Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=2)=[O:10])=[CH:4][CH:3]=1.CO[CH:21](OC)[N:22]([CH3:24])[CH3:23]>CN(C=O)C.C(OCC)(=O)C>[CH3:21][N:22]([CH3:24])[CH:23]=[C:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[C:9]([C:11]1[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=1)=[O:10]
Reactant: CSc1ccc(C(=O)Cc2ccc(F)cc2)cc1
Reactant: COC(OC)N(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CSc1ccc(C(=O)C(=CN(C)C)c2ccc(F)cc2)cc1

Procedure:
2-(4-Fluorophenyl)-1-[4-(methylthio)phenyl]ethanone from Example 1, Step 1 (17.2 g, 66 mmol) was stirred with 15 mL dimethylformamide dimethylacetal in 80 mL dry DMF at 120° C. for 24 hours under nitrogen. The reaction mixture was cooled, diluted with two volumes of ethyl acetate, and the solution washed successively with water and brine and dried over Na2SO4. The solvent was removed under high vacuum and the resulting brown oil (23.9 g) was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[N:14]=[CH:13][C:12]([CH2:15][C:16]([NH2:18])=[O:17])=[C:11]([NH:19][CH2:20][C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[CH:22]=2)[CH:10]=1.[CH:29](OC)(OC)OC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[N:8]1([C:9]2[N:14]=[CH:13][C:12]([CH2:15][C:16]([NH2:18])=[O:17])=[C:11]([NH:19][CH2:20][C:21]3[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[CH:22]=3)[CH:10]=2)[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=[CH:29]1
Reactant: COC(OC)OC
Reactant: NC(=O)Cc1cnc(Nc2ccccc2N)cc1NCc1cc(F)cc(F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: NC(=O)Cc1cnc(-n2cnc3ccccc32)cc1NCc1cc(F)cc(F)c1
Reaction time: 4 h
Yield: 94 %

Procedure:
9 mg of 6-[(2-aminophenyl)amino]-4-[(3,5-difluorobenzyl)amino]pyridine-3-carboxyamide (the compound of step 1 of Example 365) was suspended in 0.2 ml of methanol, to which 0.2 mL of trimethyl orthoformate and a catalytic amount of p-toluenesulfonic acid monohydrate were added at room temperature, and stirred at the same temperature for 4 hours. The solvent was evaporated, saturated sodium bicarbonate was added to the residue, extracted with chloroform, the extract was washed with water, and dried on anhydrous sodium sulfate. The solvent was evaporated to obtain 9 mg (yield 94%) of the title compound as a light brown solid.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH:7]([CH3:17])[CH2:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:5]=[N:4][C:3]=1[C:18]([NH2:20])=[O:19].[CH3:21][N:22]([CH3:34])[C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30](OC)=O)=[CH:25][CH:24]=1>>[CH3:34][N:22]([CH3:21])[C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30]2[NH:20][C:18](=[O:19])[C:3]3[N:4]=[N:5][N:6]([CH:7]([CH3:17])[CH2:8][CH2:9][CH2:10][C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)[C:2]=3[N:1]=2)=[CH:25][CH:24]=1
Reactant: COC(=O)Cc1ccc(N(C)C)cc1
Reactant: CC(CCCc1ccccc1)n1nnc(C(N)=O)c1N
Product: CC(CCCc1ccccc1)n1nnc2c(=O)[nH]c(Cc3ccc(N(C)C)cc3)nc21

Procedure:
Analogously to the procedure of Example 5, the title compound is prepared from 1.0 g (3.8 mmol) of 5-amino-1-(1-methyl-4-phenyl-butyl)-1H-[1,2,3]triazole-4-carboxamide and 1.77 g (9.15 mmol) of methyl 4-dimethylaminophenylacetate.
Reaction SMILES: C1(O[C:8](=[O:40])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[C:20]([C:22]4[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=4[S:29]([CH3:32])(=[O:31])=[O:30])[N:19]=[C:18]([N:33]4[CH2:38][CH2:37][O:36][CH2:35][C@@H:34]4[CH3:39])[N:17]=3)=[CH:12][CH:11]=2)C=CC=CC=1.[NH2:41][C@H:42]([CH3:45])[CH2:43][OH:44]>>[F:28][C:26]1[CH:25]=[CH:24][C:23]([S:29]([CH3:32])(=[O:31])=[O:30])=[C:22]([C:20]2[N:19]=[C:18]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][C@@H:34]3[CH3:39])[N:17]=[C:16]([C:13]3[CH:12]=[CH:11][C:10]([NH:9][C:8]([NH:41][C@H:42]([CH3:45])[CH2:43][OH:44])=[O:40])=[CH:15][CH:14]=3)[CH:21]=2)[CH:27]=1
Reactant: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)Oc3ccccc3)cc2)cc(-c2cc(F)ccc2S(C)(=O)=O)n1
Reactant: C[C@@H](N)CO
Product: C[C@H](CO)NC(=O)Nc1ccc(-c2cc(-c3cc(F)ccc3S(C)(=O)=O)nc(N3CCOC[C@@H]3C)n2)cc1

Procedure:
Method as described for example 58 using intermediate 32 (100 mg, 0.18 mmol) and (R)-2-aminopropan-1-ol (20 mg, 0.267 mmol). The reaction mixture was purified by prep HPLC at low pH to afford the title compound. (59 mg, 61%)
Reaction SMILES: CS([C:4]1[N:9]=[C:8]([NH:10][C:11]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:13][CH2:12]2)[C:7]([C:20]([NH2:22])=[O:21])=[CH:6][N:5]=1)=O.[C:23]([NH:26][C:27]1[CH:28]=[C:29]([CH:31]=[CH:32][CH:33]=1)[NH2:30])(=[O:25])[CH3:24].CC1C=CC(S(O)(=O)=O)=CC=1>CN1C(=O)CCC1>[C:23]([NH:26][C:27]1[CH:28]=[C:29]([NH:30][C:4]2[N:9]=[C:8]([NH:10][C:11]3([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH2:13][CH2:12]3)[C:7]([C:20]([NH2:22])=[O:21])=[CH:6][N:5]=2)[CH:31]=[CH:32][CH:33]=1)(=[O:25])[CH3:24]
Reactant: CC(=O)Nc1cccc(N)c1
Reactant: CS(=O)c1ncc(C(N)=O)c(NC2(c3ccccc3)CC2)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN1CCCC1=O
Product: CC(=O)Nc1cccc(Nc2ncc(C(N)=O)c(NC3(c4ccccc4)CC3)n2)c1
Temperature: 100 °C
Yield: 59 %

Procedure:
To a solution of 2-(methylsulfinyl)-4-(1-phenylcyclopropylamino)pyrimidine-5-carboxamide (50 mg, 0.16 mmol) in NMP (1 mL) was added 3-acetamidoaniline (27 mg, 0.18 mmol) and pTsOH*H2O (30 mg, 0.16 mmol). The mixture was heated at 100° C. for 2 h, cooled to room temperature, and purified by preparative HPLC to give 2-(3-acetamidophenylamino)-4-(1-phenylcyclopropylamino)pyrimidine-5-carboxamide (38 mg). MS found for C22H22N6O2 as (M+H)+ 403.5. λ=251.1.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[CH2:5][N:6]1[C:10]2[N:11]=[C:12]([NH2:20])[N:13]=[C:14]([C:15]3[O:16][CH:17]=[CH:18][CH:19]=3)[C:9]=2[N:8]=[N:7]1.[F:24][C:25]1[CH:32]=[CH:31][C:28]([CH:29]=O)=[CH:27][CH:26]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C1COCC1>[F:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH:1][C:2]2[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=2)[CH2:5][N:6]2[C:10]3[N:11]=[C:12]([NH2:20])[N:13]=[C:14]([C:15]4[O:16][CH:17]=[CH:18][CH:19]=4)[C:9]=3[N:8]=[N:7]2)=[CH:27][CH:26]=1
Reactant: Nc1cccc(Cn2nnc3c(-c4ccco4)nc(N)nc32)c1
Reactant: O=Cc1ccc(F)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Nc1nc(-c2ccco2)c2nnn(Cc3cccc(NCc4ccc(F)cc4)c3)c2n1
Temperature: 40 °C
Reaction time: 0.25 h
Yield: 39 %

Procedure:
A suspension of 3-(3-aminobenzyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine (200 mg, 0.65 mmol) and 4A molecular sieves in THF (10 mL) was treated with 4-fluorobenzaldehyde (0.04 mL, 0.37 mmol), heated to 40° C. for 3 h, cooled to room temperature, treated sodium triacetoxyborohydride (400 mg, 1.89 mmol) and acetic acid (0.1 mL) and stirred for 15 minutes. The reaction was quenched by addition of sat. NaHCO3 (5 mL), extracted with EtOAc (2×5 mL) and the combined organic phase dried (MgSO4), concentrated in vacuo and purified by chromatography [(SiO2; EtOAc:Heptane (1:2)] to give the title compound (60 mg, 44%) as a white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][CH2:11][C@H:12]([OH:24])[CH2:13][N:14]2[CH2:23][CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15]2)=[O:9])[CH:3]=1.[O:25]1[CH2:28][CH:27]([NH2:29])[CH2:26]1.CCN(C(C)C)C(C)C>CC(O)C>[CH2:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:22][CH2:23][N:14]1[CH2:13][C@@H:12]([OH:24])[CH2:11][NH:10][C:8]([C:4]1[CH:3]=[C:2]([NH:29][CH:27]2[CH2:28][O:25][CH2:26]2)[N:7]=[CH:6][N:5]=1)=[O:9]
Reactant: NC1COC1
Reactant: O=C(NC[C@H](O)CN1CCc2ccccc2C1)c1cc(Cl)ncn1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC[C@H](O)CN1CCc2ccccc2C1)c1cc(NC2COC2)ncn1
Temperature: 110 °C
Reaction time: 16 h
Yield: 16.3 %

Procedure:
To a solution of (S)-6-chloro-N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxy propyl)pyrimidine-4-carboxamide (347 mg, 1 mmol) in i-PrOH (5 mL) was added oxetan-3-amine (73.1 mg, 1 mmol) and DIPEA (129 mg, 1 mmol). The resulting mixture was stirred at 110° C. for 16 hours, at which time LCMS showed the completion of the reaction. After evaporation of the solvent, the residue was purified by preparative HPLC to give the target compound (S)—N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-6-(oxetan-3-ylamino)pyrimidine-4-carboxamide (62.5 mg, yield: 16.3%). 1H NMR (400 MHz, MeOD-d4) δ 8.24 (s, 1H), 7.15-7.05 (m, 4H), 7.02-6.98 (m, 1H), 5.09 (s, 1H), 4.95 (t, J=6.8 Hz, 2H), 4.59 (t, J=6.3 Hz, 2H), 4.10-4.03 (m, 1H), 3.72 (s, 2H), 3.56-3.46 (m, 2H), 2.96-2.91 (m, 2H), 2.87-2.80 (m, 2H), 2.65 (d, J=6.3 Hz, 2H). LCMS (m/z): 384.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C@H:10]([CH2:15][CH3:16])[C:11]([O:13]C)=[O:12])=[CH:5][C:4]=1[C:17](=[O:36])[NH:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]2[CH:32]=[C:31]([F:33])[C:30]([F:34])=[C:29]([F:35])[CH:28]=2)=[CH:22][CH:21]=1.[OH-].[Li+].O>CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C@H:10]([CH2:15][CH3:16])[C:11]([OH:13])=[O:12])=[CH:5][C:4]=1[C:17](=[O:36])[NH:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]2[CH:28]=[C:29]([F:35])[C:30]([F:34])=[C:31]([F:33])[CH:32]=2)=[CH:22][CH:21]=1
Reactant: CC[C@@H](Cc1ccc(OC)c(C(=O)NCc2ccc(Oc3cc(F)c(F)c(F)c3)cc2)c1)C(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC[C@@H](Cc1ccc(OC)c(C(=O)NCc2ccc(Oc3cc(F)c(F)c(F)c3)cc2)c1)C(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 40.5 %

Procedure:
To a solution of compound (465 mg, 0.927 mmol) of Example 16 in methanol (9 mL) were added 1 mol/L aqueous solution of lithium hydroxide (2.04 mL) and water (3 mL), and the mixture was stirred for 4 hours at room temperature. The reaction mixture was allowed to stand statically for 2 days and then stirred for 18 hours at 50° C. Water was added to the reaction mixture, which was filtered. After the filtrate was cooled to 0° C., it was brought to pH 4 with 3 mol/L hydrochloric acid. The precipitated powder was collected by filtration, dried and submitted to silica gel column chromatography (hexane:ethyl acetate=10:1→2:1) to afford 289 mg of crude powder. This was purified by recrystallization (acetonitrile) to afford 183 mg of white powdery title compound. Yield 40%.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:11]([CH2:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:14][CH3:15])(=O)C.CO.[OH-].[Na+]>O>[CH2:14]([C:7]1[CH:8]=[CH:9][CH:10]=[C:11]([CH2:12][CH3:13])[C:6]=1[CH2:5][OH:4])[CH3:15]
Reactant: CCc1cccc(CC)c1COC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCc1cccc(CC)c1CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 113.4 %

Procedure:
A mixture of 2,6-diethylbenzyl acetate (2.11 g, 10.2 mmol), MeOH (20 mL), H2O (6 mL), and NaOH (1.99 g, 50 mmol, 5 eq) was stirred at RT overnight. After concentrating, the mixture was extracted with heptane (50 mL). The organic layer was dried (Na2SO4), filtered, and evaporated to give 1.90 g of title product. 1H NMR (300 MHz, CDCl3) δ 1.23 (t, 1H, OH), 1.24 (t, 6H), 1.37 (br s, 1H), 2.79 (q, 4H), 4.75 (d, 2H), 7.09 (d, 2H), 7.21 (dd, 1H). The following compound was prepared by making appropriate substitutions to the above procedure: (2,6-Dimethylphenyl)methanol. 1H NMR (300 MHz, CDCl3) δ 1.25 (t, 1H, OH), 2.41 (s, 6H), 4.72 (d, 2H), 7.0-7.15 (m, 3H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[C:10](=[O:14])[CH2:9][CH2:8]2)([CH3:4])([CH3:3])[CH3:2].[N:15](OCCC(C)C)=[O:16].Cl>CO>[C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[C:10](=[O:14])[C:9](=[N:15][OH:16])[CH2:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)CCON=O
Reactant: CC(C)(C)c1ccc2c(c1)CCC2=O
Agent: Cl
Solvent: CO
Product: CC(C)(C)c1ccc2c(c1)CC(=NO)C2=O
Temperature: 25 °C
Reaction time: 44 h
Yield: 137.7 %

Procedure:
5-tert-butyl-indan-1-one (9.39 g, 39 mmol) was dissolved in 150 ml methanol. Isoamyl nitrite (5 g, 43 mmol) and conc. HCl (5 ml) were added, and the reaction stirred at ambient temperature for 44 hours. The solvents were removed under vacuum to give 11.67 grams of crude product which was used without further purification. 1H NMR (300 MHz, CDCl3) 7.82 (d, 1H), 7.51 (s, 1H), 7.49 (d, 1H), 3.83 (s, 2H), 3.50 (s, 1H, OH) 1.34 (s, 9H). MS (CSI) m/e 218 (M+H)+, 235 (M+NH4)+
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30](Br)[N:29]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[Cl:35][C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[C:37]=1B(O)O>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([C:37]5[C:36]([Cl:35])=[CH:41][CH:40]=[CH:39][C:38]=5[Cl:42])[N:29]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(Br)n4)cc3)cc2)CC1
Reactant: OB(O)c1c(Cl)cccc1Cl
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(-c5c(Cl)cccc5Cl)n4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 42, Step 2, using 1-{4′-[4-(6-bromo-pyridin-2-ylamino)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and 2,6-dichloro-phenylboronic acid.
Reaction SMILES: [C:1]([Cl:6])(=[O:5])[C:2](Cl)=[O:3].[CH3:7][O:8][CH2:9][CH2:10]OCC(O)=O>CN(C=O)C.C(Cl)Cl>[CH3:7][O:8][CH2:9][CH2:10][O:3][CH2:2][C:1]([Cl:6])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COCCOCC(=O)O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COCCOCC(=O)Cl
Reaction time: 17 h

Procedure:
Under a nitrogen atmosphere, 2.56 ml (29.8 mmol) of oxalyl chloride and 2 drops of DMF are added to 1.69 ml (14.9 mmol) of 2-(2-methoxyethoxy)-acetic acid (Fluka; Buchs/Switzerland) in 75 ml of methylene chloride. After 17 h at RT, the reaction mixture is carefully concentrated by evaporation in a RE with the exclusion of moisture. A 1H-NMR spectrum of the residue exhibits the signals of the title compound in addition to signals of ≈40% solvent (especially methylene chloride): 1H-NMR (200 MHz, CDCl3): 3.37 (s, MeO), 3.58 and 3.77 (2d, J=5 Hz, CH2 --CH2), 4.48 (s, CH2). That mixture is used above.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]([OH:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][CH2:19][CH3:20].O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:18][CH2:19][CH3:20])=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: O=Cc1cc(Br)ccc1O
Reactant: CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCOc1ccc(Br)cc1C=O
Temperature: 90 °C
Reaction time: 3 h

Procedure:
In DMF (160 ml) was dissolved 5-bromosalicylaldehyde (20 g). To the mixture was added at room temperature potassium carbonate (17.9 g) and then was added 1-bromopropane (10.8 ml), and the mixture was stirred at 90° C. for 3 hours and cooled to room temperature. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (hexane/ethyl acetate=6/1) to give 5-bromo-2-propoxybenzaldehyde (21.9 g).
Reaction SMILES: [F:1][C:2]([F:22])([C:18]([F:21])([F:20])[F:19])[C:3]([F:17])([F:16])[C:4]([F:15])([F:14])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]O.[BrH:23].S(=O)(=O)(O)O>O>[Br:23][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]([F:15])([F:14])[C:3]([F:17])([F:16])[C:2]([F:22])([F:1])[C:18]([F:21])([F:20])[F:19]
Reactant: Br
Reactant: OCCCCCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: O=S(=O)(O)O
Solvent: O
Product: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)CCCCCCCCBr
Temperature: 100 °C

Procedure:
To a mixture of 15.22 g of 8-(nonafluorobutyl)-1-octanol and 200 mL of 48 weight percent hydrobromic acid was slowly added 20 mL of concentrated sulfuric acid. The reaction mixture was heated at 100° C. for 18 hr and poured into 800 mL of water. The mixture was extracted with 2×200 mL portions of hexanes, and the combined organic phases were washed with 2×200 mL portions of saturated aqueous sodium bicarbonate, 2 ×200 mL portions of 3 formal aqueous sodium thiosulfate, and one 100 mL portion of brine, and then dried over anhydrous magnesium sulfate. The solution was concentrated to a dark liquid, which was eluted through 2 inches (5 cm) of silica with 500 mL of hexanes. Concentration of the eluent yielded a clear, light yellow liquid, and bulb-to-bulb distillation gave 9.14 g of 1-bromo-8-(nonafluorobutyl)octane as a clear, light yellow liquid, b.p. 105-110° C. at 0.05 torr (7 Pa).
Reaction SMILES: [N:1]1([CH2:6][CH:7]([CH2:17][O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([NH2:16])=O)[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[NH2:16][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][O:8][CH:7]([CH2:17][O:18][CH2:19][C:20]1[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=1)[CH2:6][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: COc1ccc(COCC(Cn2ccnc2)OCCCCCC(N)=O)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(COCC(Cn2ccnc2)OCCCCCCN)cc1
Temperature: 25 °C

Procedure:
6-[2-(1H-Imidazol-1-yl)-1[[4-methoxyphenyl)methoxy]methyl]ethoxy]hexanamide (Example 20, 0.3 g, 0.0008 mol) in dry tetrahydrofuran (2 ml) was added to a stirred suspension of lithium aluminium hydride (0.5 g, 0.013 mol) in dry tetrahydrofuran (10 ml) under a nitrogen atmosphere. The resulting suspension was stirred under reflux for 24 hours cooled to room temperature and the residual lithium aluminium hydride destroyed using ethyl acetate (15 ml) followed by dilute sodium hydroxide solution (2N, 20 ml), the resulting solution was filtered and the filter cake was washed with ethyl acetate (50 ml), the organic layer was separated, dried (MgSO4) and evaporated to an oil which was purified by column chromatography (silica gel, ethylacetate to 10% methanol in ethyl acetate) to yield the title compound as an oil.
Reaction SMILES: [CH:1]([C:3]1[CH:15]=[CH:14][C:6]([C:7]([NH:9][C:10](=[O:13])[O:11][CH3:12])=[O:8])=[C:5]([CH3:16])[CH:4]=1)=O.Cl.[NH2:18][OH:19]>CO.O>[OH:19][N:18]=[CH:1][C:3]1[CH:15]=[CH:14][C:6]([C:7]([NH:9][C:10](=[O:13])[O:11][CH3:12])=[O:8])=[C:5]([CH3:16])[CH:4]=1
Reactant: NO
Reactant: COC(=O)NC(=O)c1ccc(C=O)cc1C
Agent: Cl
Solvent: CO
Solvent: O
Product: COC(=O)NC(=O)c1ccc(C=NO)cc1C
Yield: 102.8 %

Procedure:
In a solution of 41 mg of methyl N-[4-formyl-2-methyl benzoyl]carbamate in 4 mL of methanol and 1 mL of water, 15 mg of hydroxylamine hydrochloride was added at room temperature with stirring, and continued to stir at the same temperature for 1.5 hour. After the completion of the reaction, 10 mL of water was added in the reaction mixture, and extracted with ethyl acetate (10 mL×2). The combined organic phases were dehydrated with and dried over saturated sodium chloride aqueous solution and then anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 45 mg of the aimed product as white crystal.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]([O:11][CH3:12])=[O:10])=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.[NH2:22][C@@H:23]1[CH2:28][CH2:27][CH2:26][C@H:25]([OH:29])[CH2:24]1>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([NH:22][C@@H:23]2[CH2:28][CH2:27][CH2:26][C@H:25]([OH:29])[CH2:24]2)[C:5]([C:9]([O:11][CH3:12])=[O:10])=[CH:4][N:3]=1
Reactant: COC(=O)c1cnc(Cl)nc1Cl
Reactant: N[C@@H]1CCC[C@H](O)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)c1cnc(Cl)nc1N[C@@H]1CCC[C@H](O)C1
Temperature: -78 °C
Reaction time: 1 h
Yield: 67 %

Procedure:
To a stirring solution of methyl 2,4-dichloropyrimidine-5-carboxylate (4.00 g, 19.32 mmol) in THF (85 mL) was added DIEA (3.37 mL, 19.32 mmol). The resulting mixture was cooled to −78° C. in a dry ice/acetone bath. A solution of (1S,3R)-3-aminocyclohexanol (2.448 g, 21.25 mmol; prepared as described in Tetrahedron: Asymmetry 15:2051-2056 (2004)) in 40 mL THF was added at such a rate that the temperature remained at −78° C. The resulting mixture was stirred at −78° C. for 1 h. The reaction mixture was then concentrated to dryness and diluted with 200 mL ethyl acetate and 75 mL of a 1:1 mixture of water and an aqueous saturated sodium bicarbonate solution. The layers were separated and the aqueous layer back-extracted with 100 mL ethyl acetate. The combined ethyl acetate layers were washed with 50 mL of a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated to an oil that solidified upon standing. The solid was triturated with diethyl ether (5 mL), filtered, rinsed with diethyl ether (5 mL) and dried in vacuo to afford methyl 2-chloro-4-((1R,3S)-3-hydroxycyclohexylamino)pyrimidine-5-carboxylate (3.7 g, 12.95 mmol, 67% yield) that was used without further purification. MS (ESI) m/z 286.0 [M+1]+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]#[N:11])[CH:5]=[CH:6][C:7]=1[OH:8].CO[C:14](OC)([CH3:16])[CH3:15].CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:15][C:14]1([CH3:16])[O:8][C:7]2[CH:6]=[CH:5][C:4]([CH2:9][C:10]#[N:11])=[CH:3][C:2]=2[O:1]1
Reactant: N#CCc1ccc(O)c(O)c1
Reactant: COC(C)(C)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC1(C)Oc2ccc(CC#N)cc2O1
Yield: 16.3 %

Procedure:
To a solution of (3,4-dihydroxy-phenyl)-acetonitrile (0.20 g, 1.3 mmol) in toluene (4 mL) was added 2,2-dimethoxy-propane (0.28 g, 2.6 mmol) and TsOH (0.010 g, 0.065 mmol). The mixture was heated at reflux overnight. The reaction mixture was evaporated to remove the solvent and the residue was dissolved in ethyl acetate. The organic layer was washed with NaHCO3 solution, H2O, brine, and dried over Na2SO4. The solvent was evaporated under reduced pressure to give a residue, which was purified by column chromatography on silica gel (petroleum ether/ethyl acetate 10:1) to give 2-(2,2-dimethylbenzo[d][1,3]dioxol-5-yl)acetonitrile (40 mg, 20%). 1H NMR (CDCl3, 400 MHz) δ 6.68-6.71 (m, 3 H), 3.64 (s, 2 H), 1.67 (s, 6 H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][NH:6][CH:7]([CH3:17])[C:8]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)=O)[CH3:2].[CH:19]1([N:22]=[C:23]=[O:24])[CH2:21][CH2:20]1>O1CCCC1>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][N:6]1[C:7]([CH3:17])=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[N:22]([CH:19]2[CH2:21][CH2:20]2)[C:23]1=[O:24])[CH3:2]
Reactant: O=C=NC1CC1
Reactant: CCOC(=O)CNC(C)C(=O)c1ccc(Cl)cc1
Solvent: C1CCOC1
Product: CCOC(=O)Cn1c(C)c(-c2ccc(Cl)cc2)n(C2CC2)c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
355 mg (1.32 mmol) of N-[2-(4-chlorophenyl)-1-methyl-2-oxoethyl]-glycine ethyl ester from Example 117A are placed in 5 ml tetrahydrofuran, treated with 109 mg (1.32 mmol) of cyclopropyl isocyanate and stirred overnight at room temperature. The reaction mixture is evaporated and the residue purified by flash chromatography on silica gel (eluent: first dichloromethane, then dichloromethane/methanol 200:1→100:1). 425 mg (91% of theory) of the target compound are thus obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:13]3[C:14]([CH2:17][CH2:18]O)=[N:15][N:16]=[C:12]3[CH2:11][N:10]=[C:9]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])[C:8]=2[CH:27]=1)([O-:3])=[O:2].[C:28]1(=[O:38])[NH:32][C:31](=[O:33])[C:30]2=[CH:34][CH:35]=[CH:36][CH:37]=[C:29]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCOCC1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:13]3[C:14]([CH2:17][CH2:18][N:32]4[C:28](=[O:38])[C:29]5=[CH:37][CH:36]=[CH:35][CH:34]=[C:30]5[C:31]4=[O:33])=[N:15][N:16]=[C:12]3[CH2:11][N:10]=[C:9]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])[C:8]=2[CH:27]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2c(c1)C(c1ccccc1Cl)=NCc1nnc(CCO)n1-2
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: O=C1c2ccccc2C(=O)N1CCc1nnc2n1-c1ccc([N+](=O)[O-])cc1C(c1ccccc1Cl)=NC2

Procedure:
In the manner given in Example 2, 8-nitro-1-(2-hydroxyethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a]-[1,4]benzodiazepine in dioxane is treated with phthalimide, triphenylphosphine and subsequently with diethyl azodicarboxylate to give 8-nitro-1-(2-phthalimidoethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.