Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH:13]1([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:15][CH2:14]1.Cl[Si:23]([CH3:26])([CH3:25])[CH3:24]>O1CCCC1>[CH:13]1(/[CH:16]=[C:17](\[O:19][CH2:20][CH3:21])/[O:18][Si:23]([CH3:26])([CH3:25])[CH3:24])[CH2:15][CH2:14]1
Reactant: CCOC(=O)CC1CC1
Reactant: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCO/C(=C\C1CC1)O[Si](C)(C)C
Temperature: -75 °C
Reaction time: 0.5 h

Procedure:
A solution of n-butyllithium in hexanes (1.6M, 26 ml) was added with stirring to a solution of diisopropylamine (6.2 ml) in tetrahydrofuran (8 ml) at below -25° C. under nitrogen. After 30 min, the mixture was cooled to -75° C. and ethyl cyclopropylacetate (4.5 g) added dropwise keeping the temperature below -65° C. The mixture was then maintained below -75° C. for 3 h before chlorotrimethylsilane (3.8 ml) was added below 65° C. The reaction was allowed to warm to ambient temperature and then evaporated to dryness. The residue was slurried with hexane and filtered. The filtrate was evaporated to an orange oil which was distilled in vacuo to give the title compound (4.0 g) as a clear mobile liquid, b.p 80-82° C., 3×10-2 bar.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:13]3[C:14]([CH2:17]Cl)=[N:15][N:16]=[C:12]3[CH2:11][N:10]=[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])[C:8]=2[CH:26]=1)([O-:3])=[O:2].[I-].[K+].[CH3:29][CH:30]=[CH:31][CH2:32][NH2:33]>O1CCCC1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:13]3[C:14]([CH2:17][NH:33][CH2:32][CH2:31][CH:30]=[CH2:29])=[N:15][N:16]=[C:12]3[CH2:11][N:10]=[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])[C:8]=2[CH:26]=1)([O-:3])=[O:2]
Reactant: CC=CCN
Reactant: O=[N+]([O-])c1ccc2c(c1)C(c1ccccc1Cl)=NCc1nnc(CCl)n1-2
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=CCCNCc1nnc2n1-c1ccc([N+](=O)[O-])cc1C(c1ccccc1Cl)=NC2

Procedure:
In the manner given in Preparation 39, 8-nitro-1-(chloromethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a]-[1,4]benzodiazepine, potassium iodide, and methylallylamine in tetrahydrofuran are reacted to give 8-nitro-1-[(allylmethylamino)methyl]-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine. Preparation 42 8-Bromo-1-[(allylethylamino)methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:15])[N:9]2[CH2:12][CH:13]=O)=[CH:4][CH:3]=1.[NH:16]1[CH2:21][CH2:20][CH:19]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:18][CH2:17]1.C(Cl)(Cl)Cl.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CO>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:15])[N:9]2[CH2:12][CH2:13][N:16]2[CH2:17][CH2:18][CH:19]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:27])([CH3:26])[CH3:28])[CH2:20][CH2:21]2)=[CH:4][CH:3]=1
Reactant: O=CCn1c(=O)ccc2ccc(F)cc21
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)NC1CCN(CCn2c(=O)ccc3ccc(F)cc32)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 117.3 %

Procedure:
A mixture of (7-fluoro-2-oxo-1(2H)-quinolinyl)acetaldehyde (594 mg; 2.89 mmol) and 1,1-dimethylethyl 4-piperidinylcarbamate (578 mg; 2.89 mmol) in a 1:1 mixture of chloroform and methanol (20 ml:20 ml) was stirred at rt under argon for 1 h. The mixture was then treated with NaBH(OAc)3 (1.83 g; 8.67 mmol) and stirred at rt for a 1 h. More 1,1-dimethylethyl 4-piperidinylcarbamate (297 mg; 1.45 mmol) was added and the reaction was stirred under the same conditions for a further 0.5 h. This was then again treated with NaBH(OAc)3 (915 mg; 4.34 mmol) and stirred at rt for a further 0.75 h. More 1,1-dimethylethyl 4-piperidinylcarbamate (118 mg; 0.578 mmol) was then added, the reaction was stirred at rt for a further 10 mins, followed by addition of NaBH(OAc)3 (366 mg; 1.73 mmol), the reaction was stirred for a further 25 mins. The solvents were removed and the crude residue purified by chromatography on silica gel using a 010% MeOH/DCM gradient to provide the impure desired compound (1.32 g, 117%)
Reaction SMILES: Br[C:2]1[N:7]2[N:8]=[C:9]([NH2:11])[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[CH3:12][S:13]([NH:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1)(=[O:15])=[O:14]>>[NH2:11][C:9]1[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([C:20]3[CH:19]=[CH:18][C:17]([NH:16][S:13]([CH3:12])(=[O:14])=[O:15])=[CH:22][CH:21]=3)[N:7]2[N:8]=1
Reactant: Nc1nc2cccc(Br)n2n1
Reactant: CS(=O)(=O)Nc1ccc(B(O)O)cc1
Product: CS(=O)(=O)Nc1ccc(-c2cccc3nc(N)nn23)cc1
Yield: 15.2 %

Procedure:
N-[4-(2-Amino-[1,2,4]triazolo[1,5-a]pyridin-5-yl)-phenyl]-methanesulfonamide was prepared from 5-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (1.80 g, 8.45 mmol) and 4-methylsulfonylaminophenyl boronic acid (2.0 g, 9.30 mmol), in a manner analogous to Step 73c. The residue was purified on a 40 g Isco silica gel column using a gradient of 0-15% methanol in dichloromethane as an eluent. N-[4-(2-Amino-[1,2,4]triazolo[1,5-a]pyridin-5-yl)-phenyl]-methanesulfonamide (389 mg, 15%) was isolated as a beige powder. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 10.06 (s, 1H), 7.96 (d, J=10.7 Hz, 2H), 7.49 (t, J=17.1 Hz, 7.5 Hz, 1H), 7.34 (d, J=8.6 Hz, 3H), 7.00 (d, J=7.5 Hz, 1H), 6.01 (s, 2H), 3.09 (s, 3H). MS=304 (MH)+. 84b) N-[4-(2-Amino-[1,2,4]triazolo[1,5-a]pyridin-5-yl)-phenyl]-methanesulfonamide (162 mg, 0.534 mmol) and 1-(4-bromo-phenyl)-4-methyl-piperazine (150 mg, 0.587 mmol) were combined in a manner analogous to Example 77 to yield N-(3-{2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-[1,2,4]triazolo[1,5-a]pyridin-5-yl}-phenyl)-methanesulfonamide TFA salt (14 mg, 6%) as a yellow powder following purification via preparative HPLC on a Phenomenex Luna column using 0.1% TFA in MeCN and 0.1% TFA in Water as eluent. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 10.13 (s, 1H), 9.40 (s, 1H), 8.05 (d, J=7.5 Hz, 1H), 7.58 (m, 3H), 7.39 (d, J=7.5 Hz, 2H), 7.27 (d, J=8.6 Hz, 2H), 6.95 (d, J=9.6 Hz, 2H), 4.16 (m, 2H), 3.68 (m, 2H), 3.20 (m, 3H), 3.12 (s, 3H), 2.86 (m, 5H). MS=478 (MH)+.
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:7]([F:10])([F:9])[F:8])=[N:5][N:6]=1.NC(N)=[S:13].[OH-].[K+].Cl>C(O)C.O>[SH:13][C:2]1[S:3][C:4]([C:7]([F:10])([F:9])[F:8])=[N:5][N:6]=1
Reactant: FC(F)(F)c1nnc(Br)s1
Reactant: NC(N)=S
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: FC(F)(F)c1nnc(S)s1
Yield: 59.1 %

Procedure:
699 g (3 moles) of 2-bromo-5-trifluoromethyl-1,3,4-thiadiazole and 248 g (3.3 moles) of thiourea in a mixture of 600 ml of ethanol and 75 ml of water were heated for 2 hours under reflux. A solution of 223 g of potassium hydroxide in 2 liters of water was rapidly added dropwise to the reaction solution while it was still hot, and the mixture was once more heated under reflux, for 5 minutes. The cooled solution was adjusted to pH 5 with dilute hydrochloric acid and extracted repeatedly with methylene chloride. After drying and concentrating, the residue was recrystallized from a litte petroleum ether. The mother liquor yielded further product. 330 g (59% of theory) of 2-mercapto-5-trifluoromethyl-1,3,4-thiadiazole of melting point 73° C were obtained. ##STR85##
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[O:8][CH2:7][CH2:6][C:5]2=[O:13].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[O:8][CH2:7][CH2:6][C:5]2=[O:13]
Reactant: O=C1CCOc2cc(O)c(F)cc21
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C1CCOc2cc(OCc3ccccc3)c(F)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 73 %

Procedure:
A mixture of 6-fluoro-7-hydroxychroman-4-one (the compound of Preparation 29, 0.93 g, 5.11 mmol), benzyl bromide (0.61 mL, 5.13 mmol), potassium carbonate (1.41 g, 10.2 mmol) in acetone (100 mL) was stirred at ambient temperature overnight. The mixture was cooled, filtered, and concentrated to a yellow solid. This residue was recrystallized from ethyl acetate/ether to give 1.02 g (73%) of 6-fluoro-7-benzyloxychroman-4-one in two crops as cream white crystals which had: mp 155-156° C.; NMR δ 7.58 (d, J=11 Hz, 1 H), 7.46-7.33 (m, 5 H), 6.54 (d, J=6.7 Hz, 1 H), 5.16 (d, 2 H), 4.50 (t, J=6.4 Hz, 2 H), 2.75 (t, J=6.4 Hz, 2 H). Analysis calculated for C16H13FO2 : C, 70.58; H, 4.81. Found: C, 70.45; H, 4.80.
Reaction SMILES: [CH2:1]([S-:3])[CH3:2].[Na+].[Br:5][C:6]1[CH:11]=[CH:10][C:9](F)=[C:8]([Cl:13])[CH:7]=1.O>CN(C)C=O>[Br:5][C:6]1[CH:11]=[CH:10][C:9]([S:3][CH2:1][CH3:2])=[C:8]([Cl:13])[CH:7]=1
Reactant: Fc1ccc(Br)cc1Cl
Reactant: CC[S-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCSc1ccc(Br)cc1Cl
Temperature: 65 °C
Reaction time: 2 h
Yield: 80.2 %

Procedure:
Sodium ethanethiolate (2.0 g) was added to a solution of 4-bromo-2-chloro-1-fluorobenzene (5.0 g) in N,N-dimethylformamide (20 mL), and the mixture was stirred at 65° C. for two hours. The reaction solution was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and filtered. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=90:1→0:100) to give the title compound as a colorless oil (4.8 g).
Reaction SMILES: [NH2:1][C@@H:2]([C@H:10]([C@@H:12]1[C@@H:16]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[C@@H:15]([O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])[C@H:14]([N:33]2[CH:38]=[CH:37][C:36](=[O:39])[N:35]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=3)[C:34]2=[O:49])[O:13]1)[OH:11])[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[CH:50]1[C:62]2[CH:61]([CH2:63][O:64][C:65](=[O:84])[NH:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][C:77](=[O:83])[NH:78][CH2:79][CH2:80][CH:81]=O)[C:60]3[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=3)[C:54]=2[CH:53]=[CH:52][CH:51]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C.O1CCCC1>[Si:18]([O:17][C@H:16]1[C@@H:15]([O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:27])[CH3:28])[C@H:14]([N:33]2[CH:38]=[CH:37][C:36](=[O:39])[N:35]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=3)[C:34]2=[O:49])[O:13][CH:12]1[C@H:10]([OH:11])[C@@H:2]([C:3]([O:5][C:6]([CH3:7])([CH3:9])[CH3:8])=[O:4])[NH:1][CH2:81][CH2:80][CH2:79][NH:78][C:77](=[O:83])[CH2:76][CH2:75][CH2:74][CH2:73][CH2:72][CH2:71][CH2:70][CH2:69][CH2:68][CH2:67][NH:66][C:65](=[O:84])[O:64][CH2:63][CH:61]1[C:60]2[CH:59]=[CH:58][CH:57]=[CH:56][C:55]=2[C:54]2[C:62]1=[CH:50][CH:51]=[CH:52][CH:53]=2)([C:21]([CH3:22])([CH3:23])[CH3:24])([CH3:20])[CH3:19]
Reactant: COc1ccc(Cn2c(=O)ccn([C@@H]3O[C@H]([C@H](O)[C@H](N)C(=O)OC(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]3O[Si](C)(C)C(C)(C)C)c2=O)cc1
Reactant: O=CCCNC(=O)CCCCCCCCCCNC(=O)OCC1c2ccccc2-c2ccccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COc1ccc(Cn2c(=O)ccn([C@@H]3OC([C@H](O)[C@H](NCCCNC(=O)CCCCCCCCCCNC(=O)OCC4c5ccccc5-c5ccccc54)C(=O)OC(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]3O[Si](C)(C)C(C)(C)C)c2=O)cc1
Yield: 64.9 %

Procedure:
By using an analogous procedure to that described for Example 1, a solution of tert-butyl (2S,3R)-2-amino-3-[(2R,3R,4R,5R)-3,4-bis{[tert-butyl-(dimethyl)silyl]oxy}-5-(3-(4-methoxybenzyl)-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl)-tetrahydro-2-furanyl]-3-hydroxypropanoate (125 mg, 0.173 mmol, obtained from Reference Example 6), 9H-fluoren-9-ylmethyl-11-oxo-11-[(3-oxopropyl)amino]undecyl-carbamate (99 mg, 0.208 mmol, obtained from Reference Example 30), acetic acid (2 drops) and sodium triacetoxyborohydride (73 mg, 0.346 mmol) in anhydrous tetrahydrofuran (4 ml) was stirred at room temperature under nitrogen for 5.5 hours. The product was purified by chromatography (flash column, silica gel, ethyl acetate) to provide tert-butyl (21S)-21-[(R)-[(3R,4R,5R)-3,4-bis{[tert-butyl(dimethyl)silyl]oxy}-5-(3-(4-methoxybenzyl)-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl)tetrahydro-2-furanyl](hydroxy)methyl]-1-(9H-fluoren-9-yl)-3,15-dioxo-2-oxa-4,16,20-triazadocosan-22-oate (133 mg, 65%) as a white solid.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[CH:4]=[O:5].[CH:14]1([CH2:17][NH:18][CH2:19][CH2:20][CH3:21])[CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+].O>C1(C)C=CC=CC=1>[CH:14]1([CH2:17][N:18]([CH2:19][CH2:20][CH3:21])[C:2]2[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=2[CH:4]=[O:5])[CH2:16][CH2:15]1
Reactant: CCCNCC1CC1
Reactant: O=Cc1cc(C(F)(F)F)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCCN(CC1CC1)c1ccc(C(F)(F)F)cc1C=O
Temperature: 120 °C
Reaction time: 4 h
Yield: 100.1 %

Procedure:
2-Fluoro-5-trifluoromethyl-benzaldehyde (5.38 g) and cyclopropylmethyl-propyl-amine (4.75 g) are dissolved in toluene (50 ml), and thereto is added potassium carbonate (11.6 g) and the mixture is stirred at 120° C. for 4 hours. The reaction solution is cooled to room temperature, and thereto is added water and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=19:1→4:1) to give 2-(cyclopropylmethyl-propyl-amino)-5-trifluoromethyl-benzaldehyde (8.0 g). MS (m/z): 286 [M+H]+
Reaction SMILES: [CH:1]([Si:4]([C:11]#[CH:12])([CH:8]([CH3:10])[CH3:9])[CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].Br[C:14]1[CH:15]=[C:16]([CH:19]=[O:20])[O:17][CH:18]=1.C(OCCCC)(C)=O>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C(OCC)(=O)C>[CH:8]([Si:4]([C:11]#[C:12][C:14]1[CH:15]=[C:16]([CH:19]=[O:20])[O:17][CH:18]=1)([CH:5]([CH3:6])[CH3:7])[CH:1]([CH3:3])[CH3:2])([CH3:10])[CH3:9]
Reactant: C#C[Si](C(C)C)(C(C)C)C(C)C
Reactant: O=Cc1cc(Br)co1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCCCOC(C)=O
Solvent: CCOC(C)=O
Product: CC(C)[Si](C#Cc1coc(C=O)c1)(C(C)C)C(C)C
Reaction time: 2 h
Yield: 72 %

Procedure:
Triisopropylsilylacetylene (9.0 mL) was added dropwise to a mixture of 4-bromofuran-2-carbaldehyde (2.0 g), PdCl2(PPh3)2 (0.40 g), CuI (0.22 g), TEA (7.9 mL) and AcOBu (20 mL) at 110 to 120° C. over the course of 6 hours in a nitrogen atmosphere, and then the mixture was stirred for 2 hours. After the reaction mixture was allowed to cool, ethyl acetate (50 mL), OH type silica gel (1.0 g), cellpure (1.2 g) and activated carbon (20 mg) were added. The insolubles were filtered out, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by OH type silica gel column chromatography (gradient elution with hexane/ethyl acetate=100/0→65/35) to obtain 4-[(triisopropylsilanyl)ethynyl]furan-2-carbaldehyde (black oil) (2.3 g, 72%).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]([NH2:9])=[O:8])[N:6]=1.[C:10]([C:14]1[CH:15]=[C:16]2[C:21](=[C:22]([F:24])[CH:23]=1)[C:20](=[O:25])[N:19]([C:26]1[CH:36]=[CH:35][CH:34]=[C:33](B3OC(C)(C)C(C)(C)O3)[C:27]=1[CH2:28][O:29]C(=O)C)[N:18]=[CH:17]2)([CH3:13])([CH3:12])[CH3:11]>>[C:10]([C:14]1[CH:15]=[C:16]2[C:21](=[C:22]([F:24])[CH:23]=1)[C:20](=[O:25])[N:19]([C:26]1[C:27]([CH2:28][OH:29])=[C:33]([C:2]3[S:3][CH:4]=[C:5]([C:7]([NH2:9])=[O:8])[N:6]=3)[CH:34]=[CH:35][CH:36]=1)[N:18]=[CH:17]2)([CH3:13])([CH3:11])[CH3:12]
Reactant: NC(=O)c1csc(Br)n1
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Product: CC(C)(C)c1cc(F)c2c(=O)n(-c3cccc(-c4nc(C(N)=O)cs4)c3CO)ncc2c1
Yield: 10 %

Procedure:
This compound was prepared with the same method as described in Example 1 by using 2-bromothiazole-4-carboxylic acid amide (intermediate-2) and acetic acid 2-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl ester (intermediate 5). The desired compound was prepared in two steps (10% yield). 1H NMR (300 MHz, DMSO-d6) δ 8.59 (d, J=2.4 Hz, 1H), 8.46 (s, 1H), 7.94 (d, J=1.8 Hz, 1H), 7.88-7.79 (m, 2H), 7.66-7.63 (m, 2H), 4.61-4.52 (m, 2H), 1.46 (s, 9H). LC-MS calcd for C23H21FN4O3S 452.13, obsd 453 [M+1]+.
Reaction SMILES: [C:1]([C:3]1([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:5][CH2:4]1)#[N:2].[H][H]>C(O)C.[Ni]>[NH2:2][CH2:1][C:3]1([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:5][CH2:4]1
Reactant: [H][H]
Reactant: CCOC(=O)C1(C#N)CC1
Agent: [Ni]
Solvent: CCO
Product: CCOC(=O)C1(CN)CC1
Temperature: 40 °C
Reaction time: 12 h
Yield: 93 %

Procedure:
To a solution in ethanol (127 mL) of the compound (14.0 g) obtained in step (1) above, a Raney nickel catalyst (about 2.8 g) was added. In a hydrogen atmosphere, the mixture was stirred at room temperature for 12 hours and further stirred at 40° C. for 12 hours. After being cooled to room temperature, the reaction mixture was filtered through Celite (registered trademark) and the filtrate was concentrated under reduced pressure. The resulting precipitate was recovered by filtration and washed with ethanol. The filtrate was concentrated to give the titled compound as a red oil (13.4 g).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]([CH:12]=[CH:13][CH:14]=2)[NH2:11])[CH2:4][CH2:3]1.Cl[C:16]1[N:34]=[C:19]2[C:20]([NH:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH3:33])[CH:27]=3)=[CH:21][CH:22]=[CH:23][N:18]2[N:17]=1>>[CH3:33][O:32][C:28]1[CH:27]=[C:26]([CH:31]=[CH:30][CH:29]=1)[CH2:25][NH:24][C:20]1[C:19]2[N:18]([N:17]=[C:16]([NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[C:8]([N:5]4[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]4)[CH:9]=3)[N:34]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: COc1cccc(CNc2cccn3nc(Cl)nc23)c1
Reactant: CN1CCN(c2cccc(N)c2)CC1
Product: COc1cccc(CNc2cccn3nc(Nc4cccc(N5CCN(C)CC5)c4)nc23)c1

Procedure:
N(8)-(3-Methoxy-benzyl)-N(2)-[3-(4-methyl-piperazin-1-yl)-phenyl]-[1,2,4]triazolo[1,5-a]pyridine-2,8-diamine was prepared from 3-(4-methylpiperazin-1-yl)aniline (74.2 mg, 0.388 mmol) and (2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-(3-methoxy-benzyl)-amine (99.9 mg, 0.346 mmol) in a manner analogous to Example 2d. Product isolated as a red foam (11.16 mg, 7%). 1H NMR (400 MHz, CD3OD, δ, ppm): 7.85 (d, J=7.0 Hz, 1H), 7.32 (s, 1H), 7.24 (t, J=15.5, 7.8 Hz, 1H), 7.19-7.09 (m, 2H), 6.99 (s, 2H), 6.82 (d, J=8.0 Hz, 1H), 6.75 (t, J=14.2, 7.0 Hz, 1H), 6.57 (d, J=7.8 Hz, 1H), 6.41 (d, J=7.5 Hz, 1H), 4.48 (m, 2H), 3.77 (s, 3H), 3.24 (s, 4H), 2.65 (s, 4H), 2.37 (s, 3H). MS=444 (MH)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C:11]3[C:20]4[C:15](=[CH:16][C:17]([O:23][CH2:24][C@@H:25]5[CH2:27][O:26]5)=[C:18]([O:21][CH3:22])[CH:19]=4)[N:14]=[CH:13][N:12]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH3:28][NH:29][CH3:30]>C1COCC1.CN(C=O)C>[OH:26][C@@H:25]([CH2:27][N:29]([CH3:30])[CH3:28])[CH2:24][O:23][C:17]1[CH:16]=[C:15]2[C:20]([C:11]([O:10][C:6]3[CH:5]=[C:4]4[C:9](=[CH:8][CH:7]=3)[NH:1][CH:2]=[CH:3]4)=[N:12][CH:13]=[N:14]2)=[CH:19][C:18]=1[O:21][CH3:22]
Reactant: COc1cc2c(Oc3ccc4[nH]ccc4c3)ncnc2cc1OC[C@@H]1CO1
Reactant: CNC
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]ccc4c3)ncnc2cc1OC[C@@H](O)CN(C)C
Temperature: 75 °C
Reaction time: 3 h
Yield: 85 %

Procedure:
A mixture of (2S)-4-(indol-5-yloxy)-6-methoxy-7-(oxiran-2-ylmethoxy)quinazoline (100 mg, 0.28 mmol), (prepared as described for the starting material in Example 297), and dimethylamine (0.42 ml of a 2M solution in THF, 0.84 mmol) in DMF (5 ml) was stirred at 75° C. for 3 hours under an atmosphere of nitrogen and then allowed to cool to ambient temperature. The solvents were removed in vacuo and the residue purified by trituration with methanol to give (2S)-7-(2-hydroxy-3-dimethylaminopropoxy)-4-(indol-5-yloxy)-6-methoxyquinazoline (100 mg, 85%).
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[CH2:11](N(CC)CC)C>>[N:4]1[C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[C:1](=[O:10])[O:9][CH:11]=1
Reactant: CCN(CC)CC
Reactant: Nc1ccccc1C(=O)O
Product: O=c1ocnc2ccccc12

Procedure:
involves reacting anthranilic acid derivative of Formula (1) with appropriately substituted anhydrides (2), in this case trifluoroacetate anhydride, in the presence of tertiary bases like triethylamine at elevated temperatures preferably at the reflux for 1-6 hours, preferably 2 hours. The volatile components are removed under reduced pressure and the residue treated with an ethereal solvent like diethyl ether and water. The ethereal layer was separated, dried over MgSO4 and concentrated to give the appropriate benzo[d][1,3]oxazin-4-one derivative as the product.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[CH:5][CH:4]=1.Br[CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].C(N(CC)CC)C>C(#N)C>[C:13]([O:12][C:10](=[O:11])[CH2:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:2][NH:1][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:4][CH:5]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)Cc1ccc(CN)cc1
Reactant: CC(C)(C)OC(=O)CBr
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CNCc1ccc(CC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of tert-butyl [4-(aminomethyl)phenyl]acetate (1.00 g) in acetonitrile (15.0 mL) were added tert-butyl bromoacetate (0.668 mL) and triethylamine (0.693 mL), followed by stirring at room temperature for 4 hours. The reaction suspension was concentrated under reduced pressure, and then to the residue was added ethyl acetate. The organic layer was washed with 0.1 M hydrochloric acid, a saturated aqueous sodium hydrogen carbonate solution, and a saturated aqueous sodium chloride solution in this order, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain tert-butyl N-[4-(2-tert-butoxy-2-oxoethyl)benzyl]glycinate (747 mg).
Reaction SMILES: [NH:1]=[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[SH:4](=[O:17])([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[NH:3]1.[C:18](Cl)(=[O:21])[CH2:19][CH3:20].C(N(CC)CC)C>C(Cl)(Cl)Cl>[C:18]([N:1]=[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[SH:4](=[O:17])([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:3]1)(=[O:21])[CH2:19][CH3:20]
Reactant: CCC(=O)Cl
Reactant: N=C1N[SH](=O)(c2ccccc2)c2ccccc21
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCC(=O)N=C1N[SH](=O)(c2ccccc2)c2ccccc21

Procedure:
From 12 g. 3-imino-1-phenyl-3H-1,2-benzisothiazole-1-oxide, 5 g. propionyl chloride and 6.6 g. triethylamine in chloroform, there is obtained, after heating under reflux for 3 hours and then working up the reaction mixture in the usual manner, the desired 3-(propionyl-imino)-1-phenyl-3H-1,2-benzisothiazole-1-oxide which, after recrystallisation from ethyl acetate, melts at 170°C.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)=[C:5]([NH2:14])[NH:4][N:3]=1.[Cl:15][C:16]1[CH:17]=[C:18]([C:22](=O)[CH2:23][C:24](OCC)=[O:25])[CH:19]=[CH:20][CH:21]=1>N1C=CC=CC=1>[Cl:13][C:10]1[CH:9]=[CH:8][C:7]([C:6]2[C:2]([CH3:1])=[N:3][N:4]3[C:22]([C:18]4[CH:19]=[CH:20][CH:21]=[C:16]([Cl:15])[CH:17]=4)=[CH:23][C:24](=[O:25])[NH:14][C:5]=23)=[CH:12][CH:11]=1
Reactant: Cc1n[nH]c(N)c1-c1ccc(Cl)cc1
Reactant: CCOC(=O)CC(=O)c1cccc(Cl)c1
Solvent: c1ccncc1
Product: Cc1nn2c(-c3cccc(Cl)c3)cc(=O)[nH]c2c1-c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 41.1 %

Procedure:
3-Methyl-4-(4-chlorophenyl)-1H-pyrazol-5-amine (578 mg) and ethyl 3-(3-chlorophenyl)-3-oxopropanoate (728 mg) are stirred overnight in a pyridine (30 mL) solvent at 95° C. After cooling to room temperature, the reaction solvent is removed by distillation under reduced pressure. The remainder is extracted with ethyl acetate and water. The extracted organic layer is washed with brine and dehydrated with anhydrous MgSO4. The dehydrated organic layer is distilled under reduced pressure and concentrated and then 424 mg of the target compound is yielded by column chromatography. 1H NMR (CDCl3, 300 MHz) δ 9.90 (br, 1H), 7.88 (m, 1H), 7.75 (m, 1H), 7.53 (m, 1H), 7.33 (m, 5H), 3.99 (br, 1H), 2.23 (s, 3H).