Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].S(=O)(=O)(O)O.[Br:10][C:11]1[C:24]([Br:25])=[CH:23][C:14]2[O:15][C:16]([F:22])([F:21])[C:17]([F:20])([F:19])[O:18][C:13]=2[CH:12]=1>>[Br:25][C:24]1[C:11]([Br:10])=[CH:12][C:13]2[O:18][C:17]([F:20])([F:19])[C:16]([F:21])([F:22])[O:15][C:14]=2[C:23]=1[N+:1]([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: FC1(F)Oc2cc(Br)c(Br)cc2OC1(F)F
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1c(Br)c(Br)cc2c1OC(F)(F)C(F)(F)O2
Temperature: 5 °C
Reaction time: 4 h
Yield: 88 %

Procedure:
A precooled mixture of 19 ml of nitric acid and 26 ml of concentrated sulphuric acid is slowly added dropwise at 5° C. to 73 g (0.2 mol) of 6,7-dibromo-2,2,3,3-tetrafluoro-benzo(1.4)dioxane. The mixture is subsequently stirred at 5° C. for 4 hours, poured onto ice and extracted thoroughly with ether, the extract is washed with water and sodium hydrogen carbonate solution (until neutral), and dried over magnesium sulphate, and the ether is removed. 72 g (88% of theory) of 6,7-dibromo-5-nitro-2,2,3,3-tetrafluoro-benzo(1.4)dioxane having the melting point 91° to 92° C. are isolated.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:6]=[CH:5][C:4]=1[CH2:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH3:31])[CH2:21][CH:20]1[C:32]([NH2:34])=[O:33])=[O:18].[NH:35]1[CH:39]=[C:38]([CH2:40][C:41](O)=[O:42])[N:37]=[CH:36]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH:10]2[CH2:15][CH2:14][N:13]([C:41]([CH2:40][C:38]3[N:37]=[CH:36][NH:35][CH:39]=3)=[O:42])[CH2:12][CH2:11]2)[CH:6]=[CH:5][C:4]=1[CH2:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH3:31])[CH2:21][CH:20]1[C:32]([NH2:34])=[O:33])=[O:18]
Reactant: O=C(O)Cc1c[nH]cn1
Reactant: COc1cc(OC2CCNCC2)ccc1CC(=O)N1CCN(c2ccccc2C)CC1C(N)=O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(OC2CCN(C(=O)Cc3c[nH]cn3)CC2)ccc1CC(=O)N1CCN(c2ccccc2C)CC1C(N)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-(2-Methoxy-4-(4-piperidyloxy)phenylacetyl)-4-(2-methylphenyl) piperazine-2-carboxamide (200 mg, 0.429 mmole) and 4-imidazoleacetic acid (70 mg, 0.429 mmole) were dissolved in 4 ml of dry N,N-dimethylformamide at room temperature. To this solution was added 209 mg (0.472 mmole) of benzotriazol-1-yloxy-tris(dimethylamino)-phosphonium hexafluorophosphate (BOP). The pH of the reaction mixture was adjusted to 9 with the addition of diisopropylethylamine (DEA) in 100 μL increments. The reaction mixture was stirred at ambient temperature for 2 hr whereupon all volatiles were removed under reduced pressure. The residue was suspended in ethyl acetate and this suspension was washed with water. The organic phase and some insoluble material were combined, concentrated, and azeotropically dried with toluene. The resulting semi-solid was purified via preparative thick layer chromatography on precoated silica gel plates (85:15:1.5 chloroform-methanol-concentrated ammonium hydroxide elution) to give the title compound in homogeneous form: m.p. 120°-124° C.
Reaction SMILES: [CH3:1][C:2]([NH:5][C:6]([CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])[CH3:3].[Cl:14][CH2:15][C:16](Cl)=[O:17].C(=O)([O-])[O-].[K+].[K+]>ClCCl>[Cl:14][CH2:15][C:16]([N:11]1[CH2:10][CH2:9][CH:8]([C:6]([NH:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]1)=[O:17]
Reactant: CC(C)(C)NC(=O)C1CCNCC1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CC(C)(C)NC(=O)C1CCN(C(=O)CCl)CC1
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 71.1 %

Procedure:
A solution of N-(1,1-dimethylethyl)-4-piperidinecarboxamide (201 g, 1.0 mol) in dichloromethane (1 L) was cooled under nitrogen to −5° C., and chloroacetyl chloride (124 g, 1.1 mol) in 300 mL of dichloromethane was added dropwise over 30 minutes while maintaining the reaction mixture at 0 to 5° C. Then 20% aqueous potassium carbonate solution (450 g, 0.65 mol) was added dropwise over 30 minutes while keeping reaction temperature between 0 and 5° C. The reaction mixture was stirred for an additional 30 minutes at 0° C., and then allowed to warm to room temperature. The layers were separated, and the aqueous layer was extracted with dichloromethane (200 mL). The combined dichloromethane layers were concentrated under reduced pressure to yield a solid, which was triturated with 400 mL of hexanes. The slurry was filtered, and the filter cake was washed with 100 mL of hexanes and dried in a vacuum oven overnight at 50° C. to give 185.5 g of 1-(2-chloroacetyl)-N-(1,1-dimethylethyl)-4-piperidinecarboxamide as a solid, melting at 140.5-141.5° C.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[CH2:10][N:9]([CH3:11])[CH2:8][C:6]=2[N:7]=1.[CH2:18]([NH:20][C:21]([NH:23][C:24]1[CH:29]=[CH:28][C:27](B2OC(C)(C)C(C)(C)O2)=[C:26]([F:39])[CH:25]=1)=[O:22])[CH3:19]>>[CH2:18]([NH:20][C:21]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([C:2]2[N:3]=[C:4]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[C:5]3[CH2:10][N:9]([CH3:11])[CH2:8][C:6]=3[N:7]=2)=[C:26]([F:39])[CH:25]=1)=[O:22])[CH3:19]
Reactant: CCNC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)c(F)c1
Reactant: CN1Cc2nc(Cl)nc(N3CCOCC3)c2C1
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CN(C)C3)c(F)c1
Yield: 26 %

Procedure:
Method as example 147 using 4-(2-chloro-6-methyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)morpholine (intermediate 21) and 1-ethyl-3-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea (intermediate 28) as starting materials. The crude reaction mixture was partitioned between EtOAc (25 ml) and water (25 ml). The organic layer was recovered, passed through a hydrophobic frit and the solvent removed in vacuo. Residue was then purified by prep. HPLC at high pH to afford a light yellow solid (61 mg, 0.15 mmol, 26%).
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:3][CH2:2]1.[C:6]([O:10][C:11](=[O:20])[NH:12][CH2:13][C:14](=[O:19])N(OC)C)([CH3:9])([CH3:8])[CH3:7].C(OCC)(=O)C>O1CCCC1>[C:6]([O:10][C:11](=[O:20])[NH:12][CH2:13][C:14]([CH:1]1[CH2:3][CH2:2]1)=[O:19])([CH3:7])([CH3:8])[CH3:9]
Reactant: Br[Mg]C1CC1
Reactant: CON(C)C(=O)CNC(=O)OC(C)(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCC(=O)C1CC1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
To 22 ml of a 0.5M solution of cyclopropylmagnesium bromide in tetrahydrofuran was added 2.2 g [(methoxy-methyl-carbamoyl)-methyl]-carbamic acid tert-butyl ester at −10° C. (acetone/ice) and the mixture was stirred at −10° C. for 30 min and then at ambient temperature for 30 min. (tic shows little conversion heptanes:ethyl acetate=1:1) To the resulting colorless solution was added another 22 ml of a 0.5M solution of cyclopropylmagnesium bromide in tetrahydrofuran and the mixture was stirred at ambient temperature for 18 h. The reaction mixture was quenched by addition of 10% citric acid. The phases were separated and the organic phase was purified by chromatography on silica gel with a gradient of heptane:ethyl acetate=9:1 to 1:1 to yield 1.300 g of the title compound as colorless oil. MS (EI): 199 (M+).
Reaction SMILES: [N:1]([CH:4]1[CH2:9][CH2:8][N:7]([CH3:10])[CH2:6][CH2:5]1)=[C:2]=[S:3].[CH3:11][O:12][C:13]1[CH:14]=[C:15]([NH2:20])[C:16]([NH2:19])=[CH:17][CH:18]=1>O1CCCC1>[NH2:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][CH3:11])=[CH:14][C:15]=1[NH:20][C:2]([NH:1][CH:4]1[CH2:9][CH2:8][N:7]([CH3:10])[CH2:6][CH2:5]1)=[S:3]
Reactant: CN1CCC(N=C=S)CC1
Reactant: COc1ccc(N)c(N)c1
Solvent: C1CCOC1
Product: COc1ccc(N)c(NC(=S)NC2CCN(C)CC2)c1
Yield: 100 %

Procedure:
A mixture of 37.5 parts of 4-isothiocyanato-1-methylpiperidine, 21.8 parts of 4-methoxy-1,2-benzenediamine and 270 parts of tetrahydrofuran was stirred and refluxed for 2 hours. The whole was evaporated, yielding 44 parts (100%) of N-(2-amino-5-methoxyphenyl)-N'-(1-methyl-4-piperidinyl)thiourea as a residue (interm. 26).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([NH:12][C:13](=[O:17])[CH:14]([CH3:16])[CH3:15])[NH:5][C:6](=O)[C:7]=1[N+:8]([O-:10])=[O:9].P(Cl)(Cl)([Cl:20])=O>C(N(CC)C1C=CC=CC=1)C>[Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([Cl:20])[N:5]=[C:4]([NH:12][C:13](=[O:17])[CH:14]([CH3:16])[CH3:15])[N:3]=1
Reactant: CC(C)C(=O)Nc1nc(Cl)c([N+](=O)[O-])c(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)c1ccccc1
Product: CC(C)C(=O)Nc1nc(Cl)c([N+](=O)[O-])c(Cl)n1
Temperature: 25 °C
Yield: 72 %

Procedure:
The title compound of Example 23 (10.0 g, 38.37 mmol) was heated to reflux in phosphorus oxychloride (200 ml) and N,N-diethylaniline (3-4 drops) for 5 hours under nitrogen. The solution was then cooled to room temperature, concentrated to dryness, and the syrup was dissolved in cold (~ -10° C.) methylene chloride (200 ml). The organic layer was treated with saturated aqueous sodium bicarbonate (100 ml) with vigorous stirring, and the temperature was kept below 5° C. as solid sodium bicarbonate was added portionwise to elevate the pH to between 5 and 7. The layers were separated and the aqueous phase was extracted with methylene chloride. The combined organic layers were filtered over phase-separator paper, concentrated and dried under vacuum to give the title compound (7.71 g, 72%) as a yellow-white solid sufficiently pure to employ in the next step. Recrystallisation of the solid from hexane/methylene chloride provided an analytical sample, m.p. 166°-169° C.; 'H-NMR (DMSO-d6) δ 1.09 (d, J=6.9 Hz, 6H, (CH3)2CH), 2.79 m, J=6.9 Hz, 1H, (CH3)2CH), 11.61 (s, 1H).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][CH2:11][C@H:12]([NH:14][C:15]1[C:16]2[N:17]=[CH:18][N:19]([C:29]=2[N:30]=[C:31](Br)[N:32]=1)[C@@H:20]1[O:28][C@H:25]([CH2:26][OH:27])[C@@H:23]([OH:24])[C@H:21]1[OH:22])[CH3:13].[CH2:34]([NH2:36])[CH3:35]>O1CCOCC1>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][CH2:11][C@H:12]([NH:14][C:15]1[C:16]2[N:17]=[CH:18][N:19]([C:29]=2[N:30]=[C:31]([NH:36][CH2:34][CH3:35])[N:32]=1)[C@@H:20]1[O:28][C@H:25]([CH2:26][OH:27])[C@@H:23]([OH:24])[C@H:21]1[OH:22])[CH3:13]
Reactant: CCN
Reactant: C[C@H](CSc1nc2ccccc2s1)Nc1nc(Br)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Solvent: C1COCCO1
Product: CCNc1nc(N[C@H](C)CSc2nc3ccccc3s2)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1

Procedure:
The title compound was prepared according to general method B by reaction of N-[(R)-1-(2-benzothiazolyl)thio-2-propyl]-2-bromoadenosine (Example 7) (0.24 g, 0.35 mmol) with 70% w/w aqueous ethylamine (0.23 g) in dioxan (10 ml) in a sealed vessel at 100° C. to provide the desired N-[(R)-1-(2-benzothiazolyl)thio-2-propyl]-2-(ethylamino)adenosine as a foam (following column chromatography), 1H NMR (DMSO-d6) δ1.04 (3H, br t, --NCH2CH3), 1.42 (3H, d, --CHCH3), 3.20 (3H, br m, --NCH2CH3), 3.55-3.80 (4H, m, H-5'a and H-5'b and --CH2 --), 3.95 (1H, q, H-4'), 4.15 (1H, q, H-3'), 5.16, 5.41 (2H, 2d, 2'- and 3'-OH), 5.79 (1H, d, H-1'), 6.22 (1H, t, --NHCH2CH3), 7.43, 7.54 (2H, 2 t, Ar--H), 7.98 (1H, s, H-8). HPLC retention time 17.0 min [gradient elution, 20-80% acetonitrile/water (containing 0.1% TFA)].
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]([N+:10]([O-])=O)[N:3]=1.O.O.Cl[Sn]Cl.O.C([O-])(O)=O.[Na+]>C(O)C>[Br:1][C:2]1[N:3]=[C:4]([NH2:10])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc([N+](=O)[O-])nc1Br
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1ccc(N)nc1Br
Temperature: 25 °C
Yield: 63 %

Procedure:
To a solution of 2-bromo-3-methoxy-6-nitropyridine (2.0 g, 8.6 mmol) in ethanol (20 mL) was added SnCl2.2H2O (3.9 g, 17 mmol) at room temperature. The reaction was heated at reflux for 2H. After cooling to room temperature, the reaction mixture was poured into water (50 mL), basified to pH to 8 with saturated NaHCO3 and extracted with ethyl acetate (50×3 mL). The combined organic layers were dried over Na2SO4, evaporated in vacuo and purified by chromatography on silica gel (20% ethyl acetate in petroleum ether) to afford 6-bromo-5-methoxypyridin-2-amine (1.1 g, 65%). 1H-NMR (300 MHz, CDCl3) δ 7.09 (d, J=8.4, 1H), 6.43 (d, J=8.4, 1H), 4.27 (br s, 2H), 3.82 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=O.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27][CH2:28][NH2:29]>>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([NH:29][CH2:28][CH2:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[O:20][CH3:19])=[O:14]
Reactant: COc1ccccc1CCN
Reactant: O=C(O)c1ccncc1Nc1ccc(I)cc1F
Product: COc1ccccc1CCNC(=O)c1ccncc1Nc1ccc(I)cc1F

Procedure:
3-[(2-fluoro-4-iodophenyl)amino]-N-[2-(2-methoxyphenyl)ethyl]isonicotinamide was synthesized according to the procedure for General Method 1, outlined above, starting with 0.54 mmol of 3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and 0.81 mmol of 2-(2-methoxy-phenyl)-ethylamine. LC/MS [10.19 min; 492 (M+1)]
Reaction SMILES: [F:1][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[N:15]=[C:14]([NH2:16])[CH:13]=[N:12]2)=[CH:7][CH:6]=1)([F:4])[CH3:3].[CH3:17][C:18]1[O:19][C:20]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:21]([C:23](O)=[O:24])[N:22]=1>>[F:4][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[N:15]=[C:14]([NH:16][C:23]([C:21]3[N:22]=[C:18]([CH3:17])[O:19][C:20]=3[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)=[O:24])[CH:13]=[N:12]2)=[CH:7][CH:6]=1)([F:1])[CH3:3]
Reactant: CC(F)(F)c1ccc(Cn2ncc(N)n2)o1
Reactant: Cc1nc(C(=O)O)c(-c2ccccc2)o1
Product: Cc1nc(C(=O)Nc2cnn(Cc3ccc(C(C)(F)F)o3)n2)c(-c2ccccc2)o1

Procedure:
Following general procedure Z2, starting from 2-[5-(1,1-difluoro-ethyl)-furan-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 2-methyl-5-phenyl-oxazole-4-carboxylic acid.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][C:10]([O:17][CH3:18])=[C:11]([OH:16])[CH:12]=2)[CH:7]1[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH2:27][CH3:28])[CH:21]=1)=[O:5])[CH3:2].[C:29](OC(=O)C)(=[O:31])[CH3:30]>N1C=CC=CC=1>[CH2:1]([O:3][C:4]([N:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][C:10]([O:17][CH3:18])=[C:11]([O:16][C:29](=[O:31])[CH3:30])[CH:12]=2)[CH:7]1[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH2:27][CH3:28])[CH:21]=1)=[O:5])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)N1C=Cc2cc(O)c(OC)cc2C1Cc1cccc(OCC)c1
Solvent: c1ccncc1
Product: CCOC(=O)N1C=Cc2cc(OC(C)=O)c(OC)cc2C1Cc1cccc(OCC)c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a stirred solution of 6-hydroxy-7-methoxy-1-(3-ethoxy-benzyl)-1H-isoquinoline-2-carboxylic acid ethyl ester (6 g, 0.59 mmol) in pyridine (112 mL) was added acetic anhydride (56 mL). The reaction mixture was stirred at room temperature for 15 hrs. The mixture was concentrated in vacuo to afford 6-acetoxy-7-methoxy-1-(3-ethoxy-benzyl)-1H-isoquinoline-2-carboxylic acid ethyl ester. The crude product was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C@H:11](O)[CH2:10][C@@H:9]1[CH3:19])=[O:7].[NH:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH2:27][CH2:26]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]([N:25]2[C:34]3[CH:29]([CH2:30][CH:31]=[CH:32][CH:33]=3)[CH2:28][CH2:27][CH2:26]2)[CH2:10][CH:9]1[CH3:19])=[O:7]
Reactant: c1ccc2c(c1)CCCN2
Reactant: COc1ccc(C(=O)N2c3ccccc3[C@H](O)C[C@@H]2C)cc1OC
Product: COc1ccc(C(=O)N2c3ccccc3C(N3CCCC4CC=CC=C43)CC2C)cc1OC
Yield: 39.8 %

Procedure:
Starting with cis-1-(3,4-dimethoxybenzoyl)-2-methyl-1,2,3,4-tetrahydro-4-quinolinol (400 mg, 1.22 mmol) prepared in Reference Example 1 and 1,2,3,4-tetrahydroquinoline (487 mg, 3.66 mmol), the same procedure as shown in Example 1 was repeated to give the product of interest, i.e., 1-(3,4-dimethoxybenzoyl)-2-methyl-4-(tetrahydroquinolin-1-yl)-1,2,3,4-tetrahydroquinoline (216 mg, yield: 40%) as a colorless oil. (cis:trans=1.6:1)
Reaction SMILES: [F:1][C:2]1([F:36])[CH2:8][N:7]([CH2:9][CH2:10][CH2:11][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](O)=[O:28])=[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.[O:46]1[CH2:51][CH2:50][CH:49]([NH2:52])[CH2:48][CH2:47]1>CN(C)C=O>[F:1][C:2]1([F:36])[CH2:8][N:7]([CH2:9][CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:6]2[N:18]=[C:19]([NH:22][C:23]3[CH:31]=[CH:30][C:26]([C:27]([NH:52][CH:49]4[CH2:50][CH2:51][O:46][CH2:47][CH2:48]4)=[O:28])=[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: NC1CCOCC1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(CCCc1ccccc1)CC(F)(F)C(=O)N2C
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)NC2CCOCC2)ccc1Nc1ncc2c(n1)N(CCCc1ccccc1)CC(F)(F)C(=O)N2C
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.7 %

Procedure:
To a mixture of 0.05 g (0.10 mmole) of 4-[7,7-difluoro-5-methyl-6-oxo-9-(3-phenyl-propyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino]-3-methoxy-benzoic acid (I-281), 0.07 mL (0.40 mmole) of ethyldiisopropyl amine and 0.011 g (0.11 mmole) of tetrahydro-pyran-4-ylamine in 2.0 mL of dimethylformamide was added 0.048 g (0.11 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, 100:0-95:5) gave 0.030 g of 4-[7,7-difluoro-5-methyl-6-oxo-9-(3-phenyl-propyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino]-3-methoxy-N-(tetrahydro-pyran-4-yl)-benzamide (I-286) as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=O)=[CH:5][CH:4]=1)#[N:2].Cl.[CH3:14][N:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:26]=[C:25]([C:27]3[CH:36]=[C:35]4[C:30]([CH2:31][CH2:32][NH:33][CH2:34]4)=[CH:29][CH:28]=3)[N:24]=[C:23]([NH2:37])[N:22]=2)[CH2:17][CH2:16]1>>[NH2:37][C:23]1[N:24]=[C:25]([C:27]2[CH:36]=[C:35]3[C:30]([CH2:31][CH2:32][N:33]([C:10](=[O:12])[CH2:9][C:6]4[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=4)[CH2:34]3)=[CH:29][CH:28]=2)[CH:26]=[C:21]([N:18]2[CH2:17][CH2:16][N:15]([CH3:14])[CH2:20][CH2:19]2)[N:22]=1
Reactant: N#Cc1ccc(CC(=O)O)cc1
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CNCC4)nc(N)n2)CC1
Agent: Cl
Product: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)Cc3ccc(C#N)cc3)CC4)nc(N)n2)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 41 starting from (4-cyanophenyl)acetic acid (Aldrich, Cat. #633453) and 4-(4-methylpiperazin-1-yl)-6-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidin-2-amine HCl salt. Analytic LCMS (M+H)+: m/z=468.1.
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[C:7]([CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][CH:20]([CH3:22])[CH3:21])[CH:14]=2)O)[CH:8]=[CH:9][CH:10]=1)[CH:2]([CH3:4])[CH3:3].[Cl-:23]>ClCCl>[CH2:1]([C:5]1[CH:6]=[C:7]([CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][CH:20]([CH3:22])[CH3:21])[CH:14]=2)[Cl:23])[CH:8]=[CH:9][CH:10]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: [Cl-]
Reactant: CC(C)Cc1cccc(C(O)c2cccc(CC(C)C)c2)c1
Solvent: ClCCl
Product: CC(C)Cc1cccc(C(Cl)c2cccc(CC(C)C)c2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of bis(3-isobutylphenyl)methanol (2.87 g) and oxaly chloride (1 ml) in dichloromethane (10 ml) was stirred at 25° C. for 2 hours. After evaporation of the solvent, the oily residue was distilled to give bis(3-isobutylphenyl)chloromethane (2.45 g) as pale yellow oil.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][NH2:7].CC1(C)[O:19][C:18](=O)[CH:17]=[C:16]([CH3:21])[O:15]1>CCOC(C)=O>[O:15]=[C:16]([CH3:21])[CH2:17][C:18]([NH:7][CH2:6][C:5]1[CH:8]=[CH:9][CH:10]=[C:3]([C:2]([F:11])([F:12])[F:1])[CH:4]=1)=[O:19]
Reactant: NCc1cccc(C(F)(F)F)c1
Reactant: CC1=CC(=O)OC(C)(C)O1
Solvent: CCOC(C)=O
Product: CC(=O)CC(=O)NCc1cccc(C(F)(F)F)c1
Temperature: 150 °C
Reaction time: 2 h
Yield: 71.1 %

Procedure:
3-(Trifluoromethyl)benzylamine (2.0 ml, 13.95 mmol) was mixed with 2,2,6-trimethyl-4H-1,3-dioxin-4-one (2.0 ml, 15.12 mmol), The mixture was stirred at 150° C. for 2 hours followed by 60 hours at 50° C. The reaction was cooled, diluted with EtOAc (50 ml), washed with 1M HCl (40 ml), NaHCO3 (2*40 ml, sat aq), dried over MgSO4 and evaporated. The crude product was purified by precipitation from toluene/pet.ether to give 2.57 g (71%) of 3-oxo-N-(3-(trifluoromethyl)benzyl)butanamide as pale solids.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([C:12](=[O:15])[CH2:13]Br)=[CH:4][C:3]=1[Cl:16].[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][CH2:24][O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][NH:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C(N(CC)C(C)C)(C)C>O1CCCC1>[NH2:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([CH:12]([CH2:13][N:32]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][O:25][CH2:24][CH2:23][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][N:17]=2)[OH:15])=[CH:4][C:3]=1[Cl:16]
Reactant: c1ccc(CNCCCCCCOCCc2ccccn2)cc1
Reactant: Nc1c(Cl)cc(C(=O)CBr)cc1C(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Nc1c(Cl)cc(C(O)CN(CCCCCCOCCc2ccccn2)Cc2ccccc2)cc1C(F)(F)F
Reaction time: 1 h
Yield: 43.6 %

Procedure:
1-[4-Amino-3-chloro-5-(trifluoromethyl)phenyl]-2-bromoethanone (2.1 g), N-[6-[2-(2-pyridinyl)ethoxy]hexyl]benzenemethanamine (2.20 g) and N,N-diisopropylethylamine (0.94 g) were stirred together in tetrahydrofuran (45 ml) for 24 h at room temperature under nitrogen. The mixture was filtered and the filtrate evaporated in vacuo. The residue was dissolved in methanol (80 ml) and sodium borohydride (0.63 g) was added portionwise to the solution at 0° under nitrogen. The mixture was stirred for 1 h and then 2N hydrochloric acid (40 ml) was added. The solvent was evaporated in vacuo, the residue partitioned between 8% sodium bicarbonate solution (150 ml) and ethyl acetate (100 ml). The organic phase was separated, and the aqueous phase re-extracted with ethyl acetate (100 ml). The combined organic extracts were dried and evaporated in vacuo to give a yellow oil. Purification by FCC eluting with toluene-ethanol-triethylamine (98:2:1) afforded the title compound as a yellow oil (1.59 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:24][CH3:25])[CH2:22]O)[C:11](=[O:26])[C@:10]([CH2:28][C:29]([O:31][CH3:32])=[O:30])([CH3:27])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[CH2:33]([SH:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C(C=P(CCCC)(CCCC)CCCC)#N>C1(C)C=CC=CC=1>[CH2:33]([S:40][CH2:22][C@@H:21]([N:12]1[C@H:13]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[C@@H:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[CH2:9][C@@:10]([CH2:28][C:29]([O:31][CH3:32])=[O:30])([CH3:27])[C:11]1=[O:26])[CH2:24][CH3:25])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: SCc1ccccc1
Reactant: CC[C@@H](CO)N1C(=O)[C@@](C)(CC(=O)OC)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: CC[C@@H](CSCc1ccccc1)N1C(=O)[C@@](C)(CC(=O)OC)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 100 °C

Procedure:
To a solution of methyl 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetate (214.4 mg, 0.448 mmol; Example 186, Step A) in toluene (2.0 mL) was added benzyl mercaptan (0.106 mL, 0.90 mmol), followed by cyanomethylenetributylphosphorane (0.235 mL, 0.896 mmol; TCI). The solution was heated at 100° C. for 3.75 hours, then concentrated in vacuo. Purification of the residue by chromatography on silica gel (12 g SiO2, 0% to 50% EtOAc in hexanes) provided the title compound as colorless oil.