Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.CO.C(OC([N:11]([C:39]1[C:48]([N+:49]([O-:51])=[O:50])=[CH:47][CH:46]=[CH:45][C:40]=1[C:41]([O:43][CH3:44])=[O:42])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25]2[N:29]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=3)[N:28]=[N:27][N:26]=2)=[CH:15][CH:14]=1)=O)(C)(C)C.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:38][O:37][C:34]1[CH:35]=[CH:36][C:31]([CH2:30][N:29]2[C:25]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[C:16]3[CH:15]=[CH:14][C:13]([CH2:12][NH:11][C:39]4[C:48]([N+:49]([O-:51])=[O:50])=[CH:47][CH:46]=[CH:45][C:40]=4[C:41]([O:43][CH3:44])=[O:42])=[CH:18][CH:17]=3)=[N:26][N:27]=[N:28]2)=[CH:32][CH:33]=1
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1N(Cc1ccc(-c2ccccc2-c2nnnn2Cc2ccc(OC)cc2)cc1)C(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc([N+](=O)[O-])c1NCc1ccc(-c2ccccc2-c2nnnn2Cc2ccc(OC)cc2)cc1
Temperature: 3 °C
Reaction time: 2 h
Yield: 101 %

Procedure:
To hydrogen chloride-methanol (30%; 26.9 g, net 8.08 g, 222 mmol) was added methyl 2-(N-tert-butoxycarbonyl-N-{(2′-[1-(p-methoxybenzyl)-1H-tetrazol-5-yl]biphenyl-4-yl)methyl}amino)-3-nitrobenzoate (compound 20a, 5.00 g, 7.68 mmol) over 13 min by four portions at 4-5° C. The mixture was stirred at about 3° C. for 2 hr, and warmed to 9° C. over 1 hr. The reaction was monitored by TLC (eluent: toluene/ethyl acetate (2:1)). The reaction mixture was cooled to 3° C., and saturated aqueous sodium hydrogen carbonate solution (180 mL) was added dropwise thereto at 30° C. or lower. The mixture was extracted twice with ethyl acetate (450 mL, 250 mL), and the combined organic layers were washed with saturated brine (200 mL), dried over magnesium sulfate (10 g), and concentrated under reduced pressure at 40° C. or lower. To the concentrate was added chloroform, and the solvent was evaporated under reduced pressure in a bath at 40° C. to give methyl 2-[({2′-[1-(p-methoxybenzyl)-1H-tetrazol-5-yl]biphenyl-4-yl}methyl)amino]-3-nitrobenzoate (compound 21a, 4.27 g, 101%) as a yellowish brown amorphous solid.
Reaction SMILES: C([NH:4][C:5]1[N:10]=[C:9]([NH:11][C:12]2[CH:17]=[C:16]([NH:18][C:19]([C:21]3[CH:26]=[CH:25][N:24]=[C:23]([N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)[CH:22]=3)=[O:20])[CH:15]=[CH:14][C:13]=2[CH3:33])[CH:8]=[CH:7][N:6]=1)C=C.CS(O)(=O)=O>CC(N(C)C)=O.[Pd]>[NH2:4][C:5]1[N:10]=[C:9]([NH:11][C:12]2[CH:17]=[C:16]([NH:18][C:19]([C:21]3[CH:26]=[CH:25][N:24]=[C:23]([N:27]4[CH2:28][CH2:29][O:30][CH2:31][CH2:32]4)[CH:22]=3)=[O:20])[CH:15]=[CH:14][C:13]=2[CH3:33])[CH:8]=[CH:7][N:6]=1
Reactant: C=CCNc1nccc(Nc2cc(NC(=O)c3ccnc(N4CCOCC4)c3)ccc2C)n1
Agent: [Pd]
Agent: CS(=O)(=O)O
Solvent: CC(=O)N(C)C
Product: Cc1ccc(NC(=O)c2ccnc(N3CCOCC3)c2)cc1Nc1ccnc(N)n1
Temperature: 140 °C

Procedure:
A mixture of 2-allylamino-4-[2-methyl-5-(2-morpholinopyrid-4-ylcarbonylamino)anilino]pyrimidine (0.151 g), methanesulphonic acid (0.1 ml) and 30% palladium-on-carbon (0.034 g) in DMA (1 ml) was stirred and heated to 140° C. for 24 hours. The mixture was cooled to ambient temperature and filtered. A mixture of methylene chloride and isohexane was added to the filtrate. The resultant precipitate was isolated and purified by column chromatography on silica using a 89:10:1 mixture of methylene chloride, methanol and a saturated aqueous ammonium hydroxide solution as eluent. There was thus obtained the title compound as a solid (0.01 g); NMR Spectrum: (DMSOd6) 2.16 (s, 3H), 3.47 (m, 4H), 3.7 (m, 4H), 4.78 (br m, 4H), 5.98 (m, 1H), 7.01 (m, 1H), 7.16 (m, 2H), 7.39 (m, 1H), 7.65 (m, 1H), 7.72 (m, 1H), 8.17 (m, 1H); Mass Spectrum: M+H+ 406.
Reaction SMILES: C1(O)C=CC=CC=1.BrCCCCCCCCCCCO.[O:21]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][OH:39])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O(CCCCCCCCCCC(O)=O)C1C=CC=CC=1.Cl.Cl.[CH2:62]([O:69][C:70](=[O:78])[CH2:71][C@@H:72]([NH2:77])[CH2:73][N:74]([CH3:76])[CH3:75])[C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1>>[CH2:62]([O:69][C:70](=[O:78])[CH2:71][C@@H:72]([NH:77][C:38](=[O:39])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:73][N:74]([CH3:75])[CH3:76])[C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1
Reactant: CN(C)C[C@H](N)CC(=O)OCc1ccccc1
Reactant: OCCCCCCCCCCCOc1ccccc1
Agent: Cl
Agent: O=C(O)CCCCCCCCCCOc1ccccc1
Agent: OCCCCCCCCCCCBr
Solvent: Oc1ccccc1
Product: CN(C)C[C@@H](CC(=O)OCc1ccccc1)NC(=O)CCCCCCCCCCOc1ccccc1

Procedure:
The title compound, m/e=405.7 ([M−H]−), was produced in analogy with example 18, steps 1 to 4. Thus, phenol was alkylated in step 1 with 11-bromo-1-undecanol, leading to 11-phenoxy-undecan-1-ol, which was oxidized in step 2 to 11-phenoxy-undecanoic acid. This was coupled in step 3 with (R)-3-amino-4-dimethylamino-butyric acid benzyl ester dihydrochloride to produce (R)-4-dimethylamino-3-[11-phenoxy-undecanoylamino]-butyric acid benzyl ester, which was hydrogenated in step 4.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]3[C:20]([N:21]=[C:22]4[CH2:28][CH2:27]C[CH2:25][CH2:24][C:23]=24)=[CH:19][CH:18]=[N:17]3)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1N2N=CC=C2N=C2C=1CCCC2.C(OC1C=CC(B(O)O)=CC=1)C1C=CC=CC=1>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]3[N:17]=[CH:18][CH:19]=[C:20]3[N:21]=[C:22]3[C:23]=2[CH2:24][CH2:25][CH2:27][CH2:28]3)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(COc2ccc(-c3c4c(nc5ccnn35)CCCCC4)cc2)cc1
Agent: Clc1c2c(nc3ccnn13)CCCC2
Agent: OB(O)c1ccc(OCc2ccccc2)cc1
Product: c1ccc(COc2ccc(-c3c4c(nc5ccnn35)CCCC4)cc2)cc1

Procedure:
Using the method described for the preparation of 10-(4-benzyloxy-phenyl)-6,7,8,9-tetrahydro-5H-1,4,10a-triaza-cyclohepta[f]indene, the reaction of 9-chloro-5,6,7,8-tetrahydro-pyrazolo[5,1-b]quinazoline and 4-benzyloxyphenyl boronic acid provided the title compound.
Reaction SMILES: C([Si](C)(C)[O:6][C:7]1[CH:8]=[CH:9][C:10]2[N:19]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][N:30]4[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]4)=[CH:23][CH:22]=3)[C:18]3[C:17]4[CH:36]=[CH:37][CH:38]=[CH:39][C:16]=4[S:15][CH2:14][CH2:13][C:12]=3[C:11]=2[CH:40]=1)(C)(C)C>CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1COCC1>[N:30]1([CH2:29][CH2:28][O:27][C:24]2[CH:25]=[CH:26][C:21]([CH2:20][N:19]3[C:18]4[C:17]5[CH:36]=[CH:37][CH:38]=[CH:39][C:16]=5[S:15][CH2:14][CH2:13][C:12]=4[C:11]4[CH:40]=[C:7]([OH:6])[CH:8]=[CH:9][C:10]3=4)=[CH:22][CH:23]=2)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2c(c1)c1c(n2Cc2ccc(OCCN3CCCCC3)cc2)-c2ccccc2SCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Oc1ccc2c(c1)c1c(n2Cc2ccc(OCCN3CCCCC3)cc2)-c2ccccc2SCC1

Procedure:
9-(tert-Butyl-dimethyl-silanyloxy)-12-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-6,7-dihydro-12H-5-thia-12-aza-dibenzo[a,e]azulene (130 mg, 0.222 mmol) in 5 mL 1.0 N TBAF in THF solution was stirred for 30 min at room temperature. The reaction was worked up by CH2Cl2 extraction three times from water. The combined organic layer was dried and concentrated and purified by column using 4:1 CH2Cl2 and methanol solution to yield the title compound as a brown solid.
Reaction SMILES: [NH2:1][C:2]1([C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:13]=[C:14]4[C:19]([CH3:20])=[C:18]([CH3:21])[C:17]([C:22]([O:24]C)=O)=[N:16][N:15]4[C:26]=3[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3]1.CO.[NH3:35]>>[NH2:1][C:2]1([C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:13]=[C:14]4[C:19]([CH3:20])=[C:18]([CH3:21])[C:17]([C:22]([NH2:35])=[O:24])=[N:16][N:15]4[C:26]=3[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:8][CH:7]=2)[CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)c1nn2c(-c3ccccc3)c(-c3ccc(C4(N)CCC4)cc3)nc2c(C)c1C
Reactant: N
Solvent: CO
Product: Cc1c(C(N)=O)nn2c(-c3ccccc3)c(-c3ccc(C4(N)CCC4)cc3)nc2c1C
Temperature: 130 °C
Yield: 77 %

Procedure:
A solution of methyl 2-[4-(1-aminocyclobutyl)phenyl]-7,8-dimethyl-3-phenylimidazo[1,2-b]pyridazine-6-carboxylate [that was prepared in a manner analgous to that described for Example 51] (80 mg, ˜90% purity, 0.170 mmol, 1.0 eq) in 2.41 ml 7N ammonia in MeOH (˜100 eq of NH3) was heated for 2 hours at 130° C. by the use of a single mode microwave oven (Biotage). On cooling the volatile components were removed in vacuo. The crude mixture was purified via MPLC (Biotage Isolera; 11 g SNAP NH2 cartridge: hexane/EtOAc 1:1→EtOAc) to give 54 mg (77% yield) of the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[Li]CCCC.[CH3:14][S:15]SC>C1(C)C=CC=CC=1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([S:15][CH3:14])=[N:3][CH:4]=1
Reactant: Brc1ccc(Br)nc1
Reactant: CSSC
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Product: CSc1ccc(Br)cn1
Temperature: -78 °C
Reaction time: 2 h
Yield: 63.6 %

Procedure:
To a stirred solution of 2,5-dibromopyridine (5.00 g, 21.11 mmol) in anhydrous toluene (300 mL) at −78° C. under nitrogen was slowly added a solution of n-BuLi (10.13 mL, 25.33 mmol, 2.5M in hexanes). After 2 h at −78° C., methyl disulfide (2.47 mL, 27.44 mmol) was added. The reaction mixture was stirred for 1 h at −78° C. and was allowed to warm to room temperature, quenched with saturated NH4Cl to form a two-phase system. The organic layer was separated, washed with sat NH4C1, H2O and brine, dried over anhydrous MgSO4, filtered and concentrated. The residue was purified by flash chromatography on silica gel (AcOEt/hexane, 5/95) to afford the title compound 50 (2.74 g, 13.43 mmol, 64% yield) as a pale yellow oily liquid. 1H NMR (400 MHz, CDCl3) δ(ppm): 8.49 (dd, J=2.3, 0.6 Hz, 1H), 7.60 (dd, J=8.5, 2.4 Hz, 1H), 7.09 (dd, J=8.6, 0.8 Hz, 1H), 2.57 (s, 3H).
Reaction SMILES: [C:1](Cl)(=O)C.ClCC([NH:9][C:10]([CH3:23])([CH3:22])[CH2:11][C:12]1[CH:13]=[C:14]([CH2:18][C:19]([OH:21])=[O:20])[CH:15]=[CH:16][CH:17]=1)=O>CO>[CH3:1][O:21][C:19](=[O:20])[CH2:18][C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([CH2:11][C:10]([NH2:9])([CH3:23])[CH3:22])[CH:13]=1
Reactant: CC(=O)Cl
Reactant: CC(C)(Cc1cccc(CC(=O)O)c1)NC(=O)CCl
Solvent: CO
Product: COC(=O)Cc1cccc(CC(C)(C)N)c1
Yield: 87 %

Procedure:
Acetyl chloride (154.5 g, 1.97 mol) was added to a solution of {3-[2-(2-chloro-acetylamino)-2-methyl-propyl]-phenyl}-acetic acid (preparation 48), (20 g, 0.66 mol) in methanol (350 mL) and the mixture was heated under reflux for 18 hours. The reaction mixture was then concentrated in vacuo to afford the title compound as a brown oil in 87% yield, 154.5 g. 1H NMR (300 MHz, CDCl3) δ: 7.22 (1H, m), 7.18-7.05 (3H, m), 3.71 (3H, s), 3.58 (2H, s), 2.62 (2H, s), 1.12 (6H, s) ppm; GCMS m/z 206 [M−H]−.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[C:8]([O:11]C)[CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14]>ClCCl>[CH3:1][C:2]1[C:6]2[CH:7]=[C:8]([OH:11])[CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)c1oc2ccc(OC)cc2c1C
Solvent: ClCCl
Product: CCOC(=O)c1oc2ccc(O)cc2c1C

Procedure:
Ethyl 3-methyl-5-methoxybenzofuran carboxylate (8.53 mmol) was dissolved in dichloromethane (10 ml) and a 1.0 M solution of boron tribromide methyl sulphide complex in dichloromethane (25.59 mmol) was added. The mixture was heated at reflux over night. The solvent was evaporated under vacuo and the residue purified by flash chromatography to obtain ethyl 3-methyl-5-hydroxybenzofuran carboxylate as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1>CS(C)=O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[CH2:12][CH2:11]2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Reactant: Clc1ccccn1
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(N2CCN(c3ccccn3)CC2)cc1

Procedure:
From 1-(4-nitro-phenyl)-piperazine and 2-chloropyridine, by heating in DMSO to give 1-(4-nitro-phenyl)-4-pyridin-2-yl-piperazine then catalytic hydrogenation over Raney nickel in methanol.
Reaction SMILES: [CH2:1]([C:5]1[S:9][C:8]([C:10]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=3)[O:12][N:11]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[F:22][C@@H:23]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:24]O.N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH2:1]([C:5]1[S:9][C:8]([C:10]2[CH:14]=[C:13]([C:15]3[CH:16]=[CH:17][C:18]([O:21][CH2:24][C@@H:23]([F:22])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[CH:19][CH:20]=3)[O:12][N:11]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCCCCC[C@H](F)CO
Reactant: CCCCc1ccc(-c2cc(-c3ccc(O)cc3)on2)s1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCCCCC[C@H](F)COc1ccc(-c2cc(-c3ccc(CCCC)s3)no2)cc1

Procedure:
3-(5-Butylthiophen-2-yl)-5-{4-[(S)-2-fluorodecyloxy]-phenyl}-isoxazole is prepared similar to Example 6, but 3-(5-butylthiophen-2-yl)-5-(4-hydroxyphenyl)-isoxazole is etherified with (S)-2-fluoro-1-decanol by the method of Mitsunobu (diethyl azodicarboxylate/triphenylphosphine in tetrahydrofuran; Synthesis 1981, 1).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][S:7]([C:10]1[CH:15]=[CH:14][C:13](Br)=[CH:12][CH:11]=1)(=[O:9])=[O:8].[F:17][C:18]([F:29])([F:28])[C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1.C([O-])([O-])=O.[Na+].[Na+]>C(O)C.C1(C)C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([C:22]2[CH:23]=[CH:24][C:19]([C:18]([F:29])([F:28])[F:17])=[CH:20][CH:21]=2)=[CH:12][CH:11]=1)(=[O:9])=[O:8]
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: O=S(=O)(NCCCCO)c1ccc(Br)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: O=S(=O)(NCCCCO)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1

Procedure:
4-Bromophenyl-sulfonic acid-(4-hydroxybutyl)-amide (1 g) was dissolved in ethanol (8 mL) and toluene (8 mL). 4-Trifluoromethylphenyl boronic acid (1 g) was added, followed by 2 M Na2CO3 (8 mL). Tetrakis(triphenylphosphine) palladium (0.25 g) was added and the mixture heated to reflux under nitrogen for 3 hours with vigorous stirring. The organic solvents were evaporated and the residue dissolved in ethyl acetate (100 mL) and washed with water (100 mL) then saturated NaCl solution (100 mL). The organic phase was dried (Na2SO4), evaporated and the residue purified by column chromatography (ethyl acetate/petrol) to give the title compound as a white solid. δC (DMSO, 62.9 MHz): 25.9, 29.6, 42.6, 60.2, indistinct m, 140.4, 142.2 and 142.6. δH (DMSO, 250 MHz): 1.41 (4H, m), 2.77 (2H, m), 3.33 (2H, m), 4.39 (1H, t, NH), 7.83-7.94 (6 H, m) and 7.96 (2H, d, J 8.5).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]([OH:11])([C:9]#[CH:10])[CH3:8])[CH:3]=1.Br[C:13]1[CH:26]=[C:25]2[C:16]([O:17][CH2:18][CH2:19][N:20]3[C:24]2=[N:23][C:22]([C:27]([NH2:29])=[O:28])=[CH:21]3)=[CH:15][CH:14]=1>CS(C)=O.C(N(CC)CC)C.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>[OH:11][C@@:7]([C:4]1[CH:3]=[C:2]([CH3:1])[O:6][N:5]=1)([CH3:8])[C:9]#[C:10][C:13]1[CH:14]=[CH:15][C:16]2[O:17][CH2:18][CH2:19][N:20]3[C:24](=[N:23][C:22]([C:27]([NH2:29])=[O:28])=[CH:21]3)[C:25]=2[CH:26]=1
Reactant: C#CC(C)(O)c1cc(C)on1
Reactant: NC(=O)c1cn2c(n1)-c1cc(Br)ccc1OCC2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Cc1cc([C@@](C)(O)C#Cc2ccc3c(c2)-c2nc(C(N)=O)cn2CCO3)no1
Reaction time: 1 h

Procedure:
The title compound was prepared according to a procedure similar to that described in Procedure G Into a 8-mL sealed tube purged and maintained with an inert atmosphere of nitrogen, was placed 2-(5-methylisoxazol-3-yl)but-3-yn-2-ol (515 mg, 3.41 mmol, 3.50 equiv), 13-bromo-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca-1(14),2,4,10,12-pentaene-4-carboxamide (300 mg, 0.97 mmol, 1 equiv) and Pd(PPh3)2Cl2 (205 mg, 0.29 mmol, 0.3 equiv) in DMSO (2 mL) and triethylamine (2 mL). The final reaction mixture was irradiated with microwave radiation for 2 h at 70° C. The resulting mixture was washed with 1×100 mL of water and 2×100 mL of CH3CN. The solids were collected by filtration. The residue was further purified by Chiral-Prep-HPLC with the following conditions (2#-Gilson Gx 281(HPLC-09): Column, Chiralpak IA2*25 cm, 5 um Chiral-P(IA)004IA00CJ-MB003; Phase A:MTBE Phase B:EtOH (0.2% DEA)-HPLC (10.0% EtOH for 60 min, then down to 0%); Detector, uv 254/220 nm. This resulted in 34.2 mg (9%) of 9-[(S)-3-Hydroxy-3-(5-methyl-isoxazol-3-yl)-but-1-ynyl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carboxylic acid amide as a off-white solid LC-MS (ES, m/z): 379[M+H]+; 1H-NMR (400 MHz, DMSO-d6, ppm): δ 8.536 (s, 1H), 7.802 (s, 1H), 7.558 (br s, 1H), 7.340-7.300 (m, 1H), 7.143 (br s, 1H), 7.040 (d, 1H), 6.504 (s, 1H), 6.360 (s, 1H), 4.492 (s, 4H), 2.365 (s, 3H), 1.920 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4](=[N:6][OH:7])[NH2:5].[Cl:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH:15]=O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]1[NH:5][CH:15]([C:14]2[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=2[Cl:12])[O:7][N:6]=1
Reactant: NC(=NO)c1ccccc1Cl
Reactant: O=Cc1ccccc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Clc1ccccc1C1=NOC(c2ccccc2Cl)N1
Yield: 24 %

Procedure:
2-Chlorobenzamidoxime (3.4 g), 2-chlorobenzaldehyde (2.8 g), p-toluenesulphonic acid (1 g) and toluene (100 ml) were heated to reflux for 16 hours in Dean and Stark apparatus. The solution was then run down, and the residue was recrystallised from methanol to give 1.4 g of desired product, mp 75°-78° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7](OC2C=C3C(=CC=2)OC(C2C=CC=CC=2)CC3)=[N:8][CH:9]=1)([O-:3])=[O:2].[F:27][C:28]([F:48])([F:47])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[CH:35]1[CH2:44][CH:43]([OH:45])[C:42]2[C:37](=[CH:38][CH:39]=[C:40]([OH:46])[CH:41]=2)[O:36]1>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:46][C:40]2[CH:41]=[C:42]3[C:37](=[CH:38][CH:39]=2)[O:36][CH:35]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[C:28]([F:27])([F:47])[F:48])[CH2:44][CH:43]3[OH:45])=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: Oc1ccc2c(c1)C(O)CC(c1ccccc1C(F)(F)F)O2
Reactant: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Product: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)C(O)CC(c2ccccc2C(F)(F)F)O3)nc1

Procedure:
6-(5-Nitropyridin-2-yloxy)-2-(2-trifluoromethylphenyl)chroman-4-ol was prepared as described for 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example 1(b) starting from 350 mg of 2-(2-trifluoromethylphenyl)chroman-4,6-diol. 1H NMR (400 MHz, d6-DMSO) δ: 9.04 (d, 1H, J 2.8 Hz), 8.62 (dd, 1H, J 9.1, 2.8 Hz), 7.89 (m, 1H), 7.82-7.78 (m, 2H), 7.62 (m, 1H), 7.28 (d, 1H, J 2.7 Hz), 7.24 (d, 1H, 9.1 Hz), 7.04 (dd, 1H, J 8.7, 2.7 Hz), 6.90 (d, 1H, J 8.7 Hz), 5.7 (bs, 1H), 5.38 (d, 1H, J 11.6 Hz), 5.01 (m, 1H), 2.29 (m, 1H), 2.05 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[NH2:8].C1N=CN([C:27](N2C=NC=C2)=[O:28])C=1>C1COCC1>[O:28]=[C:27]1[NH:8][C:7]2[CH:6]=[CH:5][C:4]([C:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH:10]=3)=[CH:3][C:2]=2[NH:1]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc(N)c(N)c2)CC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc3[nH]c(=O)[nH]c3c2)CC1
Temperature: 60 °C
Reaction time: 6 h
Yield: 68 %

Procedure:
A mixture of compound 18 (0.58 g, 2 mmol) and CDI (0.34 g, 2.1 mmol) in THF (10 mL) was stirred at 60° C. for 6 h. The solvent was removed in vacuo, the residue was triturated with diethyl ether, and the resultant off-white solid was filtered and washed with diethyl ether to obtain compound 13. Yield: 68%, off-white solid, mp 244-245° C. IR (KBr, cm1) 3433, 3191 (CONH), 3037 (Ar—H), 2978 (Alph-H), 1713, 1689 (C=0), 1604, 1433 (C═C), 1244 (C—N), 1178 (C-0); 1H NMR (500 MHz, DMSO d6)g 1.39 (s, 9H, OC(CH3)3), 2.48 (br. s, 2H, CH2), 3.54 (m, 2H, CH2), 3.93 (br. s, 2H, CH2), 5.97 (br. s, 1H, CH), 6.86 (d, J=8.2 Hz, 1H, H-7), 6.95 (d, J=2.4 Hz, 1H, H-4), 6.99 (dd, J=2.4, 8.2 Hz, 1H, H-6), 10.60 (br. s, 2FI, NH). 13C NMR (125.7 MHz, DMSO d6) δ 26.84 (CH2), 28.28 (OC(CH3)3), 32.33 (CH), 42.80 (CH2), 79.08 (OC(CH3)3), 105.16 (CH), 108.52 (C-4), 117.67 (C-7), 129.20 (C-6), 130.04 (C-8), 133.28 (C-5/C-9), 134.81 (C-5/C-9), 154.73 (CO), 155.67 (CO). Anal. Calcd for C17H21N3O3: C, 64.74; H, 6.71; N, 13.32%. Found: C, 64.68; H, 6.76; N, 13.24%.
Reaction SMILES: [ClH:1].[CH2:2]([N:4]1[C:10](=[O:11])[C:9]([CH3:13])([CH3:12])[C:8](=[O:14])[N:7]([CH3:15])[C:6]2[CH:16]=[C:17]([CH2:20][N:21]([CH2:35][CH2:36][C:37]3[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=3)[C:22](=[O:34])[CH2:23][N:24]3[C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=4[NH:26][C:25]3=[O:33])[CH:18]=[CH:19][C:5]1=2)[CH3:3].[C:43](=O)([O-])[O-].[Cs+].[Cs+].CI.Cl>C(O)C.CC(O)C.O.CN(C=O)C>[ClH:1].[CH2:2]([N:4]1[C:10](=[O:11])[C:9]([CH3:13])([CH3:12])[C:8](=[O:14])[N:7]([CH3:15])[C:6]2[CH:16]=[C:17]([CH2:20][N:21]([CH2:35][CH2:36][C:37]3[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=3)[C:22](=[O:34])[CH2:23][N:24]3[C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=4[N:26]([CH3:43])[C:25]3=[O:33])[CH:18]=[CH:19][C:5]1=2)[CH3:3]
Reactant: O=C([O-])[O-]
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CN(CCc3cccnc3)C(=O)Cn3c(=O)[nH]c4ccccc43)ccc21
Agent: Cl
Agent: [Cs+]
Solvent: CC(C)O
Solvent: CCO
Solvent: CI
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CN(CCc3cccnc3)C(=O)Cn3c(=O)n(C)c4ccccc43)ccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 75.1 %

Procedure:
N-(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-2-(2-oxo-2,3-dihydrobenzoimidazol-1-yl)-N-(2-pyridin-3-ylethyl)acetamide hydrochloride(0.26 g), cesium carbonate(0.43 g), and methyl iodide(0.04 ml) were added to DMF(5 ml), and the mixture was stirred at room temperature for 1 days. Water was added to the reaction mixture, and stirred for 1 hour, followed by extraction with ethyl acetate. The organic layer was condensed under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: methanol=85:15). The purified product was condensed under reduced pressure. A 1N-hydrogen chloride in ethanol solution(0.44 ml) was added to a 2-propanol solution (5 ml) of the residue, and the liquid was stirred at room temperature, and concentrated under reduced pressure. Ethanol and ether were added to the residue. The precipitated insoluble matter was separated, washed with ether, and dried to give the title compound(0.20 g) as a white powder.
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:11]1[C:12]2[C:25]([CH3:26])=[C:24]([CH3:27])[S:23][C:13]=2[N:14]=[C:15]([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)[N:16]=1>>[N:20]1[CH:19]=[CH:18][C:17]([C:15]2[N:16]=[C:11]([NH:9][CH2:1][CH2:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[C:12]3[C:25]([CH3:26])=[C:24]([CH3:27])[S:23][C:13]=3[N:14]=2)=[CH:22][CH:21]=1
Reactant: Cc1sc2nc(-c3ccncc3)nc(Cl)c2c1C
Reactant: NCCc1ccccc1
Product: Cc1sc2nc(-c3ccncc3)nc(NCCc3ccccc3)c2c1C

Procedure:
With the procedure of Example 1, the reaction of phenethylamine with 4-chloro-2-(pyridin-4-yl)-5,6-dimethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-4-yl)-4-phenethylamino-5,6-dimethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2([C:21]3[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[CH:22]=3)[O:13][C:12]3[CH:14]=[CH:15][C:16]([C:18]([OH:20])=O)=[CH:17][C:11]=3[O:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>>[F:1][C:2]1[CH:3]=[C:4]([C:9]2([C:21]3[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[CH:22]=3)[O:13][C:12]3[CH:14]=[CH:15][C:16]([C:18]([N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)=[O:20])=[CH:17][C:11]=3[O:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: C1COCCN1
Reactant: O=C(O)c1ccc2c(c1)OC(c1cc(F)cc(F)c1)(c1cc(F)cc(F)c1)O2
Product: O=C(c1ccc2c(c1)OC(c1cc(F)cc(F)c1)(c1cc(F)cc(F)c1)O2)N1CCOCC1

Procedure:
This compound was prepared from 2,2-bis-(3,5-difluoro-phenyl)-benzo[1,3]dioxole-5-carboxylic acid and morpholine according to Example 269f; white foam, MS 459 ([M]+).