Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:9]2[CH:10]=[C:11]([CH2:14][O:15][CH:16]3[CH:21]([C:22]4[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][CH2:31][O:32][C:33]5[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=5[F:40])=[CH:24][CH:23]=4)[CH2:20][CH2:19][N:18]([C:41]([O:43][CH2:44][C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)=[O:42])[CH2:17]3)[CH:12]=[CH:13][C:8]=2[O:7][CH2:6][CH2:5]1.C(N(CC)CC)C.[C:58](Cl)(=[O:60])[CH3:59]>ClCCl>[C:58]([NH:1][CH2:2][CH2:3][N:4]1[C:9]2[CH:10]=[C:11]([CH2:14][O:15][CH:16]3[CH:21]([C:22]4[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][CH2:31][O:32][C:33]5[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=5[F:40])=[CH:24][CH:23]=4)[CH2:20][CH2:19][N:18]([C:41]([O:43][CH2:44][C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=4)=[O:42])[CH2:17]3)[CH:12]=[CH:13][C:8]=2[O:7][CH2:6][CH2:5]1)(=[O:60])[CH3:59]
Reactant: CC(=O)Cl
Reactant: NCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(OCCCOc4cc(F)ccc4F)cc3)cc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(OCCCOc4cc(F)ccc4F)cc3)cc21

Procedure:
The solution of 0.220 g of benzyl 3-[4-(2-aminoethyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-4-{4-[3-(2,5-difluorophenoxy)propoxy]phenyl}piperidine-1-carboxylate in 7.5 ml of dichloromethane is cooled to 0° C. with stirring and admixed with 0.042 ml of triethylamine. 0.023 ml of acetyl chloride in 0.50 ml of dichloromethane are slowly added dropwise. Subsequently, the mixture is stirred at 0° C. over 1 hour. The reaction mixture is poured onto ice-water (20 ml) and extracted with tert-butyl methyl ether (2×20 ml). The organic phases are washed with brine (20 ml), dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a white foam from the residue by means of flash chromatography (SiO2 60F). Rf=0.75 (200:20:1 dichloromethane-methanol-25% conc. ammonia); Rt=5.46.
Reaction SMILES: [C:1](Cl)(=O)C.[OH:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]([OH:16])=[O:15])=[CH:9][CH:8]=1>CO>[CH3:1][O:15][C:14](=[O:16])[CH2:13][C:10]1[CH:11]=[CH:12][C:7]([CH:6]=[O:5])=[CH:8][CH:9]=1
Reactant: O=C(O)Cc1ccc(CO)cc1
Reactant: CC(=O)Cl
Solvent: CO
Product: COC(=O)Cc1ccc(C=O)cc1
Reaction time: 18 h

Procedure:
Acetyl chloride (5 mL) was added cautiously to solution of (4-hydroxymethylphenyl)acetic acid (5.78 g) in methanol (200 mL), stirred for 18 hours and evaporated. The residue was dissolved in dichloromethane (100 mL) and treated with manganese (IV) oxide (29.47 g), stirred for 18 hours and filtered through Celite. The filter pad was washed with dichloromethane and the combined filtrates evaporated. Purification on silica, eluting with 20% diethyl ether in iso-hexane, afforded the subtitle compound as a white solid (3.60 g).
Reaction SMILES: C([O:3][C:4](=[O:13])[C:5]([C:7]1[S:8][C:9]([I:12])=[CH:10][CH:11]=1)=[O:6])C>O1CCOCC1.[OH-].[K+]>[I:12][C:9]1[S:8][C:7]([C:5](=[O:6])[C:4]([OH:13])=[O:3])=[CH:11][CH:10]=1
Reactant: CCOC(=O)C(=O)c1ccc(I)s1
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)C(=O)c1ccc(I)s1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
(5-Iodothiophen-2-yl)-oxo-acetic acid ethyl ester (0.298 g, 0.96 mmol) was dissolved in 1,4 dioxane (4 ml) and 20% KOH (0.5 ml). The reaction mixture was stirred at ambient temperature for 4 hours then volatile solvent was removed by rotary evaporation. The residue was dissolved in 5 ml water and extracted with diethyl ether (35 ml). The aqueous layer was acidified to pH 3-4 with glacial acetic acid, and extracted with ethyl acetate (3×35 ml). The combined ethyl acetate extracts were dried over Na2SO4 and concentrated under vacuum to provide Preparation 1c (92 mg, 34%). MS (M−H)−: 280.77; 1H NMR (300 MHz, DMSO-d6) δ7.59 (1H, d, J=3.9 Hz), 7.50 (1H, d, J=4.0 Hz).
Reaction SMILES: Cl.[NH2:2][CH:3]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH2:18][CH3:19])[CH:10]=1)[CH2:4][C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[Na+].[Na+].C(N1[C:35](=[O:36])[C:34]2=[CH:37][CH:38]=[CH:39][CH:40]=[C:33]2[C:32]1=[O:41])(OCC)=O>O.C(#N)C>[C:32]1(=[O:41])[N:2]([CH:3]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH2:18][CH3:19])[CH:10]=2)[CH2:4][C:5]([O:7][CH3:8])=[O:6])[C:35](=[O:36])[C:34]2=[CH:37][CH:38]=[CH:39][CH:40]=[C:33]12
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Reactant: CCOc1cc(C(N)CC(=O)OC)ccc1OC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CCOc1cc(C(CC(=O)OC)N2C(=O)c3ccccc3C2=O)ccc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.9 %

Procedure:
To a stirred solution of methyl 3-amino-3-(3-ethoxy-4-methoxyphenyl)propionate hydrochloride (0.87 g, 3.0 mmol) and sodium carbonate (0.32 g, 3.0 mmol) in a mixture of water (10 mL) and acetonitrile (10 mL) was added N-carbethoxyphthalimide (0.68 g, 3.0 mmol). The resulting solution was stirred for 3 hours at room temperature. The acetonitrile was removed in vacuo. To the resulting mixture was added ether (5 mL) and the mixture was stirred at room temperature overnight allowing the ether to evaporate. The resulting white solid was filtered. The solid was washed with water, air dried, and dried in vacuo (60° C.,<1 mm) to afford 1.0 g (87%) of methyl 3-phthalimido-3-(3-ethoxy-4-methoxyphenyl)propionate as a white solid: mp 86-87° C.; 1H NMR (CDCl3)δ 7.86-7.63 (m, 4H), 7.16-7.05 (m, 2H), 6.88-6.76 (m, 1H), 5.77 (dd, J=5.9, 10 Hz, 1H), 4.11 (q, J=7 Hz, 2H), 3.84 (s, 3H), 3.77 (dd, J=10, 6.7 Hz, 1H), 3.63 (s, 3H), 3.25 (dd, J=5.9, 16.5 Hz, 1H), 1.45 (t, J=7 Hz, 3H); 13C NMR (CDCl3)δ 171.0, 168.0, 149.0, 148.2, 133.9, 131.7, 130.9, 123.2, 120.2, 112.5, 111.1, 64.3, 55.8, 51.8, 50.7, 35.8, 14.6; HPLC (Waters Nova-Pak C18 column, 3.9×150 mm, 4 micron, 1 mL/min, 240 nm, 45/55, acetonitrile/0.1% aqueous phosphoric acid 6 min, 100%, Anal. Calcd. for C21H21NO6. Theoretical: C, 65.79; H, 5.52; N, 3.65. Found: C, 65.71; H, 5.70; N, 3.63.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:22][CH2:21][C@@:12]34[C:13]5[CH:14]=[C:15]([OH:20])[CH:16]=[CH:17][C:18]=5[CH2:19][C@@H:6]2[C@@H:7]3[CH2:8][CH2:9][C:10](=O)[CH2:11]4)[CH2:3][CH2:2]1.[CH2:24]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>CS(C)=O>[CH:1]1([CH2:4][N:5]2[CH2:22][CH2:21][C@@:12]34[C:13]5[CH:14]=[C:15]([OH:20])[CH:16]=[CH:17][C:18]=5[CH2:19][C@@H:6]2[C@@H:7]3[CH2:8][CH2:9][C:10](=[CH2:24])[CH2:11]4)[CH2:2][CH2:3]1
Reactant: C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1CC[C@H]2[C@H]3Cc4ccc(O)cc4[C@@]2(CCN3CC2CC2)C1
Solvent: CS(C)=O
Product: C=C1CC[C@H]2[C@H]3Cc4ccc(O)cc4[C@@]2(CCN3CC2CC2)C1

Procedure:
Reaction of 17-cyclopropylmethyl-3-hydroxy-morphinan-6-one (1.58 g, 5 mmole) with methylenetriphenylphosphorane (20 mmole) in dimethyl sulfoxide gave a crude residue which was chromatographed using 10:1 chloroform-methanol containing 1% concentrated ammonium hydroxide. Pure fractions were pooled to give 909 mg (58%) of TR-5609 which crystallized from ethanol to give 532 mg of analytically pure TR-5609, mp 220°-223°.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[C:11]([C:29]2[CH:34]=[CH:33][C:32]([O:35][C:36]([F:39])([F:38])[F:37])=[CH:31][CH:30]=2)[CH:12]=[C:13]([Cl:28])[C:14]=1[CH2:15][C@@H:16]1[CH2:20][CH2:19][N:18]([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[C:17]1=[O:27].[CH3:40][N:41]=[C:42]=[O:43]>C(Cl)Cl>[CH3:40][NH:41][C:42]([N:24]1[CH2:23][CH2:22][CH:21]([N:18]2[CH2:19][CH2:20][C@@H:16]([CH2:15][C:14]3[C:13]([Cl:28])=[CH:12][C:11]([C:29]4[CH:34]=[CH:33][C:32]([O:35][C:36]([F:39])([F:37])[F:38])=[CH:31][CH:30]=4)=[CH:10][C:9]=3[Cl:8])[C:17]2=[O:27])[CH2:26][CH2:25]1)=[O:43]
Reactant: O=C1[C@H](Cc2c(Cl)cc(-c3ccc(OC(F)(F)F)cc3)cc2Cl)CCN1C1CCNCC1
Reactant: CN=C=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNC(=O)N1CCC(N2CC[C@@H](Cc3c(Cl)cc(-c4ccc(OC(F)(F)F)cc4)cc3Cl)C2=O)CC1
Yield: 37.8 %

Procedure:
Treat a solution of (R)-3-(3,5-Dichloro-4′-trifluoromethoxy-biphenyl-4-ylmethyl)-1-piperidin-4-yl-pyrrolidin-2-one trifluoroacetic acid (Preparation 33) (85 mg, 0.17 mmol) in CH2Cl2 (4 mL) with methyl isocyanate (11 mg, 0.19 mmol). Stir the reaction overnight at room temperature. Quench the reaction with 1N HCl and extract with Et2O. Wash the organic with brine, dry over MgSO4, and filter. Purify the crude by silica gel column chromatography using Hexanes:EtOAc to elute pure product. Remove the solvent to afford 0.035 g (37%) of product. MS (m/e): 544 (M+1).
Reaction SMILES: [CH:1]1([N:4]([CH2:18][C:19]2[O:23][CH:22]=[C:21]([C:24](O)=[O:25])[CH:20]=2)[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:7])=[O:6])[CH2:3][CH2:2]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl.Cl.[CH3:59][O:60][CH:61]1[CH2:66][CH2:65][CH2:64][N:63]([CH2:67][C:68]2[CH:73]=[CH:72][C:71]([CH2:74][NH:75][CH3:76])=[CH:70][CH:69]=2)[CH2:62]1>C(Cl)Cl>[CH:1]1([N:4]([CH2:18][C:19]2[O:23][CH:22]=[C:21]([C:24]([N:75]([CH2:74][C:71]3[CH:70]=[CH:69][C:68]([CH2:67][N:63]4[CH2:64][CH2:65][CH2:66][CH:61]([O:60][CH3:59])[CH2:62]4)=[CH:73][CH:72]=3)[CH3:76])=[O:25])[CH:20]=2)[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:7])=[O:6])[CH2:3][CH2:2]1
Reactant: COc1cc(C)c(S(=O)(=O)N(Cc2cc(C(=O)O)co2)C2CC2)c(C)c1
Reactant: CNCc1ccc(CN2CCCC(OC)C2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(C)c(S(=O)(=O)N(Cc2cc(C(=O)N(C)Cc3ccc(CN4CCCC(OC)C4)cc3)co2)C2CC2)c(C)c1

Procedure:
The title compound was prepared according to general procedure BH using 5-({cyclopropyl[(4-methoxy-2,6-dimethylphenyl)sulfonyl]amino}methyl)furan-3-carboxylic acid (40 mg, 0.105 mmol), EDCI (28 mg, 0.158 mmol), HOBt (21 mg, 0.16 mmol), DIPEA (0.04 mL, 0.21 mmol), 1-{4-[(3-methoxypiperidin-1-yl)methyl]phenyl}-N-methylmethanamine dihydrochloride (36 mg, 0.13 mmol) and DCM (10 mL).
Reaction SMILES: [CH3:1][C:2]([CH3:32])([CH3:31])[C:3]([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([N:16]2[C@H:20]([C@H:21]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=3)[OH:22])[CH2:19][S:18][CH2:17]2)=[O:15])=[CH:9][CH:8]=1)=[O:4].I([O-])(=O)(=O)=[O:34].[Na+]>CO.O>[CH3:1][C:2]([CH3:32])([CH3:31])[C:3]([NH:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([NH:13][C:14]([N:16]2[C@H:20]([C@H:21]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=3)[OH:22])[CH2:19][S:18](=[O:34])[CH2:17]2)=[O:15])=[CH:11][CH:12]=1)=[O:4]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CC(C)(C)C(=O)NCc1ccc(NC(=O)N2CSC[C@H]2[C@@H](O)c2ccc(Cl)c(Cl)c2)cc1
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)(C)C(=O)NCc1ccc(NC(=O)N2CS(=O)C[C@H]2[C@@H](O)c2ccc(Cl)c(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4(R)-[(3,4-dichlorophenyl)-(S)hydroxymethyl]-thiazolidine-3-carboxylic acid {4-[(2,2-dimethyl-propionylamino)-methyl]-phenyl}-amide (11 mg, 0.022 mmol) in MeOH (2 ml) is added sodium periodate (4.9 mg, 0.023 mmol) in water (0.5 ml). The reaction mixture is stirred at 25° C. for 18 hrs. More aqueous sodium periodate is added by portions until almost complete conversion of the starting material. The reaction mixture is filtered on cellite and concentrated in vacuo. The residue is taken into methylene chloride, washed with water and brine, concentrated and purified by preparative reverse phase HPLC and flash chromatography (silica gel, 2% to 5% MeOH/NH3 in methylene chloride) sequentially to give the following two products isomeric at the sulfoxide center:
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:31]=[CH:30][C:13]3[N:14]([CH:18]4[CH2:22][CH2:21][N:20](CC5C=CC=CC=5)[CH2:19]4)[CH2:15][CH2:16][O:17][C:12]=3[CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)C.[Pd].C(O)(=O)C>[C:1]1([S:7]([C:10]2[CH:31]=[CH:30][C:13]3[N:14]([CH:18]4[CH2:22][CH2:21][NH:20][CH2:19]4)[CH2:15][CH2:16][O:17][C:12]=3[CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(c1ccccc1)c1ccc2c(c1)OCCN2C1CCN(Cc2ccccc2)C1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: O=S(=O)(c1ccccc1)c1ccc2c(c1)OCCN2C1CCNC1
Reaction time: 24 h
Yield: 44.7 %

Procedure:
7-Benzenesulfonyl-4-(1-benzyl-pyrrolidin-3-yl)-3,4-dihydro-2H-benzo[1,4]oxazine (0.127 g, 0.292 mmol) was dissolved in 15 mL ethanol and this solution was added to a flask containing 35 mg of 5% palladium on charcoal, followed by 3 drops of glacial acetic acid. The system was purged with hydrogen gas and stirring was continued for 24 hours under 1 atm. of hydrogen gas. The reaction mixture was filtered through celite, the filtrate concentrated in vacuo, and the resulting solid purified by flash (6:0.4:0.04 of CH2Cl2:MeOH:NH4OH) to give 45 mg of 7-benzenesulfonyl-4-pyrrolidin-3-yl-3,4-dihydro-2H-benzo[1,4]oxazine as free base. This solid was dissolved in 1 mL methanol and combined with 0.5 mL of 2N ethanolic hydrogen chloride and the resulting solution is concentrated in vacuo and subjected to a vacuum of 0.3 Torr for 2 hours to give a foam which was triturated twice with 50 mL ethyl ether to give, after drying under reduced pressure, 25 mg (0.07 mmol, 25%) of 7-benzenesulfonyl-4-pyrrolidin-3-yl-3,4-dihydro-2H-benzo[1,4]oxazine hydrochloride as a tan solid. MS: 345 (M+H)+, mp: 122.8-127.6° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[CH:17])([CH3:4])([CH3:3])[CH3:2].Br[C:20]1[CH:21]=[C:22]([S:27]([N:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH:31]2[CH3:36])(=[O:29])=[O:28])[CH:23]=[CH:24][C:25]=1[CH3:26]>>[C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[C:17][C:20]1[CH:21]=[C:22]([S:27]([N:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH:31]2[CH3:36])(=[O:28])=[O:29])[CH:23]=[CH:24][C:25]=1[CH3:26])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)N2CCCCC2C)cc1Br
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Product: Cc1ccc(S(=O)(=O)N2CCCCC2C)cc1C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C

Procedure:
Following the general method as outlined in Intermediate 20, starting from (4-chloro-2-ethynyl-phenoxy)-acetic acid tert-butyl ester (Intermediate 3) and 1-(3-bromo-4-methyl-benzenesulfonyl)-2-methyl-piperidine (Intermediate 140), the title compound was obtained as a yellow sticky solid after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([Sn](C)(C)C)[S:10][C:3]=12.Br[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[S:10][C:3]=12
Reactant: Brc1ccccn1
Reactant: C[Sn](C)(C)c1cc2nccc(Cl)c2s1
Product: Clc1ccnc2cc(-c3ccccn3)sc12
Yield: 30.5 %

Procedure:
This material was prepared by coupling 7-chloro-2-(trimethylstannyl)thieno[3,2-b]pyridine 39a (0.255 g, 0.77 mmole) with 2-bromopyridine (0.121 g, 0.77 mmole) using tereakis(triphenylphosphine) palladium(0) (0.036 g) as catalyst in a manner as previously described in example 39b to give a white solid (0.058 g, 31%). 1H NMR (300 MHz, CDCl3) δ8.66 (1H, m), 8.57 (1H, d, J=5.1 Hz), 8.00 (1H, s), 7.83 (3H, m), 7.27 (1H, d, J=5.1 Hz); ESIMS (MH+): 246.95.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:23])[C:5]([CH3:22])=[C:6]([CH2:12][C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=2)[C:16]([OH:18])=O)[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[CH:24]([NH2:27])([CH3:26])[CH3:25].Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:4](=[O:23])[C:5]([CH3:22])=[C:6]([CH2:12][C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=2)[C:16]([NH:27][CH:24]([CH3:26])[CH3:25])=[O:18])[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: COC1=C(OC)C(=O)C(Cc2cccc(C(=O)O)c2)=C(C)C1=O
Reactant: CC(C)N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COC1=C(OC)C(=O)C(Cc2cccc(C(=O)NC(C)C)c2)=C(C)C1=O
Yield: 37 %

Procedure:
3-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)benzoic acid (85 mg, 0.27 mmol) obtained in Example 41, isopropylamine (0.035 ml, 0.41 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (78 mg, 0.41 mmol) in dry methylene chloride (3.4 ml) were stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure and then was purified by a silica gel column chromatography (methylene chloride:methanol=20:1) to obtain the title compound (37 mg, 0.10 mmol, yield 37%).
Reaction SMILES: C[O:2][C@@H:3]([C:5]1[N:6]=[CH:7][N:8]([C:10]2[CH:27]=[C:15]3[C:16]4[C:21]([CH2:22][CH2:23][N:14]3[C:13](=[O:28])[CH2:12][N:11]=2)=[C:20]([C:24]([CH3:26])=[CH2:25])[CH:19]=[CH:18][CH:17]=4)[CH:9]=1)[CH3:4].[CH:29]1([Mg]Br)C[CH2:30]1.[NH4+].[Cl-]>C1COCC1>[CH:24]1([C:20]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:21]=2[CH2:22][CH2:23][N:14]2[C:13](=[O:28])[CH2:12][N:11]=[C:10]([N:8]4[CH:9]=[C:5]([CH:3]([CH:4]5[CH2:30][CH2:29]5)[OH:2])[N:6]=[CH:7]4)[CH:27]=[C:15]23)[CH2:26][CH2:25]1
Reactant: C=C(C)c1cccc2c1CCN1C(=O)CN=C(n3cnc([C@@H](C)OC)c3)C=C21
Reactant: Br[Mg]C1CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=C1CN=C(n2cnc(C(O)C3CC3)c2)C=C2c3cccc(C4CC4)c3CCN12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 1-(9-cyclopropyl-5-oxo-4,5,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinolin-2-yl)-1H-imidazole-4-carbaldehyde (230 mg, 0.66 mmol, it can be obtained by analogy to example 118) in THF (35 mL) was cooled to 0° C. and then treated with a solution of cPrMgBr in THF (1.39 mL, 0.70 mmol) dropwise. The mixture was stirred at 0° C. for 1 h, and an aq. solution of saturated NH4Cl was then added. The mixture was extracted with AcOEt, and the combined org. layers were dried over Na2SO4, filtered and concentrated in vacuo. Purification by flash chromatography (SiO2, AcOEt:MeOH 100:0 to 90:10) and crystallization in AcOEt gave the tile compound (66 mg). UPLC-MS: MS 389.2 (M+H+); UPLC rt 0.92 min. 1H NMR (600 MHz, DMSO-d6): δ ppm 0.21-0.46 (m, 4H); 0.58-0.70 (m, 2H); 0.91-1.00 (m, 2H); 1.08-1.25 (m, 1H); 1.91-2.04 (m, 1H); 3.01-3.17 (m, 2H); 3.88 (br s, 2H); 3.93-4.03 (m, 1H); 4.24 (br s, 2H); 4.96 (d, J=5.27 Hz, 1H); 7.12-7.25 (m, 2H); 7.25-7.35 (m, 1H); 7.49 (s, 1H); 7.91 (d, J=8.03 Hz, 1H); 8.17 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[C:6]1[O:7][C:8]2[C:13]([C:14](=[O:16])[CH:15]=1)=[CH:12][CH:11]=[C:10]([O:17][CH2:18][CH:19]1[O:21][CH2:20]1)[CH:9]=2.[C:27]1([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[C:6]1[O:7][C:8]2[C:13]([C:14](=[O:16])[CH:15]=1)=[CH:12][CH:11]=[C:10]([O:17][CH2:18][CH:19]([OH:21])[CH2:20][N:36]1[CH2:37][CH2:38][N:33]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:34][CH2:35]1)[CH:9]=2
Reactant: COc1ccc(-c2cc(=O)c3ccc(OCC4CO4)cc3o2)cc1OC
Reactant: c1ccc(N2CCNCC2)cc1
Solvent: CO
Product: COc1ccc(-c2cc(=O)c3ccc(OCC(O)CN4CCN(c5ccccc5)CC4)cc3o2)cc1OC

Procedure:
3′,4′-Dimethoxy-7-(2,3-epoxy-propoxy)-flavone, 33 (300 mg, 0.85 mmol) and 1-phenyl piperazine (0.13 mL, 0.85 mmol) in dry methanol (60 mL) were reacted in a similar manner to that described under 34 to afford 47. Yield 410 mg (94%); mp 191-193° C.; MS (FAB) 517 (M++1); IR (KBr) 3416, 1627; 1H NMR (200 MHz, CDCl3) δ 8.16 (d, J=9.5 Hz, 1H), 7.54 (dd, J=8.3 Hz, 2.1 Hz, 1H), 7.34 (d, J=1.9 Hz, 1H), 7.31-7.23 (m, 2H), 7.04-6.87 (m, 6H), 6.70 (s, 1H), 4.21-4.16 (m, 3H), 3.99 (s, 3H), 3.97 (s, 3H), 3.28 (t, J=4.8 Hz, 4H), 2.90-2.71 (m, 2H), 2.71-2.65 (m, 4H). Analysis Calcd for C30H32N2O6: C, 69.75; H, 6.24; N, 5.42. Found: C, 69.96; H, 6.57; N, 5.51.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15].[NH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>C(O)C>[OH:1][CH:2]([CH2:3][N:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[CH2:4][N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15]
Reactant: O=C1c2ccccc2C(=O)N1CC1CO1
Reactant: C1CCNCC1
Solvent: CCO
Product: O=C1c2ccccc2C(=O)N1CC(O)CN1CCCCC1
Yield: 70.8 %

Procedure:
To a solution of 2-(oxiran-2-ylmethyl)isoindoline-1,3-dione (1.0 g, 4.9 mmol) in ethanol (25 mL) was added piperidine (0.46 g, 5.4 mmol). The resulting reaction mixture was heated at reflux for 1 hour. After this time, TLC analysis showed no starting material remaining so the mixture was concentrated to afford the title product as oil (1.0 g). The titled product structure was confirmed by LC/MS analysis. MS m/z: 289.21 [M+H]+. The resulting hydroxylamine was dissolved in ethanol (20 mL) and to which was added hydrazine (0.86 g, 7.36 mmol). The resulting reaction mixture was stirred at ambient temperature for over night. After this time, TLC analysis showed no starting material remaining so the mixture was concentrated to afford the title product as oil (0.4 g). MS m/z: 159.2 [M+H]+. The crude was used as such for the next step transformation.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:12](=[O:14])[NH:11][C:10](=[O:15])[N:9]([CH3:16])[C:8]=2[N:7]=[CH:6]1)[CH2:2][CH2:3][CH3:4].Cl[CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:25])([CH3:24])[CH3:23]>>[OH:25][C:22]([CH3:24])([CH3:23])[CH2:21][CH2:20][CH2:19][CH2:18][N:11]1[C:12](=[O:14])[C:13]2[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH:6]=[N:7][C:8]=2[N:9]([CH3:16])[C:10]1=[O:15]
Reactant: CC(C)(O)CCCCCl
Reactant: CCCCn1cnc2c1c(=O)[nH]c(=O)n2C
Product: CCCCn1cnc2c1c(=O)n(CCCCC(C)(C)O)c(=O)n2C

Procedure:
The title compound was prepared by using 7-butyl-3-methylxanthine and 1-chloro-5-hydroxy-5-methylhexane as starting materials. C17H28N4O3 (molecular weight=336.4); the oily product was characterized and identified by NMR mass-spectroscopy.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)=[N:5][C:6]([CH3:9])=[CH:7][CH:8]=1.C1C(=O)N([Br:27])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:27][CH2:9][C:6]1[N:5]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[C:3]([O:2][CH3:1])=[CH:8][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc(C)nc1-c1cccc(C(F)(F)F)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc(CBr)nc1-c1cccc(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 20 h
Yield: 44 %

Procedure:
To the 3-methoxy-6-methyl-2-(3-trifluoromethyl-phenyl)-pyridine synthesized above (1.3 g, 4.86 mmol) and NBS (1.04 g, 5.83 mmol) in CCl4 (25 mL) was added benzoyl peroxide (0.12 g, 0.49 mmol). The reaction was stirred at 80° C. under N2 for 20 h. The reaction was cooled to room temperature and concentrated. The residue was dissolved in mixture of dichloromethane and hexanes (1:1, 8 mL) and purified by silica gel column chromatography using 1:1 dichloromethane-hexanes to afford 0.74 g (44%) of 6-bromomethyl-3-methoxy-2-(3-trifluoromethyl-phenyl)-pyridine as off-white solid.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=1.[OH:18][CH2:19][C:20]([CH2:22][OH:23])=[O:21]>>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:17]=[CH:16][C:13]([CH:14]([OH:15])[CH:19]([OH:18])[C:20](=[O:21])[CH2:22][OH:23])=[CH:12][CH:11]=1
Reactant: O=C(CO)CO
Reactant: O=Cc1ccc(-c2nc3ccccc3o2)cc1
Product: O=C(CO)C(O)C(O)c1ccc(-c2nc3ccccc3o2)cc1

Procedure:
Compound B was prepared as a mixture of isomers in analogy to example 1 from 4-benzoxazol-2-yl-benzaldehyde and 1,3-dihydroxyacetone.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([N:13]3[CH2:20][CH:19]4[CH:15]([CH2:16][NH:17][CH2:18]4)[CH2:14]3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[C:29]([C:34](O)=[O:35])=[CH:30][CH:31]=[CH:32][CH:33]=2)=[CH:24][CH:23]=1>>[CH3:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:34]([N:17]2[CH2:16][CH:15]3[CH:19]([CH2:20][N:13]([C:9]4[N:8]=[C:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)[CH:12]=[CH:11][N:10]=4)[CH2:14]3)[CH2:18]2)=[O:35])=[CH:26][CH:27]=1
Reactant: Cc1ccc(-c2ccccc2C(=O)O)cc1
Reactant: c1ccc(-c2ccnc(N3CC4CNCC4C3)n2)cc1
Product: Cc1ccc(-c2ccccc2C(=O)N2CC3CN(c4nccc(-c5ccccc5)n4)CC3C2)cc1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 26 and 4′-methyl-biphenyl-2-carboxylic acid. MS (ESI): mass calculated for C30H28N4O, 460.58; m/z found 461.3 [M+H]+.