Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:8][CH2:7][C:6](=[O:9])[NH:5][C:4]2[CH:10]=[CH:11][C:12]([N+:14]([O-:16])=[O:15])=[CH:13][C:3]1=2.[C:18](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C=O)C>[CH3:18][N:5]1[C:6](=[O:9])[CH2:7][CH2:8][C:2]([CH3:17])([CH3:1])[C:3]2[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[CH:10][C:4]1=2
Reactant: CC1(C)CCC(=O)Nc2ccc([N+](=O)[O-])cc21
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN1C(=O)CCC(C)(C)c2cc([N+](=O)[O-])ccc21
Reaction time: 1 h

Procedure:
Combined 5,5-Dimethyl-7-nitro-1,3,4,5-tetrahydrobenzo[b]azepin-2-one (231 mg, 0.986 mmol), cesium carbonate (650 mg, 2 mmol), iodomethane (123 uL, 2 mmol) and DMF (6 mL). Stirred at room temp. for 1 hour. Evaporated off solvent, added water and extracted into methylene chloride. Dried organic layer over sodium sulfate, filtered and concentrated under reduced pressure to yield a yellow solid, 1,5,5-Trimethyl-7-nitro-1,3,4,5-tetrahydro-benzo[b]azepin-2-one. mp 115° C.; LCMS: m/z=249.07 (M+H+), 1H NMR (400 MHz, CDCl3) δ 8.32 (d, 1H, J=2.3 Hz), 8.19 (dd, 1H, J=8.7, 2.3 Hz), 7.34 (d, 1H, J=8.6 Hz), 3.37 (s, 3H), 2.34 (m, 2H), 2.14 (m, 2H), 1.43 (s, 6H).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][N:5](C(OC(C)(C)C)=O)[C@@H:4]([CH2:14][OH:15])[CH2:3]1.[C:16]([OH:22])([C:18]([F:21])([F:20])[F:19])=[O:17]>C(Cl)Cl>[F:19][C:18]([F:21])([F:20])[C:16]([OH:22])=[O:17].[OH:15][CH2:14][C@@H:4]1[NH:5][CH2:6][C@H:2]([OH:1])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@@H]1CO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: OC[C@H]1C[C@@H](O)CN1

Procedure:
1,1-Dimethylethyl(2R,4R)-4-hydroxy-2-(hydroxymethyl)-1-pyrrolidinecarboxylate (0.185 g, 0.852 mmol) was stirred in a 1:1 solution of methylene chloride:TFA for 14 hours. The reaction was concentrated, and the crude material was used without further purification. 1H NMR (400 MHz, DMSO-D6) δ ppm 1.5 (m, 1H), 2.2 (m, 4H), 3.0 (m, 1H), 3.1 (m, 1H), 3.6 (m, 3H), 4.3 (m, 1H), 5.3 (s, br, 2H), 8.6 (s, br, 1H), 9.2 (s, br, 1H).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[C:11]1([N:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[C:18]2[C:26]([NH:28][C@H:29]([C:33]([NH:35][CH:36]([CH:45]([OH:48])[CH2:46][F:47])[CH2:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])=[O:34])[CH:30]([CH3:32])[CH3:31])=[O:27])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C>C(Cl)Cl>[C:11]1([N:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[C:18]2[C:26]([NH:28][C@H:29]([C:33]([NH:35][CH:36]([C:45](=[O:48])[CH2:46][F:47])[CH2:37][C:38]([O:40][C:41]([CH3:42])([CH3:44])[CH3:43])=[O:39])=[O:34])[CH:30]([CH3:31])[CH3:32])=[O:27])[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CC(C)[C@H](NC(=O)c1cc2ccccc2n1-c1ccccc1)C(=O)NC(CC(=O)OC(C)(C)C)C(O)CF
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)[C@H](NC(=O)c1cc2ccccc2n1-c1ccccc1)C(=O)NC(CC(=O)OC(C)(C)C)C(=O)CF
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
DMSO (0.13 mL, 1.9 mmol) was added to a methylene chloride solution of oxalyl chloride (0.29 mL, 2.0 M, 0.58 mmol in 4 mL of methylene chloride), and the resultant solution was stirred for 10 minutes under a nitrogen atmosphere at 78° C. A methylene chloride solution of N-[(1-phenylindole-2-carbonyl)valinyl]-3-amino-4-hydroxy-5-fluoropentanoic acid, t-butyl ester (200 mg, 0.38 mmol in 2 mL of dry methylene chloride) was added dropwise and resulting mixture stirred for 15 minutes at −78° C. Triethylamine (0.30 mL, 2.1 mmol) was added dropwise to the mixture, and the resultant mixture was stirred for 10 minutes at −78° C., then was allowed to warm to room temperature. The reaction mixture was partitioned between ethyl acetate and 5% KHSO4 solution and the aqueous layer was back-extracted with ethyl acetate. The combined ethyl acetate solutions were washed with 5% KHSO4 solution and brine, dried over sodium sulfate, and concentrated to give a crude product. The crude product was triturated to yield the title product as a slightly yellow powder (181 mg). TLC: (ethyl acetate/hexanes 1:1): Rf=0.43.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:26])[C:4](=[O:25])[C:5]([C:17]2[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=2)[CH:20]=O)([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH:14]([F:16])[F:15])=[CH:9][CH:8]=2)[N:6]=1.[CH2:27]([NH2:29])[CH3:28].[BH4-].[Na+].[OH-].[Na+]>C1COCC1.CO>[NH2:1][C:2]1[N:3]([CH3:26])[C:4](=[O:25])[C:5]([C:7]2[CH:8]=[CH:9][C:10]([O:13][CH:14]([F:15])[F:16])=[CH:11][CH:12]=2)([C:17]2[CH:24]=[CH:23][CH:22]=[C:19]([CH2:20][NH:29][CH2:27][CH3:28])[CH:18]=2)[N:6]=1
Reactant: CN1C(=O)C(c2ccc(OC(F)F)cc2)(c2cccc(C=O)c2)N=C1N
Reactant: CCN
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCNCc1cccc(C2(c3ccc(OC(F)F)cc3)N=C(N)N(C)C2=O)c1
Yield: 83 %

Procedure:
A small vial (2 ml) was charged with 3-[2-Amino-4-(4-difluoromethoxy-phenyl)-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl]-benzaldehyde (68 mg, 189 μmol) and THF (0.5 ml). To this was added a 2M solution of ethylamine in THF (100 μl). After stirring overnight methanol (1 ml) and sodium borohydride (11 mg) was added, then after another hour 1N sodium hydroxide (1 ml) was added and the mixture extracted with diethyl ether. The ethereal layer was concentrated by rotary evaporation, diluted with methanol and re-concentrated (repeated three times). Finally the oily residue was redissolved in diethylether/hexanes and concentrated, twice then placed under vacuum to give a white foam 61 mg (83%). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.95 (t, J=7.1 Hz, 3H) 2.38-2.44 (m, 2H, partially obscured by solvent) 2.93 (s, 3H) 3.56 (s, 2H) 6.61 (br. s., 2H) 6.66 (br. s., 1H) 7.05 (d, J=8.8 Hz, 2H) 7.12 (t, J=74.18 Hz, 1H) 7.14-7.28 (m, 3H) 7.33-7.39 (m, 1H) 7.42 (d, J=8.8 Hz, 2H); MS (APPI) m/z 389 [M+H]+
Reaction SMILES: NCC1C=C(NC(=O)N(CCC2C=CC(C(NC3C=C4C(=CC=3)C(N(C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)=NC=C4)C(O)=O)=CC=2)C)C=CC=1S(CC)(=O)=O.[C:57]([O:61][C:62]([N:64]([C:101]([O:103][C:104]([CH3:107])([CH3:106])[CH3:105])=[O:102])[C:65]1[C:74]2[C:69](=[CH:70][C:71]([NH:75][CH:76]([C:80]3[CH:85]=[CH:84][C:83]([CH2:86][CH2:87][O:88][C:89](=[O:99])[NH:90][C:91]4[CH:96]=[CH:95][CH:94]=[C:93]([C:97]#[N:98])[CH:92]=4)=[C:82]([CH3:100])[CH:81]=3)[C:77]([OH:79])=[O:78])=[CH:72][CH:73]=2)[CH:68]=[CH:67][N:66]=1)=[O:63])([CH3:60])([CH3:59])[CH3:58]>>[NH2:98][CH2:97][C:93]1[CH:92]=[C:91]([NH:90][C:89]([O:88][CH2:87][CH2:86][C:83]2[CH:84]=[CH:85][C:80]([CH:76]([NH:75][C:71]3[CH:70]=[C:69]4[C:74](=[CH:73][CH:72]=3)[C:65]([N:64]([C:62]([O:61][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:63])[C:101]([O:103][C:104]([CH3:107])([CH3:106])[CH3:105])=[O:102])=[N:66][CH:67]=[CH:68]4)[C:77]([OH:79])=[O:78])=[CH:81][C:82]=2[CH3:100])=[O:99])[CH:96]=[CH:95][CH:94]=1
Reactant: Cc1cc(C(Nc2ccc3c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc3c2)C(=O)O)ccc1CCOC(=O)Nc1cccc(C#N)c1
Agent: CCS(=O)(=O)c1ccc(NC(=O)N(C)CCc2ccc(C(Nc3ccc4c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc4c3)C(=O)O)cc2)cc1CN
Product: Cc1cc(C(Nc2ccc3c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc3c2)C(=O)O)ccc1CCOC(=O)Nc1cccc(CN)c1
Reaction time: 15 h
Yield: 45.5 %

Procedure:
Using a procedure analogous to that used to prepare 25E, 30E (308 mg, 0.44 mmol) was hydrogenated for 15 h and purified by reverse phase HPLC to give 30F (140 mg, 45%) as a yellow solid. MS (ESI) m/z 700.15 (M+H)+.
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH:15][C:16]2([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:20][CH2:19][NH:18][CH2:17]2)(=[O:14])=[O:13])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[CH2:27]=O>C(O)=O>[CH3:27][N:18]1[CH2:19][CH2:20][C:16]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])([NH:15][S:12]([C:9]2[CH:10]=[CH:11][C:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])=[CH:7][CH:8]=2)(=[O:13])=[O:14])[CH2:17]1
Reactant: CCCCCc1ccc(S(=O)(=O)NC2(CC(=O)OCC)CCNC2)cc1
Reactant: C=O
Solvent: O=CO
Product: CCCCCc1ccc(S(=O)(=O)NC2(CC(=O)OCC)CCN(C)C2)cc1
Temperature: 110 °C
Yield: 71 %

Procedure:
To a solution of ethyl 2-(3-(4-pentylphenylsulfonamido)pyrrolidin-3-yl)acetate (55 mg, 0.14 mmol) in formic acid (2 mL) was added formalin (15 μL, 0.16 mL). The solution was heated to 110° C. for 2 h. The mixture was concentrated and dissolved into CH2Cl2 (25 mL) and washed with sat. bicarbonate (2×5 mL), H2O (5 mL), dried over MgSO4 and concentrated to dryness to give the title compound as a brown oil (40 mg, 71%). MS ESI 397.2 [M+H]+, calcd for [C20H32N2O4S+H]+ 397.21.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[O:14])[N:3]=1.[CH3:22][C:23]1[NH:27][N:26]=[C:25]([NH2:28])[CH:24]=1.CCN(C(C)C)C(C)C.O>CN(C=O)C>[F:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:28][C:25]3[CH:24]=[C:23]([CH3:22])[NH:27][N:26]=3)=[N:3][C:4]([C:13]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=[O:14])=[N:5]2)=[CH:10][CH:9]=1
Reactant: O=C(c1ccc(F)cc1)c1nc(Cl)c2ccc(F)cc2n1
Reactant: Cc1cc(N)n[nH]1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Nc2nc(C(=O)c3ccc(F)cc3)nc3cc(F)ccc23)n[nH]1
Temperature: 25 °C
Reaction time: 24 h
Yield: 45 %

Procedure:
To a solution of ethyl 4-chloro-7-fluoroquinazoline-2-carboxylate (122 mg, 0.479 mmol) in 5 mL THF at −40° C. was added 1M 4-fluorophenylmagnesium bromide/THF (0.58 mL, 0.58 mmol) and the mixture was stirred at −40° C. for 2 h. Saturated aq NH4Cl was added and the mixture was concentrated under reduced pressure. The residue was partitioned between H2O (100 mL) and DCM (50 mL). The separated aqueous phase was extracted with DCM (2×50 mL) and the combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure to afford a solid (130 mg) containing (4-chloro-7-fluoroquinazolin-2-yl)(4-fluorophenyl)methanone. A solution of the solid (130 mg, ca. 0.43 mmol) and KI (78 mg, 0.47 mmol) in DMF (6 mL) was stirred at rt for 30 min, and then 5-methyl-1H-pyrazol-3-amine (88 mg, 0.88 mmol) and DIEA (96 uL, 0.56 mmol) were added. The mixture was stirred at rt for 24 h, and then water was added. The precipitated solid was collected by filtration washing with water. The solid was purified by preparative reverse-phase HPLC eluting with 10-80% ACN/H2O containing 0.05% HOAC to afford (7-fluoro-4-(5-methyl-1H-pyrazol-3-ylamino)quinazolin-2-yl)(4-fluorophenyl)methanone as a solid (96 mg, 45%). 1H NMR (300 MHz, DMSO-d6) δ ppm 2.18 (s, 3H), 6.48 (s, 1H), 7.39 (m, 2H), 7.63 (m, 2H), 8.13 (m, 2H), 8.84 (m, 1H), 10.80 (s, 1H), 12.08 (br s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8][C:9]=1[NH2:10])=[O:4].[S:17]1[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]1.C1([SiH3])C=CC=CC=1>C1COCC1.[Sn](CCCC)(CCCC)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8][C:9]=1[NH:10][CH:20]1[CH2:21][CH2:22][S:17][CH2:18][CH2:19]1)=[O:4]
Reactant: COC(=O)c1sc(-c2ccccc2)cc1N
Reactant: O=C1CCSCC1
Agent: CCCC[Sn](Cl)(Cl)CCCC
Agent: [SiH3]c1ccccc1
Solvent: C1CCOC1
Product: COC(=O)c1sc(-c2ccccc2)cc1NC1CCSCC1
Yield: 56.5 %

Procedure:
Reductive amination of 3-amino-5-phenyl-thiophene-2-carboxylic acid methyl ester (0.933 g, 4.0 mmol) and tetrahydro-thiopyran-4-one (0.464 g, 4.0 mmol)in THF (1.0 mL) employing Bu2SnCl2 (60.5 mg, 0.2 mmol) and PhSiH3 (0.476 g, 0.542 mL) was carried out as described for example 13, step 1 gave 5-phenyl-3-(tetrahydro-thiopyran-4-ylamino)-thiophene-2-carboxylic acid methyl ester (0.753 g, 56.3%). NMR 1H (CDCl3, 400 MHz): 7.64-7.6 (m, 2H), 7.44-7.34 (m, 3H), 6.9 (brm, 1H), 6.81 (brs, 1H), 3.84 (s, 3H), 3.5-3.4 (m, 1H), 2.85-2.7 (m, 4H), 2.4-2.25 (m, 2H), 1.85-1.7 (m, 2H).
Reaction SMILES: [CH2:1]([NH:5][C@H:6]1[C@H:11]([NH:12][C:13]([C:15]2[NH:16][C:17]([CH2:21][CH3:22])=[C:18]([Cl:20])[N:19]=2)=[O:14])[CH2:10][CH2:9][N:8]([C:23]2[S:24][C:25]3[C:31]([C:32]([OH:34])=[O:33])=[CH:30][CH:29]=[CH:28][C:26]=3[N:27]=2)[CH2:7]1)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[Na+].[Na+].BrC1S[C:44]2C(C(OCC)=O)=CC=C[C:45]=2N=1>>[CH2:1]([NH:5][C@H:6]1[C@H:11]([NH:12][C:13]([C:15]2[NH:16][C:17]([CH2:21][CH3:22])=[C:18]([Cl:20])[N:19]=2)=[O:14])[CH2:10][CH2:9][N:8]([C:23]2[S:24][C:25]3[C:31]([C:32]([O:34][CH2:44][CH3:45])=[O:33])=[CH:30][CH:29]=[CH:28][C:26]=3[N:27]=2)[CH2:7]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN[C@@H]1CN(c2nc3cccc(C(=O)O)c3s2)CC[C@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Reactant: CCOC(=O)c1cccc2nc(Br)sc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCCCN[C@@H]1CN(c2nc3cccc(C(=O)OCC)c3s2)CC[C@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Yield: 76 %

Procedure:
The same operation as in Example (1h) was performed using tert-butyl trans(±)-3-(butylamino)-4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}piperidine-1-carboxylate obtained in Example (77d) (16.3 mg, 0.038 mmol), sodium carbonate (40 mg, 0.38 mmol) and ethyl 2-bromo-1,3-benzothiazole-7-carboxylate obtained by the method described in Example (1f) (13.2 mg, 0.046 mmol), to obtain 15.5 mg of the title compound (76%).
Reaction SMILES: [C:1]1([CH:7]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]([C:17]3[CH:22]=[C:21]([F:23])[C:20]([O:24][CH3:25])=[CH:19][C:18]=3[OH:26])[C:9]2=[O:27])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:34]1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C(C3C=C(C)C(OC)=CC=3O)C2=O)C=CC=CC=1>>[C:28]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3([C:17]4[CH:22]=[C:21]([F:23])[C:20]([O:24][CH3:25])=[CH:19][C:18]=4[O:26][CH2:34]3)[C:9]2=[O:27])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: COc1cc(O)c(C2C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)cc1F
Reactant: COc1cc(O)c(C2C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)cc1C
Product: COc1cc2c(cc1F)C1(CO2)C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 2 and making non-critical variations using 1-(diphenylmethyl)-3-(5-fluoro-2-hydroxy-4-methoxyphenyl)-1,3-dihydro-2H-indol-2-one to replace 1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one, 1′-(diphenylmethyl)-5-fluoro-6-methoxyspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one was obtained (73%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ7.43-7.22 (m, 10H), 7.16-7.09 (m, 1H), 7.06-6.92 (m, 3H), 6.60 (d, J=6.8 Hz, 1H), 6.54-6.48 (m, 1H), 6.37 (d, J=10.0 Hz, 1H), 4.99 (d, J=9.0 Hz, 1H), 4.72 (d, J=9.0 Hz, 1H), 3.85 (s, 3H); MS (ES+) m/z 452.1 (M+1).
Reaction SMILES: ClO.[CH2:3]([N:6]1[CH2:25][CH2:24][C@:13]23[C:14]4[C:15]5[O:23][C@H:12]2[C:11](=[O:26])[CH2:10][CH2:9][C@@:8]3([O:27][CH2:28][CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C@H:7]1[CH2:20][C:19]=4[CH:18]=[CH:17][C:16]=5[O:21][CH3:22])C=C.[Cl-].[NH4+]>[Zn].CO>[OH:23][C:15]1[C:14]2[C@:13]34[CH2:24][CH2:25][N:6]([CH3:3])[C@@H:7]([C@:8]3([O:27][CH2:28][CH2:29][CH2:30][C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH2:9][CH2:10][C:11](=[O:26])[CH2:12]4)[CH2:20][C:19]=2[CH:18]=[CH:17][C:16]=1[O:21][CH3:22]
Reactant: C=CCN1CC[C@]23c4c5ccc(OC)c4O[C@H]2C(=O)CC[C@@]3(OCCCc2ccccc2)[C@H]1C5
Agent: OCl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: COc1ccc2c(c1O)[C@]13CCN(C)[C@H](C2)[C@]1(OCCCc1ccccc1)CCC(=O)C3
Reaction time: 0.08 h

Procedure:
A mixture of 4,5α-epoxy-3-methoxy-17-methyl-14-[(3-phenylpropyl)oxy]-morphinan-6-one (=14-O-(3-phenylpropyl)oxycodon) (see Example 1) (600 mg, 1.4 mmol), ammonium chloride (0.97 g, 18.0 mmol) and 30 ml MeOH was reflux heated under stirring. Then within 5 minutes activated zinc powder (0.94 g, 14.0 mmol) was added in portions and the mixture reflux heated for 6 h. After filtration from the inorganic residue, the filtrate was evaporated down, alkalised with conc. NH4OH, extracted with CH2Cl2 (3×40 ml), washed with H2O, dried over Na2SO4 and evaporated down. The evaporation residue (605 mg) was crystallised out of a little MeOH. Yield: 562 mg (86%) of compound 25. Fp. >258° C. (decomp.); IR (KBr): 3145 (OH), 1734 (CO) cm−1; 1H-NMR (CDCl3): δ 7.37-7.05 (m, 5 arom. H), 6.64 (d, 1 arom. H, J=8.3 Hz), 6.54 (d, 1 arom. H, J=8.3 Hz), 3.79 (s, OCH3), 2.30 (s, NCH3); MS (CI): m/z 436 (M++1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C:14](O)=[O:15])[CH2:10][CH2:9]2)=[CH:4][C:3]=1[C:17]1[NH:21][C:20]2[CH:22]=[CH:23][C:24]([F:26])=[CH:25][C:19]=2[N:18]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:51][N:52]([CH3:58])[CH2:53][CH2:54][CH2:55][NH:56][CH3:57]>ClCCl>[CH3:51][N:52]([CH3:58])[CH2:53][CH2:54][CH2:55][N:56]([CH3:57])[C:14]([CH:11]1[CH2:10][CH2:9][N:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([C:17]3[NH:21][C:20]4[CH:22]=[CH:23][C:24]([F:26])=[CH:25][C:19]=4[N:18]=3)[CH:4]=2)[CH2:13][CH2:12]1)=[O:15]
Reactant: CNCCCN(C)C
Reactant: O=C(O)C1CCN(c2ccc(Cl)c(-c3nc4cc(F)ccc4[nH]3)c2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CN(C)CCCN(C)C(=O)C1CCN(c2ccc(Cl)c(-c3nc4cc(F)ccc4[nH]3)c2)CC1
Temperature: 35 °C
Yield: 48.9 %

Procedure:
Method H—Step a To a vial with 1-[4-Chloro-3-(5-fluoro-1H-benzoimidazol-2-yl)-phenyl]-piperidine-4-carboxylic acid (obtained as described in general method 3,4, step e) (0.10 g, 0.26 mmol) and HATU (0.10 g, 0.27 mmol) in dichloromethane (2 mL), TEA (0.07 mL, 0.54 mmol) and N,N,N′-trimethyl-1,3-propanediamine (0.32 mmol, 0.05 mL) were added. The reaction mixture was heated at 35° C. overnight, solvent was removed and the crude was purified by PrepHPLC and SCX column to obtain 0.06 g of the title compound (49%).
Reaction SMILES: [CH2:1]([N:8](C)[CH2:9][CH2:10][CH2:11][N:12]1[C:21]2[CH2:20][CH2:19][CH2:18][CH2:17][C:16]=2[C:15](=[O:22])[NH:14][C:13]1=[O:23])C1C=CC=CC=1.C([O-])=O.[NH4+]>CO.O1CCCC1.[Pd]>[CH3:1][NH:8][CH2:9][CH2:10][CH2:11][N:12]1[C:21]2[CH2:20][CH2:19][CH2:18][CH2:17][C:16]=2[C:15](=[O:22])[NH:14][C:13]1=[O:23]
Reactant: CN(CCCn1c2c(c(=O)[nH]c1=O)CCCC2)Cc1ccccc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: C1CCOC1
Product: CNCCCn1c2c(c(=O)[nH]c1=O)CCCC2
Reaction time: 0.75 h
Yield: 72 %

Procedure:
A solution of 4.29 g (13.11 mmol) of 1-{3-[benzyl(methyl)amino]propyl}-5,6,7,8-tetrahydro-2,4(1H,3H)-quinazolinedione in a mixture of 50 ml of methanol and 10 ml of tetrahydrofuran is admixed with 5.6 mg of 10% palladium-on-carbon. Over a period of 45 minutes, three portions of in total 8.61 g (136.6 mmol) of ammonium formate are then added. After the addition has ended, the mixture is heated at reflux for 1.5 hours. After cooling, the mixture if filtered through a little kieselguhr and the solvent is removed under reduced pressure. This gives 2.24 g (9.44 mmol, 72% yield) of the product as a colourless solid.
Reaction SMILES: [CH2:1]([P:8]([NH:17][C@H:18]([C:20]([N:22]1[CH2:29][CH2:28][CH2:27][C@H:23]1[C:24](O)=[O:25])=[O:21])[CH3:19])([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.Cl.[CH2:41]([O:43][C:44](=[O:54])[C@H:45]([CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[NH2:46])[CH3:42].CCN=C=NCCCN(C)C>CN(C=O)C.C(OCC)(=O)C>[CH2:41]([O:43][C:44](=[O:54])[C@H:45]([CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[NH:46][C:24](=[O:25])[C@@H:23]1[CH2:27][CH2:28][CH2:29][N:22]1[C:20](=[O:21])[C@H:18]([CH3:19])[NH:17][P:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:9])[CH3:42]
Reactant: CCOC(=O)[C@@H](N)Cc1ccccc1
Reactant: C[C@H](NP(=O)(Cc1ccccc1)Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H]1CCCN1C(=O)[C@H](C)NP(=O)(Cc1ccccc1)Cc1ccccc1
Temperature: -15 °C
Reaction time: 3 h
Yield: 76.1 %

Procedure:
Dibenzylphosphoryl-L-alanyl-L-proline (1.2 g, 2.5 m mole), HOBt (338 mg, 2.5 m mole) and L-phenylalanine ethylester hydrochloride (690 mg, 3 m mole) were suspended in DMF (10 ml) and WSC (0.5 ml) were added thereto while cooling to -15° C. and stirring. The reaction was carried out for 3 hours under cooling and then overnight at room temperature. To the reaction solution, ethyl acetate (100 ml) was added, and the mixture was washed with 1N hydrochloric acid and water in order, and dried with anhydrous sodium sulfate. The the dried solution was distilled under reduced pressure to obtain an oily dibenzylphosphoryl-L-alanyl-L-prolyl-L-phenylalanine ethylester material (1.3 g). The oily material gave a single spot with Rf 0.7 by thin layer chromatography (developing solvent; chloroform:methanol:acetic acid=95:5:3, colour forming method: spraying of 25% hydrobromic acid and 0.1% ninhydrine, and heating).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1>[Ni].C1COCC1>[CH3:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:6]=[CH:7][C:2]([C:11]3[CH:12]=[CH:13][C:8]([C:5]4[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=4)=[CH:9][CH:10]=3)=[CH:3][CH:4]=2)=[CH:9][CH:10]=1
Reactant: COc1ccc(-c2ccc(Br)cc2)cc1
Agent: [Ni]
Solvent: C1CCOC1
Product: COc1ccc(-c2ccc(-c3ccc(-c4ccccc4)cc3)cc2)cc1
Yield: 151.6 %

Procedure:
15 In another 1-liter three-necked flask, 31.5 g (120 mmol) of 4-bromo-4'-metoxybiphenyl and 108 mg (0.2 mmol) of NiC12(1,3-bis(diphenylphosphino)propane) (NiCl2 (dppp)) were added, which were dissolved into 500 ml of anhydrous THF. This solution was kept at 0° C. under a nitrogen atmosphere, and the Grignard reagent was added dropwise over a period of about 1 hour with stirring. During the addition, the orange color of the Ni catalyst disappeared, and the reaction mixture became brown. The reaction mixture was then refluxed with stirring for 5 hours to complete the reaction. After the reaction, the precipitated white solid was filtered, and washed with a small amount of THF. Recrystallization from sulforane gave 30.6 g (yield, 76%) of 4-metoxy-p-quaterphenyl (MQ). The liquid-crystal transition temperature of the MQ was 328° C.
Reaction SMILES: C[O:2][C:3]1[CH:36]=[CH:35][C:6]2=[C:7]3[C:15](=[CH:16][CH:17]=[C:5]2[CH:4]=1)[C:14]1[C:9](=[CH:10][C:11]([O:18]C)=[CH:12][CH:13]=1)[CH:8]3[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][N:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)=[CH:22][CH:21]=1.[Cl-].[Al+3].[Cl-].[Cl-].C(S)C>ClCCCl>[OH:2][C:3]1[CH:36]=[CH:35][C:6]2=[C:7]3[C:15](=[CH:16][CH:17]=[C:5]2[CH:4]=1)[C:14]1[C:9](=[CH:10][C:11]([OH:18])=[CH:12][CH:13]=1)[CH:8]3[C:20]1[CH:21]=[CH:22][C:23]([O:26][CH2:27][CH2:28][N:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)=[CH:24][CH:25]=1
Reactant: COc1ccc2c(c1)C(c1ccc(OCCN3CCCCC3)cc1)c1c-2ccc2cc(OC)ccc12
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCS
Solvent: ClCCCl
Product: Oc1ccc2c(c1)C(c1ccc(OCCN3CCCCC3)cc1)c1c-2ccc2cc(O)ccc12

Procedure:
One g of the compound of Example 11 was added to 1.9 g of aluminum chloride and 1.3 g of ethanethiol in 25 ml of 1,2-dichloroethane and the reaction was carried out and the product isolated as described in Example 14. One g of impure oily product was obtained, which was purified by Waters Prep 500 liquid chromatography over normal phase silica gel, using a gradient solvent which began with 2% methanol in chloroform and progressed to 30% methanol in chloroform. The product-containing fractions were evaporated to dryness under vacuum to obtain 0.7 g of the desired product as a tan foam.
Reaction SMILES: C([O:8][C:9](=O)[CH:10]([C:21]1[C:26]([C:27]([F:30])([F:29])[F:28])=[CH:25][C:24]([N+:31]([O-])=O)=[CH:23][C:22]=1[N+:34]([O-])=O)C(OCC1C=CC=CC=1)=O)C1C=CC=CC=1>[Pd].C(O)C>[NH2:31][C:24]1[CH:23]=[C:22]2[C:21]([CH2:10][C:9](=[O:8])[NH:34]2)=[C:26]([C:27]([F:30])([F:29])[F:28])[CH:25]=1
Reactant: O=C(OCc1ccccc1)C(C(=O)OCc1ccccc1)c1c([N+](=O)[O-])cc([N+](=O)[O-])cc1C(F)(F)F
Agent: [Pd]
Solvent: CCO
Product: Nc1cc2c(c(C(F)(F)F)c1)CC(=O)N2

Procedure:
Palladium/carbon was added to an ethanol solution of [2,4-dinitro-6-(trifluoromethyl)phenyl]malonic acid dibenzyl ester and the reaction was carried out under a hydrogen atmosphere to obtain 6-amino-4-(trifluoromethyl)-1,3-dihydro-2H-indol-2-one.