Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C=C2C(=CC=1)CC(C1C(C)=CC=CC=1N)CC2.Cl.[N:22]1([CH2:29][CH2:30][O:31][C:32]2[CH:40]=[CH:39][C:35]([C:36](Cl)=O)=[CH:34][CH:33]=2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.N1(CCOC2C=C[C:54]([CH2:55][NH:56][C:57]3[CH:62]=[CH:61][CH:60]=[C:59]([CH3:63])[C:58]=3[CH:64]3[CH2:73][CH2:72][C:71]4[C:66](=[CH:67][CH:68]=[C:69]([O:74][CH3:75])[CH:70]=4)[CH2:65]3)=CC=2)CCCCCC1>>[N:22]1([CH2:29][CH2:30][O:31][C:32]2[CH:40]=[CH:39][C:35]([CH2:36][N:56]([CH2:55][CH3:54])[C:57]3[CH:62]=[CH:61][CH:60]=[C:59]([CH3:63])[C:58]=3[CH:64]3[CH2:73][CH2:72][C:71]4[C:66](=[CH:67][CH:68]=[C:69]([O:74][CH3:75])[CH:70]=4)[CH2:65]3)=[CH:34][CH:33]=2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: COc1ccc2c(c1)CCC(c1c(C)cccc1NCc1ccc(OCCN3CCCCCC3)cc1)C2
Reactant: O=C(Cl)c1ccc(OCCN2CCCCCC2)cc1
Agent: COc1ccc2c(c1)CCC(c1c(C)cccc1N)C2
Agent: Cl
Product: CCN(Cc1ccc(OCCN2CCCCCC2)cc1)c1cccc(C)c1C1CCc2cc(OC)ccc2C1

Procedure:
Synthesized from 2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)-3-methylphenylamine and 4-(2-azepan-1-ylethoxy)benzoyl chloride hydrochloride according to an analogous synthetic method to Example 152, [4-(2-azepan-1-ylethoxy)benzyl][2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)-3-methylphenyl]amine (565 mg) was used according to an analogous synthetic method to Example 36 to provide [4-(2-azepan-1-ylethoxy)benzyl]ethyl[2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)-3-methylphenyl]amine (437 mg). This compound (435 mg) was used according to an analogous synthetic method to Example 111 to provide the title compound (253 mg).
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][N:9]=[C:10]([NH2:11])[C:5]2=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:14][CH:13]=2)[N:3]=1.[NH:25]1[CH:29]=[CH:28][C:27](B(O)O)=[N:26]1.C(=O)([O-])[O-].[K+].[K+].COCCOC.O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN(C=O)C>[O:18]([C:15]1[CH:16]=[CH:17][C:12]([C:4]2[N:3]=[C:2]([C:29]3[CH:28]=[CH:27][NH:26][N:25]=3)[N:6]3[CH:7]=[CH:8][N:9]=[C:10]([NH2:11])[C:5]=23)=[CH:13][CH:14]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Nc1nccn2c(Br)nc(-c3ccc(Oc4ccccc4)cc3)c12
Reactant: OB(O)c1cc[nH]n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Solvent: CN(C)C=O
Product: Nc1nccn2c(-c3cc[nH]n3)nc(-c3ccc(Oc4ccccc4)cc3)c12

Procedure:
A mixture of 3-bromo-1-(4-phenoxyphenyl)-imidazo[1,5-a]pyrazin-8-ylamine (20.0 mg, 0.052 mmol), 1H-pyrazol-3-yl boronic acid (6.46 mg, 0.057 mmol), Pd(PPh3)4 (10 mg, 0.01 mmol), potassium carbonate (21.8 mg, 0.157 mmol) and DME/H2O (v:v=5:1, 2 mL) was microwaved at 300 watt, 100° C. for 30 min. The solution was transferred to a 20 mL vial, and 1 mL of DMF was added. The solution was concentrated in vacuo until only DMF remained. The mixture was passed through a syringe filter pad, and prepared for Gilson HPLC separation. The fractions containing the pure product were collected and concentrated in vacuo to afford the title compound as a yellow solid. 1H NMR (400 MHz, CDCl3): δ=6.99 (d, J=2.5 Hz, I H), 7.07-7.13 (m, 3H), 7.13-7.20 (m, 3H), 7.37-7.45 (m, 2H), 7.63-7.69 (m, 2H), 7.76 (d, J=2.5 Hz, 1H), 8.65 (br. s., 1H). MS (ES+): m/z 369.10 (100) [MH+]. HPLC: tR=20.39 min (ZQ3, polar—5 min).
Reaction SMILES: [CH:1]([N:4](C(C)C)CC)(C)[CH3:2].[Si:10]([O:17][CH:18]([CH2:22][S:23][S:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:19]([OH:21])=[O:20])([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11].BrCC#N>CN(C=O)C.C(OCC)C>[Si:10]([O:17][CH:18]([CH2:22][S:23][S:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:19]([O:21][CH2:2][C:1]#[N:4])=[O:20])([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)(C)SSCC(O[Si](C)(C)C(C)(C)C)C(=O)O
Agent: N#CCBr
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)(C)SSCC(O[Si](C)(C)C(C)(C)C)C(=O)OCC#N
Reaction time: 1.5 h
Yield: 71 %

Procedure:
Diisopropylethylamine (98.0 μl, 0.56 mmol) was added to a solution of 2-(tert-butyldimethylsilyloxy)-3-(tert-butyldisulfanyl)propionic acid prepared by the method known in the literature (J. Am. Chem. Soc. 2008, 130, 4919) (Compounds 24, 60.0 mg, 0.185 mmol) and 2-bromoacetonitrile (26.0 μl, 0.373 mmol) in DMF (1.8 ml) at room temperature, and the reaction solution was stirred at the same temperature for 1.5 hours. The reaction mixture was diluted with diethyl ether and washed with a saturated aqueous ammonium chloride solution and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by normal-phase silica gel column chromatography (hexane/ethyl acetate) to afford cyanomethyl 2-(tert-butyldimethylsilyloxy)-3-(tert-butyldisulfanyl)propionate (Compound 25) (48 mg, 71%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][C@@H:6]1[CH2:10][C@@H:9]([O:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH2:8][NH:7]1.Cl[C:17]([O:19][CH2:20][CH:21]=[CH2:22])=[O:18].[OH-].[Na+]>O1CCCC1.O>[CH2:20]([O:19][C:17]([N:7]1[CH2:8][C@H:9]([O:11][S:12]([CH3:15])(=[O:13])=[O:14])[CH2:10][C@H:6]1[CH2:5][O:4][CH2:3][CH2:2][OH:1])=[O:18])[CH:21]=[CH2:22]
Reactant: CS(=O)(=O)O[C@H]1CN[C@H](COCCO)C1
Reactant: C=CCOC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1COCCO

Procedure:
To a solution of (2S,4R)-2-(2-hydroxyethyloxymethyl)-4-methanesulfonyloxypyrrolidine (30.5 g) in a mixture of tetrahydrofuran (120 ml) and water (120 ml) was dropwise added a solution of allyl chloroformate (14.5 ml) in tetrahydrofuran (14.5 ml) under ice-cooling with stirring, keeping the pH between 9-10 with 4N aqueous sodium hydroxide. The mixture was stirred at the same condition for one hour and extracted with ethyl acetate (200 ml). The organic layer was dried over magnesium sulfate and evaporated under reduced pressure to give a syrup. The syrup was subjected to a column chromatography on silica gel (400 g) and eluted with a mixture of methanol and dichloromethane (2:98 V/V) to give (2S,4R)-1-allyloxycarbonyl-2-(2-hydroxyethyloxymethyl)-4-methanesulfonyloxypyrrolidine (28.03 g).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.O.[NH2:12][C:13]1[CH:14]=[C:15]([B:19]([OH:21])[OH:20])[CH:16]=[CH:17][CH:18]=1.[C:22](=O)([O-])[O-:23].[Na+].[Na+].CN(C=O)C>C(OCC)(=O)C>[N+:8]([C:7]1[C:2]([N:12]([CH:22]=[O:23])[C:13]2[CH:14]=[C:15]([B:19]([OH:21])[OH:20])[CH:16]=[CH:17][CH:18]=2)=[N:3][CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: O=C([O-])[O-]
Reactant: Nc1cccc(B(O)O)c1
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=CN(c1cccc(B(O)O)c1)c1ncccc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 1 h

Procedure:
. A mixture of 2-chloro-3-nitropyridine (5.0 g, 32.2 mmol), 3-aminophenylboronic acid monohydrate (5.11 g, 32.2 mmol), sodium carbonate (13.7 g, 32.2 mmol), and DMF (100 ml) was stirred at 100° C. for 1 h. After cooling to room temperature, ethyl acetate (500 ml) was added and the solids were filtered off. The solution was transferred to a separatory funnel and washed with aqueous hydrochloric acid (3×200 ml, 1M). The organic phase was dried and the solvent removed. Yield 6.5 g, mp 242°-245° C.
Reaction SMILES: [CH3:1][C:2]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([CH3:20])[CH2:3][C@H:4]1[CH2:9][C@H:8]([C:10]2[O:14][NH:13][C:12](=[O:15])[CH:11]=2)[CH2:7][CH2:6][N:5]1[C:16]([O:18][CH3:19])=[O:17]>CCCCCCC.CC(O)C>[CH3:20][C:2]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)([CH3:1])[CH2:3][C@@H:4]1[CH2:9][C@@H:8]([C:10]2[O:14][NH:13][C:12](=[O:15])[CH:11]=2)[CH2:7][CH2:6][N:5]1[C:16]([O:18][CH3:19])=[O:17]
Reactant: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1CC(C)(C)c1ccccc1
Solvent: CC(C)O
Solvent: CCCCCCC
Product: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@H]1CC(C)(C)c1ccccc1
Yield: 44.3 %

Procedure:
Racemic trans-methyl 2-(2-methyl-2-phenylpropyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)-piperidine-1-carboxylate (0.82 g, 2.28 mmol) was subjected to chiral separation using Chiralcel IC, mobile phase heptane/IPA 80/20 at 40° C. which resulted in (2S,4S)-methyl 2-(2-methyl-2-phenylpropyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (0.361 g, 1.01 mmol).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([NH:28][OH:29])[CH2:11][S:12]([N:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:26]=[C:25]([Cl:27])[N:24]=[CH:23][N:22]=2)[CH2:17][CH2:16]1)(=[O:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:30]1CCC[CH2:31]1>C(O)=O>[CH2:1]([O:8][CH2:9][CH:10]([N:28]([OH:29])[CH:31]=[O:30])[CH2:11][S:12]([N:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:26]=[C:25]([Cl:27])[N:24]=[CH:23][N:22]=2)[CH2:17][CH2:16]1)(=[O:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(CC(COCc1ccccc1)NO)N1CCN(c2cc(Cl)ncn2)CC1
Reactant: C1CCOC1
Solvent: O=CO
Product: O=CN(O)C(COCc1ccccc1)CS(=O)(=O)N1CCN(c2cc(Cl)ncn2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 1-{[3-benzyloxy-2-(hydroxyamino)propyl]sulphonyl}-4-(6-chloropyrimidin-4-yl)piperazine (29.5 g) in tetrahydrofuran (150 ml) and formic acid (25 ml), was added in portions to the above solution at 25° C. over 25 minutes. The solution was stirred at room temperature for 1 hour. The solution was evaporated (water-bath temperature 30° C.) and the residual gum was dissolved in ethyl acetate (500 ml). This solution was treated with saturated aqueous sodium hydrogen carbonate solution (2×250 ml) and the mixture (pH8) was stirred at room temperature for 16 hours. The ethyl acetate layer was separated, washed with saturated brine (100 ml), dried (Na2SO4), and evaporated to dryness. The residual foam was dissolved in methanol (70 ml) and the solution was stirred for 16 hours. The solution was evaporated to dryness (water-bath temperature 30° C.). The residual foam was stirred in ethanol (250 ml), solid separated and the mixture was stirred for 18 hours. The solid was collected by filtration, slurry washed with diethyl ether (100 ml), and dried to give N-[2-(benzyloxy)1-({[4-(6-chloropyrimidin-4-yl)piperazino]sulphonyl}methyl)ethyl]-N-hydroxyformamide (25.5 g). mp 118-120° C.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][CH2:8][C@H:7]([NH:11][C:12]2[C:17]([C:18]3[N:19]=[C:20]4[CH:26]=[CH:25][N:24](COCC[Si](C)(C)C)[C:21]4=[N:22][CH:23]=3)=[CH:16][N:15]=[C:14](S(C)(=O)=O)[N:13]=2)[CH2:6]1)(=[O:4])=[O:3].[CH3:39][N:40]([CH3:46])[C@@H:41]1[CH2:45][CH2:44][NH:43][CH2:42]1.CS(C)(=O)=O>>[CH3:39][N:40]([CH3:46])[C@@H:41]1[CH2:45][CH2:44][N:43]([C:14]2[N:13]=[C:12]([NH:11][C@H:7]3[CH2:8][CH2:9][CH2:10][N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:6]3)[C:17]([C:18]3[N:19]=[C:20]4[CH:26]=[CH:25][NH:24][C:21]4=[N:22][CH:23]=3)=[CH:16][N:15]=2)[CH2:42]1
Reactant: C[Si](C)(C)CCOCn1ccc2nc(-c3cnc(S(C)(=O)=O)nc3N[C@H]3CCCN(S(C)(=O)=O)C3)cnc21
Reactant: CN(C)[C@@H]1CCNC1
Agent: CS(C)(=O)=O
Product: CN(C)[C@@H]1CCN(c2ncc(-c3cnc4[nH]ccc4n3)c(N[C@H]3CCCN(S(C)(=O)=O)C3)n2)C1

Procedure:
A solution of ((S)-1-methanesulfonyl-piperidin-3-yl)-{2-methanesulfonyl-5-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-pyrimidin-4-yl}-amine derived from Example 84, step 1, dimethyl-(R)-pyrrolidin-3-yl-amine was used to displace the methylsulfone similar to examples above and the de-protection step was similar to step 5, Example 76, to give [2-((R)-3-dimethylamino-pyrrolidin-1-yl)-5-(5H-pyrrolo[2,3-b]pyrazin-2-yl)-pyrimidin-4-yl]-((S)-1-methanesulfonyl-piperidin-3-yl)-amine. MS (ES+): 486.
Reaction SMILES: C(OC(C1N=[N:8][C:9]([O:12][C:13]2[C:14]([CH3:19])=[N:15][CH:16]=[CH:17][CH:18]=2)=[CH:10]C=1)=O)C.[OH2:20].[NH2:21][NH2:22]>C(O)C>[CH3:19][C:14]1[C:13]([O:12][CH:9]2[NH:8][CH2:13][CH:14]([C:19]([NH:21][NH2:22])=[O:20])[NH:15][CH2:10]2)=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: NN
Reactant: O
Reactant: CCOC(=O)c1ccc(Oc2cccnc2C)nn1
Solvent: CCO
Product: Cc1ncccc1OC1CNC(C(=O)NN)CN1
Temperature: 50 °C
Yield: 121.4 %

Procedure:
6-(2-Methylpyridin-3-yloxy)-pyridazine-3-carboxylic acid ethyl ester (D11) (1.07 g, 4.13 mmol) and hydrazine monohydrate (0.23 ml, 7.22 mmol) in ethanol (100 ml) was stirred at room temperature for 1 hour then heated at 50° C. for 1 hour and finally heated at reflux for 4 hours. A second portion of hydrazine monohydrate (0.23 ml, 7.22 mmol) was added and the mixture refluxed for a further 2 hours. After being allowed to cool the solvent was removed in vacuo. The off-white solid residue was subjected to column chromatography using 25% MeOH/EtOAc as eluant, resulting in a white crystalline product (0.63 g, 62%).
Reaction SMILES: Cl[C:2]1[C:3](=[O:15])[N:4]([C@H:9]([CH2:12][O:13][CH3:14])[CH2:10][CH3:11])[CH:5]=[C:6]([Cl:8])[N:7]=1.[Cl:16][C:17]1[CH:18]=[C:19]2[C:23](=[C:24]([Cl:26])[CH:25]=1)[NH:22][CH2:21][CH2:20]2>>[Cl:8][C:6]1[N:7]=[C:2]([N:22]2[C:23]3[C:19](=[CH:18][C:17]([Cl:16])=[CH:25][C:24]=3[Cl:26])[CH2:20][CH2:21]2)[C:3](=[O:15])[N:4]([C@H:9]([CH2:12][O:13][CH3:14])[CH2:10][CH3:11])[CH:5]=1
Reactant: Clc1cc(Cl)c2c(c1)CCN2
Reactant: CC[C@@H](COC)n1cc(Cl)nc(Cl)c1=O
Product: CC[C@@H](COC)n1cc(Cl)nc(N2CCc3cc(Cl)cc(Cl)c32)c1=O

Procedure:
Prepared in a similar fashion as described for Example 413 using 3,5-dichloro-1-[(1S)-1-(methoxymethyl)propyl]-2(1H)-pyrazinone and 5,7-dichloroindoline as the starting materials. mp 143–146° C.; 1H NMR (300 MHz, CDCl3): δ 7.16 (d, J=1.9 Hz, 1 H), 7.09 (d, J=1.9 Hz, 1 H), 7.03 (s, 1 H), 4.93–4.88 (m, 1 H), 4.32 (t, J=8.1 Hz, 2 H), 3.65 (dd, J=10.6, 5.5 Hz, 1 H), 3.54 (dd, J=10.6, 3.5 Hz, 1 H), 3.33 (s, 3 H), 3.11 (t, J=8.1 Hz, 2 H), 1.90–1.70 (m, 2 H), 0.91 (t, J=7.5 Hz, 3 H); HRMS (ESI) calcd for C17H19N3O2Cl3 (M+H)+: 402.0543; found m/z 402.0520.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[CH2:6][CH2:7][NH2:8].[F:14][C:15]([F:28])([F:27])[C:16]1[CH:26]=[CH:25][C:19]([CH2:20][CH2:21][C:22](O)=[O:23])=[CH:18][CH:17]=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[CH2:6][CH2:7][NH:8][C:22](=[O:23])[CH2:21][CH2:20][C:19]1[CH:18]=[CH:17][C:16]([C:15]([F:27])([F:28])[F:14])=[CH:26][CH:25]=1
Reactant: O=C(O)CCc1ccc(C(F)(F)F)cc1
Reactant: COc1ccc(CCN)cc1OC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1ccc(CCNC(=O)CCc2ccc(C(F)(F)F)cc2)cc1OC
Yield: 70.4 %

Procedure:
3,4-Dimethoxyphenethylamine 42a (3.62 g, 3.4 mL, 20 mmol, 1.0 eq) was added to a solution of 4-(trifluoromethyl)hydrocinnamic acid 43 (4.36 g, 20 mmol, 1.0 eq) in toluene (75 mL). After 5 min a thick suspension formed. The suspension was heated to reflux, giving a clear solution. The mixture was heated at reflux for 24 h using a Dean-Stark trap to remove water that was formed. The mixture was partially cooled, diluted with ethyl acetate (100 mL) and concentrated under reduced pressure to near dryness. The thick slurry was diluted with ethyl acetate (200 mL) and the solution washed sequentially with 1N hydrochloric acid (100 mL), aqueous sodium bicarbonate solution (200 mL), water (100 mL) and brine (100 mL). The organic solution was dried over sodium sulfate, filtered and the filtrate concentrated under reduced pressure. The solid was triturated with heptanes (50 mL), filtered and dried to give 5.37 g (70%) of 44a as a white, fluffy solid.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][CH:5]=[C:4]([F:12])[C:3]=1[OH:13].[CH2:14]([O:16][C:17](=[O:21])[C:18]#[C:19][CH3:20])[CH3:15].N12CCCN=C1CCCCC2>O1CCCC1>[CH2:14]([O:16][C:17](=[O:21])/[CH:18]=[C:19](/[O:13][C:3]1[C:4]([F:12])=[CH:5][CH:6]=[C:7]([O:8][CH:9]([CH3:11])[CH3:10])[C:2]=1[F:1])\[CH3:20])[CH3:15]
Reactant: CC#CC(=O)OCC
Reactant: CC(C)Oc1ccc(F)c(O)c1F
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CCOC(=O)/C=C(\C)Oc1c(F)ccc(OC(C)C)c1F
Yield: 73.6 %

Procedure:
To a stirred mixture of 2,6-difluoro-3-isopropoxy-phenol (5.74 g, 0.031 mol) and ethyl-2-butynoate (6.85 g, 0.061 mol) in tetrahydrofuran (50 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (4.64 g, 0.030 mol) slowly. After addition was complete the mixture was stirred at reflux for 6 h. Upon completion of the reaction the tetrahydrofuran was removed in vacuo and the residue was diluted in diethyl ether and washed first with 1N aqueous hydrochloric acid, then 10% aqueous sodium hydroxide solution, a saturated sodium chloride solution and dried over magnesium sulfate. The mixture was filtered and evaporated which afforded (E)-3-(2,6-difluoro-3-isopropoxy-phenoxy)-but-2-enoic acid ethyl ester as a brown oil (6.85 g, 75%) and used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15]Cl)=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[C:6]=2[CH:24]=1.[NH2:25][OH:26].[H-].[Na+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][NH:25][OH:26])=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[C:6]=2[CH:24]=1
Reactant: NO
Reactant: ClCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: ONCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2

Procedure:
In the manner given in Example 15, 8-chloro-1-(chloromethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine is treated with a cold mixture of hydroxylamine and sodium hydride in dimethylformamide to give 8-chloro-1-[(hydroxyamino)methyl]-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[N:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:13]([O:15]CC)=[O:14].[C:18]1([NH:24][NH2:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>C(O)CCC.[OH-].[Na+]>[OH2:14].[CH3:12][C:8]1[CH:9]=[CH:10][C:11]2[C:2]3[C:3]([C:13](=[O:15])[N:24]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:25]=3)=[CH:4][NH:5][C:6]=2[N:7]=1.[CH3:12][C:8]1[CH:9]=[CH:10][C:11]2[C:2]3[C:3]([C:13](=[O:15])[N:24]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:25]=3)=[CH:4][NH:5][C:6]=2[N:7]=1
Reactant: NNc1ccccc1
Reactant: CCOC(=O)c1cnc2nc(C)ccc2c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCO
Solvent: O
Product: Cc1ccc2c3nn(-c4ccccc4)c(=O)c-3c[nH]c2n1

Procedure:
A mixture of 3.0 g of ethyl 4-chloro-7-methyl-1,8-naphthyridine-3-carboxylate (prepared according to U.S. Pat. No. 3,786,043) and 1.42 g of phenylhydrazine in 30 ml of n-butanol is refluxed for 18 hours. The mixture is chilled in an ice bath and filtered to give a solid which is taken up in 50 ml of 1N sodium hydroxide and sufficient water to dissolve. The resulting solution is filtered to remove insoluble, washed with ether and neutralized with 3.0 g of ammonium chloride. The resulting mixture is filtered collecting a solid which is washed with water and dried to yield 7-methyl-2-phenylpyrazolo[4,3-c][1,8]naphthyridin-3(5H)-one hemihydrate, m.p. 305°-308°.
Reaction SMILES: [N+](C1C=C([N+]([O-])=O)C=CC=1NN)([O-])=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=[N:34][CH:35]([P:44]([O:49][CH2:50][CH3:51])([O:46][CH2:47][CH3:48])=[O:45])[C:36]([O:38][CH2:39][C:40]([Cl:43])([Cl:42])[Cl:41])=[O:37])C1C=CC=CC=1.C(Cl)(Cl)Cl>C(O)C>[NH2:34][CH:35]([P:44]([O:46][CH2:47][CH3:48])([O:49][CH2:50][CH3:51])=[O:45])[C:36]([O:38][CH2:39][C:40]([Cl:42])([Cl:43])[Cl:41])=[O:37]
Reactant: CCOP(=O)(OCC)C(N=Cc1ccccc1)C(=O)OCC(Cl)(Cl)Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: NNc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Solvent: ClC(Cl)Cl
Solvent: CCO
Solvent: O
Product: CCOP(=O)(OCC)C(N)C(=O)OCC(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A mixture of 2,4-dinitrophenyl hydrazine (1.875 g., 9.47 mMol) and p-toluenesulfonic acid monohydrate (1.800 g., 9.47 mMol) in ethanol (200 ml.) is stirred at room temperature for 45 minutes. To the resulting orange suspension is added trichloroethyl N-benzylidene-α-amino-diethylphosphonoacetate (3.881 g., 9.02 mMol) in a small volume of chloroform. The mixture is stirred for 30 minutes at room temperature, then filtered to remove benzaldehyde 2,4-dinitrophenyl hydrazone. The filtrate is evaporated in vacuo to an orange oil which is taken up in water (50 ml.) and washed with chloroform (4 × 25 ml.) to remove the remainder of the hydrazone. The aqueous phase (pH 2) is cooled in ice, adjusted to pH 10 with 2 N NaOH, saturated with NaCl, and extracted with methylene chloride (2 × 25 ml). The combined extracts are dried over MgSO4 and evaporated in vacuo to give trichloroethyl α-amino-diethylphosphonoacetate as a pale yellow liquid.
Reaction SMILES: Br[C:2]1[CH:3]=[N+:4]([O-])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][NH2:18])=[CH:15][CH:14]=1>>[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][NH:18][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[N+:8]([O-:10])=[O:9])=[CH:15][CH:14]=1
Reactant: O=[N+]([O-])c1cc[n+]([O-])cc1Br
Reactant: NCc1ccc(F)cc1
Product: O=[N+]([O-])c1ccncc1NCc1ccc(F)cc1
Yield: 35.8 %

Procedure:
In accordance with the same procedures as in Preparation 2, except for using 3-bromo-4-nitropyridin-N-oxide prepared in Step 2 of Preparation 1 and 4-fluorobenzylamine, the titled compound was obtained as a yellow solid. (Yield: 35.8%)
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[O:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][OH:21])[CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[O:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][O:21][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=2[N+:10]([O-:12])=[O:11])[CH2:15][CH2:14]1
Reactant: OCCN1CCOCC1
Reactant: N#Cc1ccc(F)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: N#Cc1ccc(OCCN2CCOCC2)c([N+](=O)[O-])c1
Yield: 50.7 %

Procedure:
4-Fluoro-3-nitrobenzonitrile (0.5 g, 3.0 mmol), 2-morpholinoethanol (0.37 mL, 3.0 mmol), and potassium carbonate (0.42 g, 3.0 mmol) in DMSO (2 mL) were heated at 50° C. for 16 hours. Water (10 mL) was added to the reaction mixture, and the solid was collected via filtration. The solid was washed with water (3×2 mL) to afford Intermediate 27A (422 mg, 50.6% yield) as a tan solid. HPLC: Rt=0.78 min. (PHENOMENEX® S5 4.6×30 mm, 10-90% aqueous methanol containing 0.1% TFA, 4 min. gradient, flow rate=5 mL/min., detection at 254 nm). MS (ES): m/z=278.16 [M+H]+.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[F:8][C:9]1[CH:23]=[CH:22][C:12]([CH:13](Cl)[C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[CH:11][CH:10]=1>ClCCl.[Zn].II>[CH2:6]([O:5][C:3](=[O:4])[CH2:2][CH:13]([C:12]1[CH:22]=[CH:23][C:9]([F:8])=[CH:10][CH:11]=1)[C:14]1[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=1)[CH3:7]
Reactant: CCOC(=O)CBr
Reactant: Fc1ccc(C(Cl)c2ccc(F)cc2)cc1
Agent: II
Agent: [Zn]
Solvent: ClCCl
Product: CCOC(=O)CC(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 79.9 %

Procedure:
A suspension of zinc (5.7 g, 87.2 mmol) in dichloromethane (20 ml) was treated with iodine (0.1 g) and heated under reflux. A solution of ethyl bromoacetate (10.0 g, 59.8 mmol) in dichloromethane was then added dropwise over 15 min and the resulting mixture was heated for another 15 min. The thick paste was then cooled to 0-5° C. and treated dropwise with a solution of 4,4′-difluorobenzhydryl chloride (11.93 g, 50.0 mmol) in dichloromethane (20 ml). The cooling bath was then removed and the mixture was stirred at 22° C. for another 2 h. The reaction mixture was quenched by the addition of 1N hydrochloric acid and ethyl acetate. The organic phase was washed with water, saturated sodium bicarbonate, brine and dried (magnesium sulfate). Evaporation of the solvent under reduce pressure and distillation of the residue in vacuo gave 11.6 g (80%) of the title material as a clear oil: bp 95-100° C./0.1 torr (bulb to bulb distillation, air bath temperature). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.14 (3H, t, J=7.1 Hz, CH3), 3.01 (2H, d, J=8.1 Hz, CH2), 4.06 (2H, q, J=7.1 Hz, CH2), 4.54 (1H, t, J=8.1 Hz, CH),7.0 (4H, m, aromatics), 7.2 (4H, m, aromatics). Anal. Calcd for C17H16F2O2: C, 70.34; H, 5.56. Found: C, 70.44; H, 5.50.