47]([O:49][CH2:50][CH3:51])=[O:48])[N:37]=3)=[CH:24][CH:23]=4)=[O:43])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)C(=O)CBr
Reactant: CC(C)Cn1c(CNC(=O)OCC2c3ccccc3-c3ccccc32)c(-c2ccccc2)c2cc(C(N)=S)ccc2c1=O
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1csc(-c2ccc3c(=O)n(CC(C)C)c(CNC(=O)OCC4c5ccccc5-c5ccccc54)c(-c4ccccc4)c3c2)n1
Yield: 70.2 %

Procedure:
A solution of 9H-fluoren-9-ylmethyl[6-(aminocarbothioyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl]methylcarbamate (Example 194(2)) (2.35 g, 4 mmol) and ethyl bromopyruvate (1.56 g, 8 mmol) in ethanol (20 ml) was refluxed under heating for 1 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give ethyl 2-[3-[[[(9H-fluoren-9-ylmethoxy)carbony]amino]methyl]-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl]-1,3-thiazole-4-carboxylate (1.92 g, 70.3%) as crystals.
Reaction SMILES: C(S[C:4](=[N:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH:5]([CH3:7])[CH3:6])C.[CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][C:16]=1[C:25]([NH:27][NH2:28])=O.C(O)CCC>C1(C)C=CC=CC=1>[CH:5]([C:4]1[N:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:25]([C:16]2[CH:17]=[CH:18][C:19]3[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:15]=2)=[N:27][N:28]=1)([CH3:7])[CH3:6]
Reactant: NNC(=O)c1ccc2ccccc2c1
Reactant: CCSC(=Nc1ccccc1)C(C)C
Solvent: CCCCO
Solvent: Cc1ccccc1
Product: CC(C)c1nnc(-c2ccc3ccccc3c2)n1-c1ccccc1
Temperature: 120 °C
Reaction time: 20 h
Yield: 37 %

Procedure:
First, 5.7 g of N-[1-(ethylsulfanyl)isobutylidene]aniline, 4.4 g of 2-naphthohydrazide, and 40 mL of 1-butanol were put in a 100 mL three-neck flask, and heated and stirred at 120° C. for 20 hours to be reacted. After the reaction, 1-butanol was distilled off to give a brown oily substance. Toluene was added to this oily substance, whereby a solid was precipitated, and then filtrated to give the solid. The resulting solid was recrystallized from toluene, so that 2.7 g of 3-isopropyl-5-(2-naphthyl)-4-phenyl-4H-1,2,4-triazole (abbreviation: HiPrntz) was prepared as a white solid with a yield of 37%. The synthetic scheme of Step 1 is shown by (a-13). As described above, the objective compound of Example 14 has a favorable yield.
Reaction SMILES: [BH4-].[Na+].[CH:3]([C:5]1[S:9][CH:8]=[C:7]([C:10]#[N:11])[C:6]=1[Cl:12])=[O:4]>>[OH:4][CH2:3][C:5]1[S:9][CH:8]=[C:7]([C:10]#[N:11])[C:6]=1[Cl:12]
Reactant: N#Cc1csc(C=O)c1Cl
Agent: [BH4-]
Agent: [Na+]
Product: N#Cc1csc(CO)c1Cl
Reaction time: 0.17 h

Procedure:
6.3 g (166 mmol) of sodium borohydride were added portionwise at 5° C. to a solution of 28.5 g (166 mmol) of 5-formyl-4-chlorothiophene-3-carbonitrile in 400 ml of rose slightly and the color changed to dark red. A vigorous evolution of gas was observed. After 10 minutes, the reaction mixture was concentrated under a water pump vacuum, taken up in 200 ml of ethyl acetate, extracted with 200 ml of 1 M hydrochloric acid and washed twice with in each case 250 ml of water and with saturated sodium chloride solution, the organic phase was dried over magnesium sulfate, the desiccant was filtered off, and the solvent was distilled off under a water pump vacuum at room temperature. This gave 22 g (76%) of the title compound as dark red oil which was employed in the following reactions without further purification. 1H NMR (270 MHz, DMSO-d6): δ=4.65 (bs, 1H), 5.95 (t, 2H), 8.6 (s, 1H).
Reaction SMILES: [CH3:1][C:2]([N+:8]([O-:10])=[O:9])([CH3:7])[CH2:3][CH2:4][C:5]#N.[H-].C([Al+]CC(C)C)C(C)C.CCCCCC.O.S([O-])([O-])(=O)=[O:29].[Mg+2]>C(Cl)Cl>[CH3:1][C:2]([N+:8]([O-:10])=[O:9])([CH3:7])[CH2:3][CH2:4][CH:5]=[O:29]
Reactant: O=S(=O)([O-])[O-]
Reactant: CC(C)(CCC#N)[N+](=O)[O-]
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Agent: [Mg+2]
Solvent: CCCCCC
Solvent: ClCCl
Solvent: O
Product: CC(C)(CCC=O)[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 369.2 %

Procedure:
4-Methyl-4-nitrovaleronitrile (10.4 g, 13 mmol) was dissolved in methylene chloride (100 ml) and 1M diisobutyl aluminum hydride-hexane solution (100 ml) was added dropwise at −50° C. The mixture was stirred for 0.5 h, and water (8 ml) was added gradually, after which magnesium sulfate (5.0 g) was added. The mixture was filtrated and 1N hydrochloric acid (50 ml) was added. The mixture was stirred for 0.5 h and the layers were separated. The organic layer was washed with saturated brine and the solvent was evaporated. The residue was dried to give oily 4-methyl-4-nitropentanal (6.9 g, 48 mmol).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][CH2:6][CH2:7][N:8]1[C:12]2[N:13]=[C:14]([CH3:18])[N:15]=[C:16](Cl)[C:11]=2[CH:10]=[CH:9]1)[CH3:2].[C:20]([O:24][C:25](=[O:40])[C@@H:26]([NH:29][C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31])[CH2:27][NH2:28])([CH3:23])([CH3:22])[CH3:21].C(N(CC)CC)C>CN1CCCC1=O>[CH2:1]([O:3][C:4](=[O:19])[CH2:5][CH2:6][CH2:7][N:8]1[C:12]2[N:13]=[C:14]([CH3:18])[N:15]=[C:16]([NH:28][CH2:27][C@H:26]([NH:29][C:30]([O:32][CH2:33][C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)=[O:31])[C:25]([O:24][C:20]([CH3:22])([CH3:23])[CH3:21])=[O:40])[C:11]=2[CH:10]=[CH:9]1)[CH3:2]
Reactant: CCOC(=O)CCCn1ccc2c(Cl)nc(C)nc21
Reactant: CC(C)(C)OC(=O)[C@H](CN)NC(=O)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: CCOC(=O)CCCn1ccc2c(NC[C@H](NC(=O)OCc3ccccc3)C(=O)OC(C)(C)C)nc(C)nc21
Temperature: 100 °C
Reaction time: 36 h

Procedure:
To a solution of 1000 mg (3.5 mmol) of 4-(4-chloro-2-methyl-pyrrolo[2,3-d]pyrimidin-7-yl)-butyric acid ethyl ester (example 2a) in 7 ml N-methylpyrrolidone were added 1590 mg (5.4 mmol) of (2S)-3-amino-2-benzyloxycarbonylamino-propionic acid tert-butyl ester and 5.9 ml triethylamine and the reaction was stirred at 100° C. for 36 h. The reaction was diluted with 85 ml EE and extracted with water, aqueous citric acid and again with water. The organic phase was dried over MgSO4 filtered and the solvent was removed in vacuo. The residue was chromatographed on silica gel eluting with DCM/EE (2:1). Yield: 719 mg.