Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][CH2:5][C@H:6]([N:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Cl:19])[C:14]=2[NH2:18])[C:9]1=[O:20])[CH3:7])(=[O:3])[CH3:2].C(Cl)Cl.[F:24][C:25]1[CH:26]=[C:27]([CH2:35][C:36](O)=[O:37])[CH:28]=[CH:29][C:30]=1[C:31]([F:34])([F:33])[F:32].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>>[C:1]([O:4][CH2:5][C@H:6]([N:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Cl:19])[C:14]=2[NH:18][C:36](=[O:37])[CH2:35][C:27]2[CH:28]=[CH:29][C:30]([C:31]([F:32])([F:33])[F:34])=[C:25]([F:24])[CH:26]=2)[C:9]1=[O:20])[CH3:7])(=[O:3])[CH3:2]
Reactant: O=C(O)Cc1ccc(C(F)(F)F)c(F)c1
Reactant: CC(=O)OC[C@@H](C)n1ccc2c(N)c(Cl)ccc2c1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)OC[C@@H](C)n1ccc2c(NC(=O)Cc3ccc(C(F)(F)F)c(F)c3)c(Cl)ccc2c1=O
Temperature: 40 °C
Reaction time: 48 h

Procedure:
A vial was charged with (R)-2-(5-amino-6-chloro-1-oxoisoquinolin-2(1H)-yl)propyl acetate (160 mg, 0.00054 mol), methylene chloride (10 mL, 0.2 mol), 2-(3-fluoro-4-(trifluoromethyl)phenyl)acetic acid (145 mg, 0.000651 mol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (413 mg, 0.00108 mol), and N,N-diisopropylethylamine (0.189 mL, 0.00108 mol), and was stirred at 40° C. for 2 days. the solvent was removed under reduced pressureunder reduced pressure and the residue was purified by flash chromatography to afford the product as colorless oil.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.CS([C:18]1[N:23]=[CH:22][C:21]2=[CH:24][CH:25]=[C:26]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[N:33]([CH3:38])[S:34]([CH3:37])(=[O:36])=[O:35])[N:20]2[N:19]=1)=O.C(N(CC)C(C)C)(C)C>>[CH3:38][N:33]([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[C:26]1[N:20]2[C:21]([CH:22]=[N:23][C:18]([NH:14][C:11]3[CH:10]=[CH:9][C:8]([CH:5]4[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]4)=[CH:13][CH:12]=3)=[N:19]2)=[CH:24][CH:25]=1)[S:34]([CH3:37])(=[O:35])=[O:36]
Reactant: CN1CCC(c2ccc(N)cc2)CC1
Reactant: CN(c1ccccc1-c1ccc2cnc(S(C)=O)nn12)S(C)(=O)=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCC(c2ccc(Nc3ncc4ccc(-c5ccccc5N(C)S(C)(=O)=O)n4n3)cc2)CC1
Temperature: 120 °C

Procedure:
Into a 8-dram vial, 4-(1-Methyl-piperidin-4-yl)-phenylamine (0.115 g, 0.604 mmol), N-[2-(2-Methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-phenyl]-N-methyl-methanesulfonamide (0.100 g, 0.274 mmol), N,N-Diisopropylethylamine (0.1051 mL, 0.6036 mmol) and were added. The reaction was heated at 120° C. overnight. LCMS suggested presence of desired product. The solvent was removed under vacuum. The reaction mixture was purified via HPLC reverse phase chromatography with 0.1% TFA in Water and 0.1% TFA in ACN. The collected fractions were lyophilized to give N-Methyl-N-(2-{2-[4-(1-methyl-piperidin-4-yl)-phenylamino]-pyrrolo[2,1-f][1,2,4]triazin-7-yl}-phenyl)-methanesulfonamide as a yellow solid (38 mg, 36%). LCMS (E/I+) 491.16 (M+H). NMR 1H (DMSO-d6)-9.39 (s, 1H), 9.33 (s, 1H), 8.50 (d, 1H, J=7.59 Hz), 7.74 (d, 1H, J=7.59 Hz), 7.50-7.62 (m, 3H), 7.06 (d, 2H, J=7.59 Hz), 6.98 (bs, 1H), 6.93 (bs, 1H), 3.10 (s, 3H), 2.90 (s, 3H), 2.85 (d, 2H, J=11.43 Hz), 2.30-2.40 (m, 1H), 2.18 (s, 3H), 1.92 (t, 2H, J=11.43 Hz), 1.52-1.72 (m, 4H).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([CH2:10][C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[C:6]([CH3:9])[C:7]=1[CH3:8].[CH3:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1>CO>[CH3:17][C:18]1[CH:24]=[CH:23][C:21]([NH:22][C:2]2[N:3]=[N:4][C:5]([CH2:10][C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)=[C:6]([CH3:9])[C:7]=2[CH3:8])=[CH:20][CH:19]=1
Reactant: Cc1c(Cl)nnc(Cc2ccncc2)c1C
Reactant: Cc1ccc(N)cc1
Solvent: CO
Product: Cc1ccc(Nc2nnc(Cc3ccncc3)c(C)c2C)cc1

Procedure:
The compound is prepared from 0.070 g 3-chloro-4,5-dimethyl-6-(pyridin-4-yl)methylpyridazine and 0.129 g para-methylaniline in the manner described in Example 82A. Title compound is obtained after FC in CH2Cl/Methanol 19/1; m.p. 68-70° C. 1H-NMR (250 MHz, CDCl3): δ=8.45 (s, wide, 2H); 7.45 (d, 2H); 7.10 (“d”, wide, 4H); 6.10 (s, wide, 1H); 4.25 (s, 2H); 2.30 (s, 3H); 2.15 (s, 3H); 2.10 (s, 3H). ES-MS 305 (M+H).
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18][CH:19]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:14][CH:13]=2)[N:9]=1)(=[O:3])[CH3:2].O1CCCC1.[Br:41]N1C(=O)CCC1=O>CO>[C:1]([NH:4][C:5]1[S:6][C:7]([Br:41])=[C:8]([CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([NH:18][CH:19]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:25])[CH3:26])[NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:16][CH:17]=2)[N:9]=1)(=[O:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)Nc1nc(CCc2ccc(NC(NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)cc2)cs1
Solvent: CO
Solvent: C1CCOC1
Product: CC(=O)Nc1nc(CCc2ccc(NC(NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)cc2)c(Br)s1
Temperature: 25 °C
Reaction time: 4 h
Yield: 75.7 %

Procedure:
Di-tert-butyl {[(4-{2-[2-(acetylamino)-1,3-thiazol-4-yl]ethyl}phenyl)amino]methylidene}biscarbamate (310 mg) prepared in a similar manner according to Step 5 of the following Production Example 18 was dissolved in methanol (6 ml) and tetrahydrofuran (3 ml) under nitrogen atmosphere. Then N-bromosuccinimide (164 mg) was added to the solution at 0° C. The reaction mixture was stirred at room temperature for 4 hours, and concentrated in vacuo. Chloroform and saturated sodium hydrogen carbonate solution were added to the residue. The organic layer was washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by flash column chromatography over silica gel with n-hexane/ethyl acetate (2:1) as an eluent to give di-tert-butyl {[(4-{2-[2-(acetylamino)-5-bromo-1,3-thiazol-4-yl]ethyl}phenyl)amino]methylidene}biscarbamate (271.4 mg) as a colorless amorphous substance.
Reaction SMILES: [PH:1](=[O:4])([OH:3])[OH:2].[CH2:5]([C:7]([CH2:35][CH3:36])([CH:9]([OH:34])[C:10]1[N:14]=[CH:13][N:12]([C:15]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:11]=1)[CH3:8])[CH3:6].C(N(CC)CC)C.[C:44](OC(=O)C)(=[O:46])[CH3:45]>CN(C)C1C=CN=CC=1.ClCCl>[PH:1](=[O:2])([OH:4])[OH:3].[CH2:35]([C:7]([CH2:5][CH3:6])([CH:9]([O:34][C:44](=[O:46])[CH3:45])[C:10]1[N:14]=[CH:13][N:12]([C:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:11]=1)[CH3:8])[CH3:36]
Reactant: CC(=O)OC(C)=O
Reactant: CCC(C)(CC)C(O)c1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: CN(C)c1ccncc1
Agent: O=[PH](O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(C)(CC)C(OC(C)=O)c1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.4 %

Procedure:
A stirred solution of diethyl 3-hydroxy-3(1-trityl-1,2,4-triazol-3-yl)propane phosphonate (1.0 g, prepared as described in Example 24), triethylamine (0.22 g) and 4-dimethylaminopyridine (0.03 g) in dry dichloromethane (10 ml) was treated dropwise with acetic anhydride (0.28 g), whilst maintaining the temperature below 5° C. The mixture was allowed to warm to room temperature, stirred for a further two hours, diluted with dichloromethane, washed with water, dried over magnesium sulphate and evaporated under reduced pressure. The residue was chromatographed on silica, using dichloromethane-ethanol (19:1) as eluant, to give diethyl 3-acetoxy-3(1-trityl-1,2,4-triazol-3-yl)propane phosphonate (0.86 g, m.p. 100-102° C.). NMR (CDCl3): δ 1.3(6H,t), 1.65-1.9(2H,m), 2.1(3H,s), 2.2-2.35(2H,m), 4.05(4H,m), 5.9(1H,t), 7.1(6H,m), 7.3(9H,m), 7.9(1H,s). M/S: M+ 547.
Reaction SMILES: Br[CH2:2][C:3](=[O:16])[C:4]([CH3:15])([CH3:14])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=1[Cl:13].[NH:17]1[CH:21]=[N:20][CH:19]=[N:18]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:13][C:7]1[CH:8]=[C:9]([Cl:12])[CH:10]=[CH:11][C:6]=1[CH2:5][C:4]([CH3:15])([CH3:14])[C:3](=[O:16])[CH2:2][N:17]1[CH:21]=[N:20][CH:19]=[N:18]1
Reactant: CC(C)(Cc1ccc(Cl)cc1Cl)C(=O)CBr
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(Cc1ccc(Cl)cc1Cl)C(=O)Cn1cncn1
Yield: 45.6 %

Procedure:
30 g (0.09 mole) of 1-bromo-4-(2,4-dichlorophenyl)-3,3-dimethyl-2-butanone, 12.4 g (0.18 mole) of 1,2,4-triazole and 24.8 g (0.18 mole) of potassium carbonate are heated under reflux in 300 ml of acetone for 6 hours. The mixture is then allowed to cool and is filtered with suction and the mother liquor is concentrated in vacuo. The residue is taken up in methylene chloride and the mixture is washed with water, dried over sodium sulphate and concentrated in vacuo. The residue is recrystallised from diethyl ether. 12.8 g (45.6% of theory) of 4-(2,4-dichlorophenyl)-3,3-dimethyl-1-(1,2,4-triazol-1-yl)-2-butanone of melting point 85° C. are obtained. ##STR14##
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[OH:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17](=[O:19])[CH3:18])=[CH:12][CH:11]=1.N1C=CN=C1>CN(C=O)C>[Si:1]([O:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:16][C:17]([CH3:18])=[O:19])=[CH:14][CH:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(=O)Cc1ccc(O)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(=O)Cc1ccc(O[Si](C)(C)C(C)(C)C)cc1
Reaction time: 0.75 h
Yield: 79.5 %

Procedure:
A solution of tert-butyldimethylsilyl chloride (13.6 g) in DMF (50 ml) was added dropwise to stirred solution of 4-hydroxyphenylacetone (12.5 g) and imidazole (9.0 g) in DMF (150 ml) at 20° under N2. After 0.67 h additional tert-butyldimethylsilyl chloride (4.7 g) was added and the reaction stirred for 0.75 h. The reaction mixture was concentrated in vacuo and the residue partitioneed between Et2O and water. The organic phase was washed with water, brine, dried (MgSO4) and evaporated to dryness. The residue was purified by chromatography on a Biotage (90 g) eluting with cyclohexane-Et2O (9:1) to give the title compound (17.5 g), ES+ve 282 (M+NH4)+
Reaction SMILES: [CH2:1]([CH:4]([CH2:14][O:15][CH2:16][CH2:17][CH2:18][NH:19][CH:20]([CH3:22])[CH3:21])[CH2:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=O)[CH:2]=[CH2:3].Cl.[CH2:24]([O:26][NH2:27])[CH3:25]>>[CH2:24]([O:26][N:27]=[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:5][CH:4]([CH2:1][CH:2]=[CH2:3])[CH2:14][O:15][CH2:16][CH2:17][CH2:18][NH:19][CH:20]([CH3:22])[CH3:21])[CH3:25]
Reactant: CCON
Reactant: C=CCC(COCCCNC(C)C)CC(=O)c1ccccc1
Agent: Cl
Product: C=CCC(COCCCNC(C)C)CC(=NOCC)c1ccccc1

Procedure:
The procedure described in Example 88 was repeated using 3-allyl-4-(3-[N-isopropylamino]propoxy)butyrophenone and ethoxyamine hydrochloride to give 3-allyl-4-(3-[N-isopropylamino)propoxy)-butyrophenone O-ethyloxime as a solid, m.p. 124°-126° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13](=[O:14])[N:12]3[C:15]([CH3:18])=[CH:16][S:17][C:11]3=[N:10][C:9]=2[C@@H:19]([NH:21]C(=O)OC(C)(C)C)[CH3:20])[CH:5]=[CH:6][CH:7]=1.O1CCOCC1.O.[OH-].[Na+]>Cl>[NH2:21][C@H:19]([C:9]1[N:10]=[C:11]2[S:17][CH:16]=[C:15]([CH3:18])[N:12]2[C:13](=[O:14])[C:8]=1[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1)[CH3:20]
Reactant: Cc1csc2nc([C@H](C)NC(=O)OC(C)(C)C)c(-c3cccc(F)c3)c(=O)n12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1csc2nc([C@H](C)N)c(-c3cccc(F)c3)c(=O)n12
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 105.6 %

Procedure:
(S)-tert-Butyl 1-(6-(3-fluorophenyl)-3-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidin-7-yl)ethylcarbamate (4.15 g, 10.3 mmol) was dissolved in a 4.0 M solution of hydrogen chloride in 1,4-dioxane (25.7 mL, 102.8 mmol) and the solution was stirred at room temperature for 45 min. HPLC indicated that the reaction was complete. To the solution was added water (10 mL) followed by 3 N aqueous sodium hydroxide solution at 0-5° C. to adjust the pH to 10. The aqueous mixture was extracted with ethyl acetate (2×30 mL). The ethyl acetate solution was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give (S)-7-(1-Aminoethyl)-6-(3-fluorophenyl)-3-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one (3.30 g, 10.88 mmol, 103% yield). LCMS calculated for C15H15FN3OS (M+H)+: m/z 304.08. Found 303.9. 1H NMR (400 MHz, DMSO-d6) δ 7.45 (ddd, J=8.1, 7.9, 5.9 Hz, 1H), 7.19 (m, 1H), 7.12 (m, 2H) 7.04 (q, J=1.1 Hz, 1H), 3.57 (q, J=6.6 Hz, 1H), 2.64 (d, J=1.3 Hz, 3H), 1.10 (d, J=6.7 Hz, 3H)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1Br.[NH2:10][C:11]1[CH:12]=[C:13]2[C:18]3=[C:19]([CH2:21][CH2:22][CH2:23][N:17]3[CH2:16][C@@H:15]3[CH2:24][N:25](C(OC(C)(C)C)=O)[CH2:26][C@@H:14]23)[CH:20]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:10][C:11]1[CH:12]=[C:13]2[C:18]3=[C:19]([CH2:21][CH2:22][CH2:23][N:17]3[CH2:16][C@@H:15]3[CH2:24][NH:25][CH2:26][C@@H:14]23)[CH:20]=1
Reactant: Clc1ccc(Br)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N1C[C@H]2CN3CCCc4cc(N)cc(c43)[C@@H]2C1
Product: Clc1ccc(Nc2cc3c4c(c2)[C@@H]2CNC[C@H]2CN4CCC3)c(Cl)c1

Procedure:
Using 2,4-dichlorobromobenzene and following the procedures described in EXAMPLE 72, (±)-trans tert-butyl 2-amino-5,6,8a,9,11,11a-hexahydro-4H-pyrido[3,2,1-ij]pyrrolo[3,4-c]quinoline-10(8H)-carboxylate was converted into the title compound of EXAMPLE 75 as an off-white powder. 1H NMR (300 MHz, CDCl3) δ 1.25 (br s, 1H), 1.70-1.90 (br s, 1H), 1.90-2.20 (m, 2H), 2.70-2.80 (m, 4H), 2.91 (t, 1H, J=9.3 Hz), 3.30-3.60 (m, 5H), 3.54 (m, 1H), 5.78 (br s, 1H), 6.51 (s, 1H), 6.68 (s, 1H), 6.79 (d, 1H, J=8.0 Hz), 7.00 (d, 1H, J=8.0 Hz), 7.25 (s, 1H). LRMS (ES)+: 374 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]([CH2:12][CH:13]=C)[CH2:3][O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.I([O-])(=O)(=O)=[O:16].[K+]>CC(C)=O.O.[Os](=O)(=O)(=O)=O>[CH2:5]([O:4][CH2:3][C@H:2]([CH3:1])[CH2:12][CH:13]=[O:16])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: C=CCC(C)COCc1ccccc1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: C[C@H](CC=O)COCc1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 80.7 %

Procedure:
A 250 mL round-bottomed flask, equipped with a magnetic stirring bar and a thermometer was fitted with a septum and a nitrogen inlet. The apparatus was charged with benzyl 2-methyl-4-penten-1-yl ether (2.39 g, 12.5 mmol) in 75 mL of acetone and 25 mL of water. Osmium tetroxide (0.833 mL of an 0.15 M aqueous solution, 0.125 mmol) was added in one portion, followed by potassium periodate (6.04 g, 26.2 mmol) in three equal portions. The resulting slurry was stirred for 6 hours at room temperature and decanted into a 500 mL separatory funnel. The aqueous layer was extracted with 3×200 mL of diethyl ether. Each washing was stirred over the solids for 5 minutes, washed with 150 mL of saturated aqueous sodium thiosulfate and 100 mL of saturated aqueous sodium chloride. The combined organic layers were dried over sodium sulfate, filtered, concentrated and chromatographed (4×20 cm column; 4:1 hexane:ethyl acetate) to afford 1.94 g (81%) of aldehyde 4 as a colorless oil. Rf =0.37 (4:1 hexane:ethyl acetate).
Reaction SMILES: [O:1]=[C:2]1[N:13]2[C:14]3[C:10]([CH:11]=[CH:12]2)=[C:9]([CH2:15]OC(=O)C)[CH:8]=[CH:7][C:6]=3[CH2:5][NH:4][CH2:3]1.CC(O)=O>CO.[Pd]>[CH3:15][C:9]1[CH:8]=[CH:7][C:6]2[CH2:5][NH:4][CH2:3][C:2](=[O:1])[N:13]3[C:14]=2[C:10]=1[CH:11]=[CH:12]3
Reactant: CC(=O)OCc1ccc2c3c1ccn3C(=O)CNC2
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1ccc2c3c1ccn3C(=O)CNC2
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 75 %

Procedure:
Acetic acid-1-oxo-1,2,3,4-tetrahydro-[1,4]diazepino[6,7,1-hi]indole-7-ylmethyl ester (0.508 g, 1.97 mmol) was dissolved in MeOH (70 mL) and glacial AcOH (30 mL). To the solution was added 10% Pd/C (0.076 g) and the suspension was stirred under an atmosphere of H2 for 4.5 h at rt. The black suspension was filtered and the filtrate was concentrated to give a white solid, which was purified by flash silica gel chromatography eluting with a gradient of 0-1% MeOH in CHCl3 to give 0.296 g (75%) of the title compound: 1H NMR (DMSO-d6) δ 2.52 (s, 3H), 3.51-3.54 (m, 2H), 4.27-4.28 (m, 2H), 7.11 (t, 1H, J=7.5 Hz), 7.15 (s, 1H), 7.69 (d, 1H, J=7.5 Hz), 7.81 (d, 1H, J=7.5 Hz), 8.22-8.24 (m, 1H). HRMS calcd. for C12H12N2O (M+) 200.0950, found 200.0955. Anal. (C12H12N2O) C, H, N.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]2[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=2)=[CH:4][CH:3]=1.[CH2:31]([O:33][CH2:34][CH2:35]O)[CH3:32].B(F)(F)F.CCOCC>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]2[CH:23]=[CH:24][C:25]([C:26]([O:28][CH2:32][CH2:31][O:33][CH2:34][CH3:35])=[O:27])=[CH:29][CH:30]=2)=[CH:4][CH:3]=1
Reactant: CCOCCO
Reactant: O=C(O)c1ccc(NCCCCCCCCCCCC#Cc2ccc(Cl)cc2)cc1
Agent: FB(F)F
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCOCCOC(=O)c1ccc(NCCCCCCCCCCCC#Cc2ccc(Cl)cc2)cc1
Reaction time: 120 h

Procedure:
A solution of 11.8 g. of 4-[13-(4-chlorophenyl)tridec-12-ynylamino]benzoic acid, 1.00 g. of 2-ethoxyethanol and 5.35 ml. of boron trifluoride etherate in 200 ml. toluene is stirred under reflux for 48 hours. The solution is treated with an additional 5.35 ml. of boron trifluoride etherate and refluxing is continued for 120 hours. Dilution with water and methylene chloride followed by filtration affords 2-ethoxyethyl 4-[13-(4-chlorophenyl)tridec-12-ynylamino]benzoate as a white solid.
Reaction SMILES: [NH2:1][C@H:2]([C:13]1[N:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:17](=[O:25])[C:16]2=[CH:26][CH:27]=[CH:28][N:15]2[N:14]=1)[CH2:3][CH2:4][S:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[NH2:29][C:30]1[C:35]([C:36]#[N:37])=[C:34](Cl)[N:33]=[CH:32][N:31]=1.C(N(CC)C(C)C)(C)C>>[NH2:29][C:30]1[C:35]([C:36]#[N:37])=[C:34]([NH:1][C@H:2]([C:13]2[N:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:17](=[O:25])[C:16]3=[CH:26][CH:27]=[CH:28][N:15]3[N:14]=2)[CH2:3][CH2:4][S:5][CH2:6][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:33]=[CH:32][N:31]=1
Reactant: N#Cc1c(N)ncnc1Cl
Reactant: N[C@@H](CCSCc1ccccc1)c1nn2cccc2c(=O)n1-c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1c(N)ncnc1N[C@@H](CCSCc1ccccc1)c1nn2cccc2c(=O)n1-c1ccccc1
Yield: 78.6 %

Procedure:
(S)-2-(1-Amino-3-(benzylthio)propyl)-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (10 mg, 0.02 mmol) was treated with 4-amino-6-chloropyrimidine-5-carbonitrile (4 mg, 0.03 mmol) and N,N-diisopropylethylamine (24 μl, 0.14 mmol) according to the method described in Example 17. The residue was purified using SP1® Purification System (0% to 100% hexane-ethyl acetate) to obtain 8 mg (66% yield) of the title compound as a yellow solid. Purity 90%.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:4]([NH:6][C@H:7]([C:17]([NH:19][C@H:20]([C:29]([NH:31][C@H:32]([C:42]([NH:44][C@H:45]([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[CH2:46][O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:43])[CH2:33][CH2:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:30])[CH2:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:18])[CH2:8][CH2:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:5])[CH3:3].[H][H]>[Pd].CO>[NH2:1][C@H:2]([C:4]([NH:6][C@H:7]([C:17]([NH:19][C@H:20]([C:29]([NH:31][C@H:32]([C:42]([NH:44][C@H:45]([C:52]([O:54][C:55]([CH3:56])([CH3:58])[CH3:57])=[O:53])[CH2:46][O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:43])[CH2:33][CH2:34][C:35](=[O:41])[O:36][C:37]([CH3:38])([CH3:39])[CH3:40])=[O:30])[CH2:21][C:22](=[O:28])[O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:18])[CH2:8][CH2:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:5])[CH3:3]
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)N[C@@H](CC(=O)OC(C)(C)C)C(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)N[C@@H](COC(C)(C)C)C(=O)OC(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: C[C@H](N)C(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)N[C@@H](CC(=O)OC(C)(C)C)C(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)N[C@@H](COC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 97.6 %

Procedure:
6.61 g. (6.85 mmoles) of Z-27-31-OtBu are dissolved in 150 ml. of methanol with gentle heating. The solution is cooled to room temperature; 1 g. of palladium-on-carbon is added to it, and gaseous hydrogen is bubbled into the mixture for 0.5 hours. The catalyst is removed by filtration, the filtrate is evaporated to dryness, the solid residue is triturated with n-hexane; and the mixture is filtered. 5.55 g. (97.6 %) of H-27-31-OtBu are obtained. M.p.: 138°-142° C, Rf2 = 0.15.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[C:4]#[N:5].[CH3:11][C:12]([CH3:15])([O-:14])[CH3:13].[K+].O>COCCOC>[CH3:11][C:12]([O:14][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[C:4]#[N:5])([CH3:15])[CH3:13]
Reactant: N#Cc1c(F)cccc1Cl
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)Oc1cccc(Cl)c1C#N
Temperature: 25 °C
Yield: 97 %

Procedure:
To a solution of 2-fluoro-6-chlorobenzonitrile (10.35 g, 66.5 mmol) in 1,2-dimethoxyethane (50 mL) at 0° C. was added potassium t-butoxide (9.06 g, 80.7 mmol). The mixture was slowly allowed to warm to room temperature over 3 h. The reaction was poured into water and extracted with ether (3 times). The organic layers were washed with brine, dried (MgSO4) and concentrated to afford 13.52 g (97%) of 2-[(1,1-dimethylethyl)oxy]-6-chlorobenzonitrile as a pale yellow oil.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C([O-])([O-])=O.[K+].[K+].[CH:12]12[O:18][CH:13]1[CH2:14][CH2:15][CH2:16][CH2:17]2>O>[N:1]1([C@@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]2[OH:18])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: C1CCC2OC2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O[C@@H]1CCCC[C@H]1n1ccnc1
Temperature: 100 °C
Reaction time: 7 h
Yield: 26 %

Procedure:
A mixture of 20.18 g of imidazole, 81.95 g of K2CO3, and 20.0 mL of cyclohexene oxide in ca. 200 mL of H2O was stirred at room temperature for 19 h, at 100° C. (bath temp.) for 7 h, and then at room temperature overnight. The mixture was extracted with 3×500 mL of EtOAc and 500 mL of CH2Cl2. The organic layers were washed with 2×300 mL of H2O and 300 mL of brine. Combined organic layers were dried over MgSO4 and concentrated. The crude product was crystallized from EtOAc to yield 8.57 g (26%) of the crystalline solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13](=[O:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:7]=[CH:6]2.[H][H]>[Pt]=O.C(O)(C)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH:13]([OH:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:7]=[CH:6]2
Reactant: [H][H]
Reactant: CCOC(=O)C(=O)c1ccc2cc(OC)ccc2c1
Agent: O=[Pt]
Solvent: CC(C)O
Product: CCOC(=O)C(O)c1ccc2cc(OC)ccc2c1

Procedure:
Into a Paar hydrogenation bottle is added 0.144 mole of ethyl 6-methoxy-2-naphthylglyoxylate, 2 ml. of 0.1 M - ferrous sulfate solution; 220 ml. of isopropanol, and 1.0 g. of 84.1% platinum oxide. The mixture is shaken for 2 hours at room temperature with hydrogen gas until 0.144 mole of hydrogen is absorbed. The catalyst is then filtered off and the solution is evaporated in vacuo and the residue fractionally distilled to obtain ethyl 6-methoxy-2-naphthylglycolate.