Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[O:15][C:14]([NH:16][CH:17]([CH3:19])[CH3:18])=[N:13][N:12]=3)[CH:9]=2)[N:4]([S:20]([C:23]2[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH:3]=1.[Cl:30][C:31]1[N:36]=[C:35]([Sn](CCCC)(CCCC)CCCC)[CH:34]=[CH:33][N:32]=1>CN(C=O)C.C(Cl)Cl.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.[Cu]I>[Cl:30][C:31]1[N:36]=[C:35]([C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:11]4[O:15][C:14]([NH:16][CH:17]([CH3:18])[CH3:19])=[N:13][N:12]=4)[CH:9]=3)[N:4]([S:20]([C:23]3[CH:24]=[CH:25][C:26]([CH3:27])=[CH:28][CH:29]=3)(=[O:22])=[O:21])[CH:3]=2)[CH:34]=[CH:33][N:32]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4nnc(NC(C)C)o4)ccc32)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnc(Cl)n1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ccnc(Cl)n3)c3cc(-c4nnc(NC(C)C)o4)ccc32)cc1
Temperature: 100 °C
Yield: 69 %

Procedure:
A glass microwave reaction vessel was charged with 5-(3-iodo-1-tosyl-1H-indol-5-yl)-N-isopropyl-1,3,4-oxadiazol-2-amine (1.00 g, 1.914 mmol) and 2-chloro-4-(tributylstannyl)pyrimidine (0.966 g, 2.393 mmol) in DMF (5 mL) followed by tetrakis(triphenylphosphine)palladium (0.111 g, 0.096 mmol) and CuI (0.016 mL, 0.479 mmol). The reaction mixture was stirred and heated in an Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 100° C. for 1 h. The mixture was diluted with DCM and washed with water (3×50 mL) and brine. The organic layer was dried, filtered and concentrated. The residue was purified with silica gel chromatography (eluting with 5-40% EtOAc in Hexanes) to give 5-(3-(2-chloropyrimidin-4-yl)-1-tosyl-1H-indol-5-yl)-N-isopropyl-1,3,4-oxadiazol-2-amine (672 mg, 1.320 mmol, 69.0% yield) as a brown solid. MS (ESI, pos. ion) m/z: 509.0 (M+1).
Reaction SMILES: [OH:1][C@@H:2]1[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][C@H:3]1[N:10]1[CH:18]=[N:17][C:16]2[C:11]1=[N:12][C:13]([C:34](OC)=[O:35])=[N:14][C:15]=2[NH:19][CH2:20][CH:21]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[CH:38]([CH:41]1[CH2:46][CH2:45][N:44]([CH2:47][CH2:48][NH2:49])[CH2:43][CH2:42]1)([CH3:40])[CH3:39]>C(OCC)C>[OH:1][C@@H:2]1[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][C@H:3]1[N:10]1[CH:18]=[N:17][C:16]2[C:11]1=[N:12][C:13]([C:34]([NH:49][CH2:48][CH2:47][N:44]1[CH2:45][CH2:46][CH:41]([CH:38]([CH3:40])[CH3:39])[CH2:42][CH2:43]1)=[O:35])=[N:14][C:15]=2[NH:19][CH2:20][CH:21]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COC(=O)c1nc(NCC(c2ccccc2)c2ccccc2)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Reactant: CC(C)C1CCN(CCN)CC1
Solvent: CCOCC
Product: CC(C)C1CCN(CCNC(=O)c2nc(NCC(c3ccccc3)c3ccccc3)c3ncn([C@@H]4O[C@H](CO)[C@@H](O)[C@H]4O)c3n2)CC1
Temperature: 120 °C
Yield: 50.9 %

Procedure:
A mixture of methyl 9-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)-tetrahydro-2-furanyl]-6-[(2,2-diphenylethyl)amino]-9H-purine-2-carboxylate (Preparation 18) (92 mg, 0.18 mmol) and 2-(4-isopropyl-1-piperidinyl)ethylamine (Preparation 20) (100 mg, 0.6 mmol) was heated at 120° C. under a nitrogen atmosphere for 75 minutes. The reaction mixture was allowed to cool to room temperature and diethyl ether (2 ml) added to precipitate a crude product. The solvent was decanted off the gum which was then triturated with ethyl acetate (2 ml). The resulting white solid was filtered off and dried to give the title compound (59 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:17][CH3:18])=[C:6]([CH:16]=1)[CH2:7][O:8][Si](C(C)(C)C)(C)C.C([Li])CCC.[CH3:24][S:25]SC.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH3:18][O:17][C:5]1[CH:4]=[CH:3][C:2]([S:25][CH3:24])=[CH:16][C:6]=1[CH2:7][OH:8]
Reactant: COc1ccc(Br)cc1CO[Si](C)(C)C(C)(C)C
Reactant: CSSC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(SC)cc1CO
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 76 %

Procedure:
To a solution of Example 170A (2.91 g, 8.75 mmol) in 20 mL of tetrahydrofuran at −78° C. was added 1.6 M n-butyllithium in hexanes (7.1 mL, 11.4 mmol). The reaction was stirred at −78° C. for 10 min, then 1.5 mL of dimethyldisulfide was added. The reaction was warmed to ambient temperature and stirred for 2 h, then concentrated in vacuo. The residue was taken up in 50 mL of diethyl ether, then extracted with water (2×15 mL), 2 M NaOH(aq.) (1×15 mL), and brine (1×15 mL), dried over MgSO4, filtered, and concentrated in vacuo to an oil. This was taken up in 15 mL of tetrahydrofuran and treated with 2.0 g (ca. 7 mmol) of tetrabutylammonium fluoride hydrate. The reaction was stirred at ambient temperature for 1 h, then concentrated in vacuo. The residue was taken up in 30 mL of diethyl ether, then extracted with water (2×10 mL), 2M NaOH(aq.) (1×10 mL), and brine (1×10 mL), dried over MgSO4, filtered, and concentrated in vacuo to an oil. The product was purified via silica gel chromatography, eluting with a 20-40% ethyl acetate in hexanes gradient to give 1.23 g (76%) of the alcohol. The product was about 90% pure by 1H NMR analysis.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:19].Cl.[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][C:28](O)=[O:29])[CH:22]=1>>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3](=[O:19])[N:2]([NH:1][C:28](=[O:29])[CH2:27][C:23]3[CH:22]=[N:21][CH:26]=[CH:25][CH:24]=3)[N:11]=2)=[CH:13][CH:14]=1
Reactant: Nn1nc(-c2ccc(Cl)cc2)c2ccccc2c1=O
Reactant: O=C(O)Cc1cccnc1
Agent: Cl
Product: O=C(Cc1cccnc1)Nn1nc(-c2ccc(Cl)cc2)c2ccccc2c1=O

Procedure:
The product of Example 86A and 2-(pyridin-3-yl)acetic acid hydrochloride were treated using a method similar to that described in Example 57 to give the title compound. 1H NMR (500 MHz, DMSO-d6/Deuterium Oxide) δ ppm 8.83-8.84 (bs, 1H), 8.75 (d, J=5.5 Hz, 1H), 8.36-8.50 (m, 2H), 7.96-8.02 (m, 2H), 7.92 (dd, J=8.0, 5.5 Hz, 1H), 7.73-7.75 (m, 1H), 7.59-7.70 (m, 4H), 4.00 (s, 2H); MS (APCI+) M/Z 391 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:14])[CH2:5][C:4](=[O:15])[CH:3]=1.CO[CH:18](OC)[CH2:19][C:20](=O)[CH3:21].[OH-].[K+]>C(O)C.C1(C)C=CC=CC=1>[Cl:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[CH:6]1[CH2:7][C:2]2[N:1]=[CH:18][CH:19]=[C:20]([CH3:21])[C:3]=2[C:4](=[O:15])[CH2:5]1
Reactant: NC1=CC(=O)CC(c2ccccc2Cl)C1
Reactant: COC(CC(C)=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cc1ccnc2c1C(=O)CC(c1ccccc1Cl)C2
Yield: 75.5 %

Procedure:
A solution of 1-amino-5-(2-chlorophenyl)cyclohexen-3-one (2.7 g) in ethanol (50 ml) and toluene (150 m) was combined with acetyl acetoaldehyde dimethyl acetal (4.0 g) and 85% potassium hydroxide (0.67 g), and the mixture was heated under reflux. 85% Potassium hydroxide (0.14 g) was added three times at an interval of 30 minutes, and then heated under reflux further for 1 hour. The solvent was distilled off under reduced pressure, and the residue was combined with ethyl acetate, washed successively with water and saturated brine, and dried over magnesium sulfate. After concentrating under reduced pressure, the residue was subjected to a column chromatography on a silica gel (EtOAc-hexane) to obtain 7-(2-chlorophenyl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (2.5 g) as a crystal. Melting point and NMR data were in agreement with those of the compound obtained in Reference Example 2.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([O-:3])=[O:2].C([O-])([O-])=O.[K+].[K+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C=O)C.O>[CH2:17]([O:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=[N+]([O-])c1ccccc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.1 %

Procedure:
To a stirred solution of 2-nitrophenol (10.0 g, 72.0 mmol) and K2CO3 (9.96 g, 72.0 mmol) in DMF (150 mL) was added dropwise benzyl bromide (9.40 mL, 79.2 mmol) at 0° C. After being stirred at room temperature for 3 hr, the reaction mixture was diluted with water, which was extracted with Et2O. The extracts were washed with brine, dried over Na2SO4, and concentrated to dryness. Chromatography of the residue with hexane-EtOAc (2:1, v/v) as eluent gave 2-benzyloxy nitrobenzene (14.7 g, 89%) as a yellow oil. 1H-NMR (CDCl3) δ 5.24 (s, 2H), 7.04 (t, J=7.8 Hz, 1H), 7.12 (d, J=7.8 Hz, 1H), 7.31–7.50 (m, 5H), 7.51 (d, J=1.5 Hz, 1H), 7.86 (dd, J=7.8, 1.5 Hz, 1H).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[O:25]1[C:30]2([CH2:35][CH2:34][N:33]([CH2:36][C:37]3[CH:38]=[C:39]([CH2:44][CH2:45][OH:46])[CH:40]=[CH:41][C:42]=3[F:43])[CH2:32][CH2:31]2)[CH2:29][NH:28][CH2:27][CH2:26]1.[CH:47]([C:50]1[S:51][CH:52]=[C:53]([C:55](O)=[O:56])[N:54]=1)([CH3:49])[CH3:48].C(N(CC)CC)C>CN(C=O)C>[F:43][C:42]1[CH:41]=[CH:40][C:39]([CH2:44][CH2:45][OH:46])=[CH:38][C:37]=1[CH2:36][N:33]1[CH2:34][CH2:35][C:30]2([O:25][CH2:26][CH2:27][N:28]([C:55]([C:53]3[N:54]=[C:50]([CH:47]([CH3:49])[CH3:48])[S:51][CH:52]=3)=[O:56])[CH2:29]2)[CH2:31][CH2:32]1
Reactant: CC(C)c1nc(C(=O)O)cs1
Reactant: OCCc1ccc(F)c(CN2CCC3(CC2)CNCCO3)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)c1nc(C(=O)N2CCOC3(CCN(Cc4cc(CCO)ccc4F)CC3)C2)cs1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
HATU (1.1 g) was added in one portion to a cooled solution of 2-(3-(1-oxa-4,9-diazaspiro[5.5]undecan-9-ylmethyl)-4-fluorophenyl)ethanol [Example 44, step c] (0.7 g) and 2-isopropylthiazole-4-carboxylic acid (0.39 g) and triethylamine (0.95 mL) in DMF (15 mL). The reaction mixture was stirred at 20° C. for 1 hour and then partitioned between ethyl acetate and brine. The organic layer was washed with brine (×2), dried, filtered and the solvent removed under reduced pressure. The crude product was purified by flash silica chromatography, using 3% methanol in ethyl acetate containing 1% triethylamine as solvent. Fractions containing the product were evaporated to dryness to afford the subtitled compound. Yield 0.61 g.
Reaction SMILES: C[O:2][C:3](=[O:13])[C@H:4]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[NH2:5].[CH3:14][O:15][CH2:16][CH2:17][C:18]1([C:23](O)=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19]1>>[CH3:14][O:15][CH2:16][CH2:17][C:18]1([C:23]([NH:5][C@H:4]([C:3]([OH:2])=[O:13])[CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: COCCC1(C(=O)O)CCCC1
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Product: COCCC1(C(=O)N[C@@H](Cc2ccccc2)C(=O)O)CCCC1

Procedure:
4-(1,3-dimethyl-2,4-dioxo-5-pyrimidinyl)]-N-[[1-(2-methoxyethyl)cyclopentyl]carbonyl]-L-phenylalanine was prepared from 4-(1,3-dimethyl-2,4-dioxo-5-pyrimidinyl)]-L-phenylalanine methyl ester and 1-(2-methoxyethyl)cyclopentane carboxylic acid (see WO 9910312) using the general procedures described in example 2. EI-HRMS m/e calcd for C24H31N3O5 (M+H) 458.2292, found 458.2279.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C@:15]3([CH2:20][CH2:19][O:18][C:17]([NH:21]C(=O)C4C=CC=CC=4)=[N:16]3)[C:14]3[C:9](=[CH:10][CH:11]=[C:12](I)[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1.[CH3:31][O:32][C:33]1[N:34]=[CH:35][C:36]([C:39]([NH2:41])=[O:40])=[N:37][CH:38]=1.N>C1COCC1.CO>[NH2:21][C:17]1[O:18][CH2:19][CH2:20][C@:15]2([C:4]3[C:5](=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=3)[O:8][C:9]3[C:14]2=[CH:13][C:12]([NH:41][C:39]([C:36]2[CH:35]=[N:34][C:33]([O:32][CH3:31])=[CH:38][N:37]=2)=[O:40])=[CH:11][CH:10]=3)[N:16]=1
Reactant: O=C(NC1=N[C@@]2(CCO1)c1cc(I)ccc1Oc1ncc(Br)cc12)c1ccccc1
Reactant: COc1cnc(C(N)=O)cn1
Agent: N
Solvent: CO
Solvent: C1CCOC1
Product: COc1cnc(C(=O)Nc2ccc3c(c2)[C@@]2(CCOC(N)=N2)c2cc(Br)cnc2O3)cn1
Reaction time: 5 h

Procedure:
The title compound was synthesized analogous to step 1 (Method D) described in example 34, but using (S)—N-(3-bromo-7-iodo-5′,6′-dihydrospiro[chromeno[2,3-b]pyridine-5,4′-[1,3]oxazin]-2′-yl)benzamide (88 mg, 0.153 mmol, Intermediate 24B) and 5-methoxypyrazine-2-carboxamide (28.1 mg, 0.183 mmol). The residue from step 1 was dissolved in THF (1 mL) and treated with ammonia (2.0 M solution in methanol; 1.145 mL, 2.291 mmol) at 50° C. After 12 hours another portion of ammonia, (2.0 M solution in methanol; 1.145 mL, 2.291 mmol) was added and the reaction mixture was allowed to stir for additional 5 hours The solvent was removed under reduced pressure and the residue was purified by preparative reversed-phase HPLC using a Phenomenex Gemini column, 10 micron, C18, 110 Å, 100×50 mm, 0.1% TFA in CH3CNH2O, gradient 10% to 100% over 20 min. The combined fractions were concentrated. The residue was dissolved in MeOH and loaded onto a Varian Bond Elut SCX column. The product was eluted with a 2M solution of NH3 in MeOH. 10 mg of (S)—N-(2′-amino-3-bromo-5′,6′-dihydrospiro[chromeno[2,3-b]pyridine-5,4′-[1,3]oxazin]-7-yl)-5-methoxypyrazine-2-10 carboxamide were obtained as an off-white solid. MS m/z=497.1 [M]+. Calculated for C21H17BrN6O4: 497.30. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.82-1.92 (m, 1H) 1.94-2.04 (m, 1H) 4.08 (s, 3H) 4.11-4.18 (m, 1H) 4.20-4.30 (m, 1H) 7.31 (d, J=9.21 Hz, 1H) 7.69-7.77 (m, 2H) 7.94 (d, J=2.34 Hz, 1H) 8.18 (d, J=1.32 Hz, 1H) 8.32 (d, J=2.48 Hz, 1H) 9.04 (d, J=1.32 Hz, 1H) 9.55 (s, 1H).
Reaction SMILES: Cl[CH:2]1[CH2:7][NH:6][CH2:5][CH2:4][NH:3]1.[CH3:8][O:9][CH:10]([O:13][CH3:14])[CH2:11][NH2:12]>C(N(CC)CC)C>[CH3:8][O:9][CH:10]([O:13][CH3:14])[CH2:11][NH:12][C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1
Reactant: ClC1CNCCN1
Reactant: COC(CN)OC
Solvent: CCN(CC)CC
Product: COC(CNc1cnccn1)OC
Reaction time: 48 h
Yield: 6.6 %

Procedure:
To a solution of 2-chloropiperazine (1.0 g in 5 mL dry toluene) was added 2,2-dimethoxyethylamine (1.1 g) followed by 1.2 mL triethylamine and the mixture heated to reflux on an oil bath. After 48 hours, the reaction mixture was applied to a flash chromatography column (silica gel) for purification (ethyl acetate:hexane, 7:3; then 100:0) to give the title compound (101 mg).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][OH:14].[CH3:15][S:16](Cl)(=[O:18])=[O:17].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[S:16]([O:14][CH2:13][CH2:12][O:11][CH2:10][CH2:9][O:8][CH2:7][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])(=[O:18])(=[O:17])[CH3:15]
Reactant: CS(=O)(=O)Cl
Reactant: COCCOCCOCCOCCO
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCCOCCOCCOCCOS(C)(=O)=O
Reaction time: 0.33 h

Procedure:
A solution of 8.16 g (0.040M) of tetraethylene glycol monomethyl ether and 5.0 g (0.044M) of methanesulfonyl chloride in 100 ml of methylene chloride was stirred at 0° C. while 5.7 g (0.044M) of diisopropylethylamine was added dropwise so the temperature remained below 5° C. Stirring was continued at 0° C. for 20 minutes and the temperature was allowed to rise to room temperature over 2 hours. The solution was washed twice with an equal volume of water. It was then dried and concentrated to an oil, yielding 11 g (96%).
Reaction SMILES: [C:1]([N:3]=[C:4]([C:7]1[CH:8]=[N:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2)OC)#[N:2].[N+]([O-])(O)=O.[O:21]([CH2:25][CH2:26][NH2:27])[N+:22]([O-:24])=[O:23].C[O-].[Na+]>CO>[C:1]([NH:3][C:4]([C:7]1[CH:8]=[N:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:27][CH2:26][CH2:25][O:21][N+:22]([O-:24])=[O:23])#[N:2]
Reactant: COC(=NC#N)c1cnc2ccccc2c1
Reactant: NCCO[N+](=O)[O-]
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O=[N+]([O-])O
Product: N#CNC(=NCCO[N+](=O)[O-])c1cnc2ccccc2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 53.3 %

Procedure:
Methyl N-cyano-3-quinolinecarboximidate (0.32 g, 1.5 mmol) was dissolved in methanol (3 ml), 2-nitroxyethylamine nitrate (0.42 g, 2.5 mmol) and sodium methoxide (0.12 g, 2.2 mmol) were added. The mixture was stirred at room temperature for 18 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue thus obtained was subjected to chromatography on a silica gel column (WAKO GEL C-200, 30 g) eluting with dichloromethane-methanol (50:1). The eluted fractions were concentrated under reduced pressure and crystallized from dichloromethane-diethyl ether to give the title compound (0.23 g, 0.80 mmol, yield: 54%) as colorless crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH3:15])=[C:9]([N:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]3=[O:22])[C:8]=2[CH:23]=1)([O-:3])=[O:2].[Br:24]N1C(=O)CCC1=O.ClCCl>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH2:15][Br:24])=[C:9]([N:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]3=[O:22])[C:8]=2[CH:23]=1)([O-:3])=[O:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC1=C(n2ccccc2=O)c2cc([N+](=O)[O-])ccc2OC1(C)C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: CC1(C)Oc2ccc([N+](=O)[O-])cc2C(n2ccccc2=O)=C1CBr
Temperature: 60 °C
Yield: 73.2 %

Procedure:
A suspension of 6-nitro-2,2,3-trimethyl-4-(2-oxo-1,2-dihydropyridin-1-yl)-2H-1-benzopyran (1.62 g, 0.0052 mol) in carbon tetrachloride (10 ml) containing benzoyl peroxide (20 mg) was heated to 60° C. N-bromosuccinimide (0.92 g, 0.0052 mol) was added and the mixture heated at reflux for seventeen hours. The cooled solution was treated with dichloromethane and aqueous ferrous sulfate solution, the organic phase was separated and evaporated under reduced pressure. The residue was chromatographed on silica gel, eluting with dichloromethane/acetone (92.5/7.5). The product was washed with diethyl ether/pentane to give 1.49 g of 6-nitro-2,2-dimethyl-3-bromomethyl-4-(2-oxo-1,2-dihydropyridin-1-yl)-2H-1-benzopyran, m.p. 221° C.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH3:10].[F-].[K+].[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>CN(C)C=O>[CH3:10][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)[C:6]#[N:7]
Reactant: Cc1cc(C#N)ccc1Br
Reactant: C1COCCN1
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(C#N)ccc1N1CCOCC1
Temperature: 145 °C
Yield: 11.5 %

Procedure:
To a solution of 4-bromo-3-methylbenzonitrile (11 g, 56 mmol) and potassium fluoride (3.3 g, 56 mmol) in anhydrous N,N-dimethylformamide (150 mL) was added morpholine (15 g, 170 mmol) and the reaction was heated at 145° C. for 4 days. The solvent was evaporated in to vacuo and the residue was partitioned between diethyl ether and water. The phases was separated and the organic phase was dried (Na2SO4), filtered and evaporated in vacuo. Purification on a silica gel column using toluene followed by chloroform as eluents gave 1.3 g (11% yield) of the title compound as white crystals: mp 85-86° C.; EIMS (70 eV) m/z (relative intensity) 202 (71, M+).
Reaction SMILES: [C:1]1([CH2:11][N:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[NH:14][C:13]2=[O:21])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:25][C:26]1[CH:27]=[C:28]([CH:33]=[CH:34][CH:35]=1)[C:29]([O:31][CH3:32])=[O:30]>CN(C=O)C.C(OCC)(=O)C>[CH3:32][O:31][C:29](=[O:30])[C:28]1[CH:33]=[CH:34][CH:35]=[C:26]([CH2:25][N:14]2[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N:12]([CH2:11][C:1]3[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH:4]=[CH:3][CH:2]=3)[C:13]2=[O:21])[CH:27]=1
Reactant: O=c1[nH]c2ccccc2n1Cc1cccc2ccccc12
Reactant: COC(=O)c1cccc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(Cn2c(=O)n(Cc3cccc4ccccc34)c3ccccc32)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 89.6 %

Procedure:
To a solution of 1-Naphthalen-1-ylmethyl-1,3-dihydro-benzimidazol-2-one (0.1 g, 0.37 mmol) in DMF (3 mL) was added 60% NaH (22 mg, 0.55 mmol). The reaction mixture was stirred at room temperature for 10 min and then Methyl 3-(bromomethyl)benzoate (0.1 g, 0.44 mmol) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 2 h. When the reaction was complete, the mixture was diluted with ethyl acetate and washed with water (×4). The organic phase was then dried over Na2SO4 and concentrated. The resulting residue was purified by silica gel prep TLC using 100% CH2Cl2 as an elunet to afford 0.14 g of the desired product as a white foam. LCMS (ESMS): m/z 423.84 (M+H+).
Reaction SMILES: CO[C:3](=[O:19])[CH2:4][C@:5]([NH2:18])([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=1)[CH2:6][CH2:7][CH3:8].[CH3:20][NH:21][C:22]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=S>>[C:27]([O:26][C:25](=[O:31])[NH:24][C:22]1[N:21]([CH3:20])[C:3](=[O:19])[CH2:4][C@:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)([CH2:6][CH2:7][CH3:8])[N:18]=1)([CH3:30])([CH3:29])[CH3:28]
Reactant: CNC(=S)NC(=O)OC(C)(C)C
Reactant: CCC[C@](N)(CC(=O)OC)c1cccc([N+](=O)[O-])c1
Product: CCC[C@@]1(c2cccc([N+](=O)[O-])c2)CC(=O)N(C)C(NC(=O)OC(C)(C)C)=N1

Procedure:
Starting from (S)-3-amino-3-(3-nitro-phenyl)-hexanoic acid methyl ester and tert-butyl [(methylamino)carbonothioyl]carbamate, the product [(S)-1-methyl-4-(3-nitro-phenyl)-6-oxo-4-propyl-1,4,5,6-tetrahydro-pyrimidin-2-yl]-carbamic acid tert-butyl ester was obtained as an amorphous solid. MS (ESI): m/z=389.3 [M−H]−.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4[CH:19]=[CH:20][NH:21][C:15]=4[CH:14]3[CH3:22])=[O:12])[CH:10]=2)[CH:7]=1.CC1[O:25]C2CCNC(C)C=2N=1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4[O:25][C:20]([CH3:19])=[N:21][C:15]=4[CH:14]3[CH3:22])=[O:12])[CH:10]=2)[CH:7]=1
Reactant: Cc1nc2c(o1)CCNC2C
Reactant: CC1c2[nH]ccc2CCN1C(=O)c1cc2ncc(Br)cn2n1
Product: Cc1nc2c(o1)CCN(C(=O)c1cc3ncc(Br)cn3n1)C2C

Procedure:
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(7-methyl-1,4,5,7-tetrahydro-pyrrolo[2,3-c]pyridin-6-yl)-methanone is reacted with 2,4-dimethyl-4,5,6,7-tetrahydro-oxazolo[4,5-c]pyridine to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH2:11]O)[CH:5]=[C:6]([Cl:8])[CH:7]=1.S(Cl)(C1C=CC(C)=CC=1)(=O)=O.[N-:24]=[N+:25]=[N-:26].[Na+]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH2:11][N:24]=[N+:25]=[N-:26])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: [N-]=[N+]=[N-]
Reactant: OCCCc1cc(Cl)cc(Cl)c1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Product: [N-]=[N+]=NCCCc1cc(Cl)cc(Cl)c1
Yield: 97.8 %

Procedure:
3-(3,5-Dichlorophenyl)propanol (0.052 mol), tosyl chloride (0.104 mol) and sodium azide (0.104 mol) were reacted substantially as described in Example 7E to obtain 11.7 g (98%) of an oily product.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:10](=[O:11])[O:9][CH2:8]2)([O:3]C)=[O:2].C[O-].[Na+].[F:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH:21]=O.Cl>CO.O>[F:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21][CH2:8][C:7]1[CH:6]=[C:5]([C:1]([OH:3])=[O:2])[CH:14]=[CH:13][C:12]=1[C:10]([OH:9])=[O:11]
Reactant: O=Cc1ccccc1F
Reactant: COC(=O)c1ccc2c(c1)COC2=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(C(=O)O)c(CCc2ccccc2F)c1

Procedure:
8.5 G. of 5-carbomethoxyphthalide and 2.43 g. of sodium methoxide were refluxed for 15 minutes in 250 ml of methanol, and then 5.55 g. of o-fluorobenzaldehyde was added. The mixture was refluxed for 20 hours and then poured into water and acidified with dilute hydrochloric acid. The solution was extracted with ethyl acetate and the extract washed, dried and evaporated. The residue was refluxed for 48 hours in 75 ml of acetic acid and 45 ml of 57% aqueous hydriodic acid containing 7.5 g. of red phosphorus. The mixture was poured into water and filtered. The residue was dissolved in ethanol and the solution filtered and evaporated to afford 2-(o-fluorophenethyl)benzene-1,4-dicarboxylic acid which was cyclized according to the method described in Example I, A to obtain 2-carboxy-9-fluoro-10,11-dihydro-5-oxo-5H-dibenzo[a,d]cycloheptene having a m.p. of 248.5° to 249.5° C.