Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH:16]=O)[N:11]=2)=[CH:6][C:3]=1[C:4]#[N:5].[NH2:18][C@@H:19]([CH2:23][OH:24])[CH:20]([CH3:22])[CH3:21].C(O)(=O)C.C([BH3-])#N>CO>[F:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][NH:18][C@H:19]([CH:20]([CH3:22])[CH3:21])[CH2:23][OH:24])[N:11]=2)=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1cc(-c2cccc(C=O)n2)ccc1F
Reactant: CC(C)[C@@H](N)CO
Agent: [BH3-]C#N
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)[C@H](CO)NCc1cccc(-c2ccc(F)c(C#N)c2)n1
Reaction time: 2 h
Yield: 52.5 %

Procedure:
To a solution of 6-bromopicolinaldehyde (1.00 g, 5.38 mmol) in dioxane (30 mL) at ambient temperature was added 3-cyano-4-fluorophenylboronic acid (0.887 g, 5.38 mmol), 2M cesium carbonate (8.1 mL, 16.2 mmol) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (0.220 g, 0.269 mmol). The mixture was degassed (3× vacuum/purge N2), then heated at 80° C. overnight. The mixture was cooled, concentrated and partitioned between water and CH2Cl2. The organic layer was concentrated and purified by chromatography (30% ethyl acetate:hexanes) to provide 2-fluoro-5-(6-formylpyridin-2-yl)benzonitrile. To a solution of 2-fluoro-5-(6-formylpyridin-2-yl)benzonitrile (0.500 g, 2.21 mmol) in methanol (20 mL) at ambient temperature was added D-valinol (0.25 mL, 2.2 mmol), acetic acid (0.50 mL, 8.8 mmol) followed by MP-cyanoborohydride (2.49 mmol/g; 1.0 g). After 2 hours, the mixture was filtered, concentrated, and the residue partitioned between ether and 1M NaOH. The organic layer was concentrated and purified by chromatography to provide 362 mg (52%) of the title compound. MS (DCI+) m/z 314 (M+H); 1H NMR (400 MHz, DMSO-d6) δ 8.62 (dd, J=6.3, 2.3 Hz, 1H), 8.52 (ddd, J=8.9, 5.3, 2.4 Hz, 1H), 7.97-7.84 (m, 2H), 7.66 (t, J=9.0 Hz, 1H), 7.49 (dd, J=7.4, 1.1 Hz, 1H), 3.92 (d, J=3.6 Hz, 2H), 3.52-3.43 (m, 1H), 2.40-2.22 (m, 2H), 1.93-1.76 (m, 1H), 0.89 (dd, J=9.5, 6.9 Hz, 6H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][NH2:5].O([Si:14]([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[CH:15]([CH3:17])[CH3:16])S(C(F)(F)F)(=O)=O>ClCCl>[CH:15]([Si:14]([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[O:1][CH2:2][CH2:3][CH2:4][NH2:5])([CH3:17])[CH3:16]
Reactant: NCCCO
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)[Si](OCCCN)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
3-Hydroxylpropylamine (100 μL, 1.31 mmol) was dissolved in dichloromethane (4.4 mL), and triisopropylsilyl triflate (371 μL, 1.38 mmol) was added dropwise at room temperature. After stirring at room temperature for 15 minutes, the mixture was worked up according to a conventional method to give the title compound as a crude product.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C.[CH3:32][O:33][CH2:34][CH2:35][C:36]([OH:38])=O.[Cl:39][C:40]1[CH:70]=[CH:69][C:43]([CH2:44][N:45]2[C:49]3[CH:50]=[C:51]([N:55]4[CH2:60][CH2:59][NH:58][CH2:57][CH2:56]4)[C:52]([F:54])=[CH:53][C:48]=3[N:47]=[C:46]2[CH2:61][O:62][C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)=[CH:42][CH:41]=1>CN(C=O)C.O>[Cl:39][C:40]1[CH:70]=[CH:69][C:43]([CH2:44][N:45]2[C:49]3[CH:50]=[C:51]([N:55]4[CH2:60][CH2:59][N:58]([C:36](=[O:38])[CH2:35][CH2:34][O:33][CH3:32])[CH2:57][CH2:56]4)[C:52]([F:54])=[CH:53][C:48]=3[N:47]=[C:46]2[CH2:61][O:62][C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)=[CH:42][CH:41]=1
Reactant: Fc1cc2nc(COc3ccccc3)n(Cc3ccc(Cl)cc3)c2cc1N1CCNCC1
Reactant: COCCC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COCCC(=O)N1CCN(c2cc3c(cc2F)nc(COc2ccccc2)n3Cc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 0.02 h

Procedure:
71 mg of TBTU (0.22 mmol), 0.19 ml of ethyldiisopropylamine and 0.023 ml of 3-methoxy-propionic acid (0.22 mmol) were dissolved in 6 ml DMF and stirred for one minute at rt under argon. Then 100 mg of 1-(4-chloro-benzyl)-5-fluoro-2-phenoxymethyl-6-piperazin-1-yl-1H-benzoimidazole (0.22 mmol) were added and the reaction mixture was stirred for 22 h at rt. The reaction mixture was then diluted with 30 ml water and extracted with ethylacetate (twice). The combined organic phases were washed with water and brine, dried with magnesium sulfate, filtered and concentrated in vacuo, leading to 121 mg of a light red solid (97%). MS (ISP) 537.4 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C@H:12]1[C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[O:28][CH2:29][C:30]([OH:32])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:33][C:34]([F:40])([F:39])[S:35]([NH2:38])(=[O:37])=[O:36].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CN(C1C=CN=CC=1)C.CCOC(C)=O>[CH2:1]([O:8][C:9]([N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C@H:12]1[C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[O:28][CH2:29][C:30](=[O:32])[NH:38][S:35]([C:34]([F:40])([F:39])[F:33])(=[O:37])=[O:36])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NS(=O)(=O)C(F)(F)F
Reactant: O=C(O)COc1ccc(Cl)cc1[C@@H]1c2ccccc2CCN1C(=O)OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(COc1ccc(Cl)cc1[C@@H]1c2ccccc2CCN1C(=O)OCc1ccccc1)NS(=O)(=O)C(F)(F)F
Temperature: 50 °C
Reaction time: 18 h

Procedure:
To a solution of (S)-1-(2-carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (138 mg, 0.30 mmol, 1.0 eq.) in DMF (1.2 mL), trifluoromethanesulfonamide (47 mg, 0.30 mmol, 1.0 eq.), HATU (125 mg, 0.33 mmol, 1.1 eq.), DIPEA (103 μL, 0.60 mmol, 2.0 eq.), and DMAP (spatula tip) were added. The resulting mixture was stirred at 50° C. for 18 hours. The mixture was then purified by prep. HPLC (column: Waters XBridge, 30×75 mm, 10 um, UV/MS, basic conditions) and evaporated to give a white-off solid, contaminated with some DIPEA. The contaminated product was redissolved in AcOEt and washed with 1M aq. HCl soln. and sat. aq. NaCl soln. The org. phase was dried over MgSO4, filtered, and concentrated in vacuo to give the desired product as a white-off solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:44]=[C:45]([N+:47]([O-])=O)[CH:46]=1)[C:7]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17](=[O:43])/[CH:18]=[CH:19]/[C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27](=[O:42])[C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][CH2:37][C:38]([F:41])([F:40])[F:39])=[CH:30][CH:29]=2)=[CH:22][CH:21]=1)=[O:8])([O-])=O>CN(C)C=O.O.[Zn]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:44]=[C:45]([NH2:47])[CH:46]=1)[C:7]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17](=[O:43])/[CH:18]=[CH:19]/[C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27](=[O:42])[C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][CH2:37][C:38]([F:39])([F:40])[F:41])=[CH:30][CH:29]=2)=[CH:22][CH:21]=1)=[O:8]
Reactant: O=C(/C=C/c1ccc(OC(=O)c2ccc(OCCCC(F)(F)F)cc2)cc1)OCCCCCCOC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Agent: [Zn]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1cc(N)cc(C(=O)OCCCCCCOC(=O)/C=C/c2ccc(OC(=O)c3ccc(OCCCC(F)(F)F)cc3)cc2)c1
Yield: 90.7 %

Procedure:
18.80 g (0.027 Mol) of 6-{[((2E)-3-{4-[(4-(4,4,4-trifluorobutoxy)benzoyl)oxy]phenyl}prop-2-enoyl)oxy]}hexyl 3,5-dinitrobenzoate are dissolved in a mixture of 350 ml of N,N-dimethylformamide and 25 ml water. 44.28 g (0.164 Mol) ferric chloride hexahydrate are added. 17.85 g (0.273 Mol) Zinc powder are added portionwise within 40 min. The mixture is allowed to react for 2 hours. The reaction mixture is then partitioned between ethyl acetate and water and filtered. The organic phase is washed repeatedly with water, dried over sodium sulfate, filtered and concentrated by rotary evaporation. Chromatography of the residue on 400 g silica gel using toluene:ethyl acetate(2:1) as eluant yielded 15.39 g (91%) of 6-{[((2E)-3-{4-[(4-(4,4,4-trifluorobutoxy)benzoyl)oxy]phenyl}prop-2-enoyl)oxy]}hexyl 3,5-diaminobenzoate as yellowish crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1[NH:13][C:14](Cl)=[O:15].[NH2:17][C:18]1[C:27]2[CH2:26][CH2:25][CH2:24][CH2:23][C:22]=2[CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C.C(Cl)(Cl)Cl>O>[C:18]1([NH:17][C:14]([NH:13][C:4]2[CH:5]=[C:6]([C:9]([F:12])([F:11])[F:10])[CH:7]=[CH:8][C:3]=2[O:2][CH3:1])=[O:15])[C:27]2[CH2:26][CH2:25][CH2:24][CH2:23][C:22]=2[CH:21]=[CH:20][CH:19]=1
Reactant: Nc1cccc2c1CCCC2
Reactant: COc1ccc(C(F)(F)F)cc1NC(=O)Cl
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1ccc(C(F)(F)F)cc1NC(=O)Nc1cccc2c1CCCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.6 %

Procedure:
2-methoxy-5-(trifluoromethyl)phenyl carbamoylchloride (0.81 g, 3.2 mmol), 1-amino-5,6,7,8-tetrahydronaphtalene (445 μl, 3.2 mmol) and triethylamine (446 μl, 3.2 mmol) were added to chloroform (20 ml) and the resulting mixture was stirred at RT overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The solvent was evaporated in vacuuo and the residue recrystallized from toluene (20 ml). 0.45 g of the title compound was isolated.
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10](=[O:27])[CH:11]([C:20]1(O)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)[NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CN=CC=1.O=S(=O)=O.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>N1C=CC=CC=1.O>[CH2:1]([O:8][N:9]1[C:20]2([CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[CH:11]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:10]1=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NC(C(=O)NOCc1ccccc1)C1(O)CCOCC1
Agent: O=C([O-])[O-]
Agent: O=S(=O)=O
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)NC1C(=O)N(OCc2ccccc2)C12CCOCC2
Temperature: 57 °C
Reaction time: 6 h

Procedure:
N-(Benzyloxy)-N2 -(t-butoxycarbonyl)-α-(4-hydroxy-2,3,5,6-tetrahydro-4-pyranyl)glycinamide (1.9 g, 5 mmoles) in 20 ml of dry pyridine under argon was treated with 1.05 g (6.5 mmoles) of pyridine-sulfur trioxide and heated to 57° C. for 2 hours. The volatiles were removed in vacuo. Dry acetonitrile was added and evaporated four times, and the residue was treated with a solution of 5 g (36 mmole) of potassium carbonate in 12.5 ml of water, followed by 40 ml of ethyl acetate. The mixture was heated to reflux with vigorous stirring for 6 hours. The mixture was cooled, diluted with water, and the layers separated. The organics were washed with 3% potassium bisulfate and brine, dried (sodium sulfate) and evaporated to a solid. Chromatography on 350 ml of LPS-1 in hexane:ethyl acetate (1:1) and evaporation of the pure product fractions (Rf=0.56 in same solvent) gave a solid. Trituration with isopropyl ether and air drying gave the product as a white solid, 0.78 g, melting point 144°-146° C.
Reaction SMILES: [C:1]([Si:5]([CH3:16])([CH3:15])[O:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]#[C:12]CO)([CH3:4])([CH3:3])[CH3:2].C([Si](C)(C)OCCCCC#CCOC(=O)C)(C)(C)C.C(OC(=O)C)(=O)C>N1C=CC=CC=1>[C:1]([Si:5]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]#[CH:12])([CH3:15])[CH3:16])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCCCCC#CCO
Agent: CC(=O)OCC#CCCCCO[Si](C)(C)C(C)(C)C
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: C#CCCCCO[Si](C)(C)C(C)(C)C
Reaction time: 18 h

Procedure:
7-(tert-Butyl-dimethyl-silanyloxy)-hept-2-yn-1-ol (27); and Acetic acid 7-(tert-butyl-dimethyl-silanyloxy)-hept-2-ynyl ester (28, FIG. 4). A solution of 7-(tert-Butyl-dimethyl-silanyloxy)-hept-2-yn-1-ol (27) (4.507 g, 21 mmol) in pyridine (20 mL) was treated with acetic anhydride (3.0 mL, 31.8 mmol). After 18 hours, the solvent was evaporated and the residue co-evaporated with toluene. The residue was used directly in the next step.
Reaction SMILES: [C:1]1(=[O:20])[N:5]([C:6]2([C:12](Cl)=[O:13])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)[C:4](=[O:15])[C:3]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:2]12.[NH3:21]>O1CCCC1>[C:1]1(=[O:20])[N:5]([C:6]2([C:12]([NH2:21])=[O:13])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)[C:4](=[O:15])[C:3]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:2]12
Reactant: O=C1c2ccccc2C(=O)N1C1(C(=O)Cl)CCCCC1
Reactant: N
Solvent: C1CCOC1
Product: NC(=O)C1(N2C(=O)c3ccccc3C2=O)CCCCC1
Temperature: 5 °C

Procedure:
The crude 1-phthalimidocyclohexanecarbonyl chloride prepared above in Step 3 is dissolved in 3.5 l tetrahydrofuran, and the solution cooled to 5° C. Ammonia is than bubbled into the solution with stirring until infra-red analysis of the liquid phase indicates that all the acid chloride is converted to the amide. The reaction mixture is then poured into 8 l of water with stirring, the product removed by filtration, washed with water and air-dried to give 259.1 of 1-phthalimidocyclohexanecarboxamide, melting point 224°-226° C.
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:5]=2[N:6]=1.C(O[C@@H:17]1[O:29][C@H:28]([CH2:30][O:31][C:32](=[O:34])[CH3:33])[C@@H:23]([O:24][C:25](=[O:27])[CH3:26])[C@H:18]1[O:19][C:20](=[O:22])[CH3:21])(=O)C.[Si](OS(C(F)(F)F)(=O)=O)(C)(C)C>C(Cl)CCl.C(Cl)(Cl)Cl>[Cl:1][C:2]1[N:3]([C@@H:17]2[O:29][C@H:28]([CH2:30][O:31][C:32](=[O:34])[CH3:33])[C@@H:23]([O:24][C:25](=[O:27])[CH3:26])[C@H:18]2[O:19][C:20](=[O:22])[CH3:21])[C:4]2[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:5]=2[N:6]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: Fc1cc2nc(Cl)[nH]c2cc1F
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: ClCCCl
Product: CC(=O)OC[C@H]1O[C@@H](n2c(Cl)nc3cc(F)c(F)cc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 75 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 0.943 g (5 mmole) of 12 in 25 mL of ClCH2CH2Cl, was added 1.25 mL (5 mmole) of BSA at 75° C. The reaction mixture was stirred at 75° C. for 30 min. To this solution, was added 1.75 g (5.5 mmole) of 1,2,3,5-tetra-O-acetyl-β-D-ribofuranose and 1.07 mL (5.5 mmole) of TMSOTf. Stirring was continued at 75° C. for 30 min. The reaction mixture was cooled to room temperature, diluted with 100 mL of CHCl3, and extracted with sat. NaHCO3 solution (100 mL×2) and sat. NaCl solution (100 mL). The CHCl3 phase was dried (Na2SO4) and evaporated. The residue was chromatographed on a silica column (3×25 cm, eluted successively with 0.5%, 1% MeOH/CHCl3). Evaporation of the appropriate fractions and recrystallization of the residue from MeOH gave 1.257 g (3 crops, 56%) of 64 as crystalline needles. MP 90°-91° C.; MS m/e 446.0694 (5%, M+ =446.0692); 1H NMR (DMSO-d6) d 7.93 (dd, 1, 7-H, 3JF-H =10.5 Hz, 4JF-H =7.5 Hz), 7.82 (dd, 1, 4-H, 3JF-H =10.5 Hz, 4JF-H =7.5 Hz), 6.23 (d, 1, 1'-H, J1'-2' =7.0 Hz), 5.55 (t, 1, 2'-H, J2'-3' =7.0 Hz), 5.44 (m, 1, 3'-H, J3-4 =4.5 Hz), 4.45 (m, 3, 4'-H and 5'-H), 2.13, 2.10, 2.02 (3×s, 9, 3×Ac); 13C NMR (DMSO-d6) d 169.95, 169.50, 169.18 (3×OCOCH3), 148.76, 148.62, 146.10, 145.93 (C5 and C6, 1JF-C =242 Hz), 140.16 (C2), 137.01 (C3a, 3JF-C =12 Hz), 128.54 (C7a, 3JF-C =12 Hz), 107.31, 107.09 (C4, JF-C =20 Hz), 100.93, 100.66 (C7, JF-C =24 Hz), 86.89 (Cl'), 79.41 (C4'), 70.40 (C2'), 68.62 (C3'), 62.67 (C5'), 20.43, 20.28, 20.00 (3×OCOCH3).
Reaction SMILES: CS(O[CH2:6][CH:7]1[N:12]2[C:13]3[CH:14]=[CH:15][CH:16]=[C:17]([F:20])[C:18]=3[CH:19]=[C:11]2[C:10]2[N:21]=[C:22]([Cl:25])[CH:23]=[CH:24][C:9]=2[O:8]1)(=O)=O.[N-:26]=[N+:27]=[N-:28].[Na+].O>CN(C=O)C>[N:26]([CH2:6][CH:7]1[N:12]2[C:13]3[CH:14]=[CH:15][CH:16]=[C:17]([F:20])[C:18]=3[CH:19]=[C:11]2[C:10]2[N:21]=[C:22]([Cl:25])[CH:23]=[CH:24][C:9]=2[O:8]1)=[N+:27]=[N-:28]
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)OCC1Oc2ccc(Cl)nc2-c2cc3c(F)cccc3n21
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=NCC1Oc2ccc(Cl)nc2-c2cc3c(F)cccc3n21
Temperature: 60 °C
Reaction time: 6 h
Yield: 97.4 %

Procedure:
To a solution of (2-chloro-11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-6-yl)methyl methanesulfonate (5 g, 13.08 mmol) in DMF (50 mL), NaN3 (4.18 g, 39.25 mmol) was added at room temperature. The mixture was stirred at 60° C. for 6 hours under N2 protection. After H2O was added, the mixture was extracted with EtOAc (20 mL*3). The combined organic phases were washed with water and brine, dried over Na2SO4 and concentrated to provide 6-(azidomethyl)-2-chloro-11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indole (4.2 g, yield: 97.4%). The crude product was used in the next step without purification. 1H-NMR (CDCl3, 400 MHz) δ 3.62˜3.71 (m, 1H), 3.72˜3.81 (m, 1H), 5.28˜5.34 (t, J=5.6 Hz, 1H), 6.76˜6.83 (t, J=4.4 Hz, 1H), 6.92˜7.00 (m, 1H), 7.05˜7.13 (s, 1H), 7.23˜7.31 (m, 1H), 7.39˜7.51 (m, 2H), 7.57˜7.67 (d, J=8.8 Hz, 1H). MS (M+H)+: 330.
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)#[N:2].[CH3:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:11]=1[N:17]=[C:18]=[O:19]>C(OCC)C>[C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:18]([NH:17][C:11]2[CH:12]=[C:13]([CH3:16])[CH:14]=[CH:15][C:10]=2[CH3:9])=[O:19])[CH2:5][CH2:4]1)#[N:2]
Reactant: N#CC1CCNCC1
Reactant: Cc1ccc(C)c(N=C=O)c1
Solvent: CCOCC
Product: Cc1ccc(C)c(NC(=O)N2CCC(C#N)CC2)c1
Temperature: 25 °C
Yield: 98.3 %

Procedure:
A solution of 4-cyanopiperidine (11.0 g, 100 mmol) in diethyl ether (350 mL) was cooled to 0° C. with an ice-water bath. A solution of 2,5-dimethylphenyl isocyanate (14.7 g, 100 mmol) in diethyl ether (50 mL) was added into the reaction mixture over 30 minutes to give a thick precipitate. The reaction mixture was warmed to room temperature, and the resulting solids were filtered, washed with diethyl ether and air-dried to give 25.3 g of the title compound as a white powder, melting at 187-190° C.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:24]=[C:23]([CH3:25])[C:11]([O:12][CH2:13][CH2:14][CH2:15][C:16]3[CH:17]=[CH:18][C:19](=O)[NH:20][CH:21]=3)=[C:10]([CH3:26])[CH:9]=2)[N:4]=1.CI.[C:31]([O-:34])([O-])=O.[K+].[K+]>COCCOCCN(CCOCCOC)CCOCCOC.CN(C=O)C>[F:27][C:2]([F:1])([F:28])[C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:9]=[C:10]([CH3:26])[C:11]([O:12][CH2:13][CH2:14][CH2:15][C:16]3[C:31](=[O:34])[N:20]([CH3:21])[CH:19]=[CH:18][CH:17]=3)=[C:23]([CH3:25])[CH:24]=2)[N:4]=1
Reactant: Cc1cc(-c2noc(C(F)(F)F)n2)cc(C)c1OCCCc1ccc(=O)[nH]c1
Reactant: O=C([O-])[O-]
Agent: COCCOCCN(CCOCCOC)CCOCCOC
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cc1cc(-c2noc(C(F)(F)F)n2)cc(C)c1OCCCc1cccn(C)c1=O
Yield: 91.7 %

Procedure:
To a solution of 0.95 g (2.41 mmol) of 5-[3-[4-(5-trifluoromethyl-1,2,4-oxadiazol-3-yl)-2,6-dimethylphenoxy]-propyl]-2 (1H)-pyridone, 20 drops of TDA-1, and 0.5 ml of methyl iodide in 50 ml of dry DMF was added 0.96 g (3 eq) of milled K2CO3. The mixture was filtered and concentrated in vacuo to afford 0.9 g (91.8%) of 3-[3-[4-(5-trifluoromethyl-1,2,4-oxadiazol-3-yl)-2,6-dimethylphenoxy]-propyl]-1-methyl-2-pyridone, as a white solid, which was recrystallized from isopropyl acetate to yield a white solid, 143°-146° C.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=3)[N:9]=2)[N:4]([Si](C(C)C)(C(C)C)C(C)C)[CH:3]=1.[C:33]([O:37][C:38]([N:40]1[CH2:44][CH2:43][CH2:42][C:41]1([CH:46]=[O:47])[CH3:45])=[O:39])([CH3:36])([CH3:35])[CH3:34]>>[C:33]([O:37][C:38]([N:40]1[CH2:44][CH2:43][CH2:42][C:41]1([CH:46]([OH:47])[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=3)[N:9]=2)[NH:4][CH:3]=1)[CH3:45])=[O:39])([CH3:36])([CH3:35])[CH3:34]
Reactant: CC(C)(C)OC(=O)N1CCCC1(C)C=O
Reactant: COc1cc(-c2cnc3c(n2)c(I)cn3[Si](C(C)C)(C(C)C)C(C)C)cc(OC)c1OC
Product: COc1cc(-c2cnc3[nH]cc(C(O)C4(C)CCCN4C(=O)OC(C)(C)C)c3n2)cc(OC)c1OC

Procedure:
2-{Hydroxy-[2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-methyl}-2-methyl-pyrrolidine-1-carboxylic acid tert-butyl ester was prepared starting from 7-iodo-5-triisopropylsilanyl-2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazine and 2-formyl-2-methyl-pyrrolidine-1-carboxylic acid tert-butyl ester (J. Org. Chem. 72 (15), 5608-5617, 2007) following the general procedures described in these Examples.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.Br.[NH2:16][CH2:17][CH2:18]Br.C(N(CC)CC)C.[CH3:27][O:28][C:29]1[C:37]([O:38][CH3:39])=[CH:36][CH:35]=[CH:34][C:30]=1[C:31](Cl)=[O:32]>C(OCC)(=O)C.C(O)CCC>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:18][CH2:17][NH:16][C:31](=[O:32])[C:30]2[CH:34]=[CH:35][CH:36]=[C:37]([O:38][CH3:39])[C:29]=2[O:28][CH3:27])[CH2:11][CH2:10]1
Reactant: COc1ccccc1N1CCNCC1
Reactant: NCCBr
Reactant: COc1cccc(C(=O)Cl)c1OC
Agent: Br
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: COc1ccccc1N1CCN(CCNC(=O)c2cccc(OC)c2OC)CC1
Reaction time: 0.5 h
Yield: 49.8 %

Procedure:
To 1.92 g (0.01 mol) of 1-(2-methoxyphenyl)piperazine, 2,05 g (0.01 mol) of 2-aminoethylbromide hydrobromide, 2.5 g of triethylamine and 20 ml of n-butanol were added, and the mixture was refluxed for 6 hours. After the reaction, the mixture was concentrated under vacuum, and to the resulting residue, 2.5 g of anhydrous sodium carbonate, 20 ml of water and 20 ml of ethyl acetate were added. Under agitation with cooling on ice, a solution of 2.2 g (0.011 mol) of 2,3-dimethoxybenzoyl chloride in a small amount of ethyl acetate was added dropwise to the mixture. Thereafter, the mixture was stirred for 30 minutes under cooling with ice and extracted with ethyl acetate by agitation for 30 minutes at room temperature. The separated organic layer was washed with water, and 1N HCl was added until the pH became 3.0. The aqueous layer was separated, neutralized with sodium hydroxide and extracted with ethyl acetate. The resulting organic layer was washed with water, dried with Glauber's salt and concentrated under vacuum. The residue was subjected to column chromatography on silica gel (solvent: chloroform/methanol=100:1) to provide 1.99 g (yield: 50%) of 1-(2-methoxyphenyl)-4[2-(2,3-dimethoxybenzoyl)aminoethyl]piperazine. Recrystallization from isopropanol gave a colorless acicular crystal having a melting point of 133°-134° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:8]2[C:9]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:10]=3[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:12][CH2:13][C:7]2=[N:6][N:5]=1.[CH:25](=O)[CH3:26].C([BH3-])#N.[Na+].[CH2:32](N)[CH2:33]N>C(#N)C.C(O)(=O)C>[CH2:32]([N:1]([CH2:25][CH3:26])[CH2:2][CH2:3][C:4]1[N:8]2[C:9]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:10]=3[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:12][CH2:13][C:7]2=[N:6][N:5]=1)[CH3:33]
Reactant: CC=O
Reactant: NCCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Reactant: NCCN
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: CCN(CC)CCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2

Procedure:
In the manner given in Example 22, a mixture of 1-(2-aminoethyl)-8-chloro-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine, acetaldehyde and acetic acid in acetonitrile is treated with sodium cyanoborohydride and the resulting boron complex is warmed with aqueous ethylenediamine to give 1-[2-(diethylamino)ethyl]-8-chloro-6-phenyl-4H-s-triazolo-[4,3-a][1,4]benzodiazepine.