Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[C:14](=[O:15])[N:13]=[C:12]([CH2:16][C:17]2([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)[N:11]2[CH2:29][CH2:30][N:31]([CH:34]([CH3:36])[CH3:35])[C:32](=[O:33])[C:10]=12)C1C=CC=CC=1.C1(C2C=CC=CC=2)C=CC=CC=1CC1N2CCN(C)C(=O)C2=C(O)C(=O)N=1>>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([C:17]2([CH2:16][C:12]3[N:11]4[CH2:29][CH2:30][N:31]([CH:34]([CH3:36])[CH3:35])[C:32](=[O:33])[C:10]4=[C:9]([OH:8])[C:14](=[O:15])[N:13]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:23][CH:24]=1
Reactant: CC(C)N1CCn2c(CC3(c4ccc(Cl)cc4)CCCC3)nc(=O)c(OCc3ccccc3)c2C1=O
Agent: CN1CCn2c(Cc3ccccc3-c3ccccc3)nc(=O)c(O)c2C1=O
Product: CC(C)N1CCn2c(CC3(c4ccc(Cl)cc4)CCCC3)nc(=O)c(O)c2C1=O
Yield: 62.8 %

Procedure:
6-[1-(4-chlorophenyl)-cyclopentylmethyl]-9-hydroxy-2-isopropyl-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (32-03) (465 mg, 62.8%) was synthesized from 9-benzyloxy-6-[1-(4-chlorophenyl)-cyclopentylmethyl]-2-isopropyl-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (31-03) (900 mg, 1.779 mmol) as an off-white solid following the procedure as described for 6-biphenyl-2-ylmethyl-9-hydroxy-2-methyl-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (12-01).
Reaction SMILES: [C:1](C1ON=CC=1)#[N:2].[NH2:8][C:9]1[S:10][CH:11]=[C:12]([CH3:19])[C:13]=1[C:14](OCC)=O.O=P(Cl)(Cl)Cl>>[CH3:19][C:12]1[C:13]2[CH:14]=[N:2][CH:1]=[N:8][C:9]=2[S:10][CH:11]=1
Reactant: CCOC(=O)c1c(C)csc1N
Reactant: N#Cc1ccno1
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1csc2ncncc12

Procedure:
With the procedure of Example 477, the reaction of 5-cyanoisoxazole and 2-amino-4-methyl-3-ethoxycarbonyl-thiophene, and the subsequent reaction with POCl3 yields 4-chloro-2-isoxazol-5-yl)-5-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:14][CH2:15][CH2:16][OH:17])=[C:4]([S:8]([N:11]([CH3:13])[CH3:12])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH:18](O)=O>Cl>[OH:17][CH2:16][CH2:15][N:14]1[C:3]2[C:4]([S:8]([N:11]([CH3:13])[CH3:12])(=[O:9])=[O:10])=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=[CH:18]1
Reactant: CN(C)S(=O)(=O)c1cccc(N)c1NCCO
Reactant: O=CO
Agent: Cl
Product: CN(C)S(=O)(=O)c1cccc2ncn(CCO)c12

Procedure:
A solution of 3-amino-2-[(2-hydroxyethyl)amino]-N,N-dimethylbenzenesulfonamide (69 mg, 0.266 mmol) in formic acid (2 mL) and 2 M hydrochloric acid (2 mL) was heated at reflux for 1 h. The volatiles were removed in vacuo, and the residue was partitioned between an aqueous sodium hydroxide solution and ethyl acetate. The organic phase was dried over magnesium sulfate and concentrated in vacuo affording 1-(2-hydroxyethyl)-N,N-dimethyl-1H-benzimidazole-7-sulfonamide, 66 mg. MS (ES) m/z 270 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:10])=[N:4][S:5][C:6]=1[C:7]([OH:9])=[O:8].[C:11](Cl)(=O)[CH2:12][CH2:13][CH3:14].Cl>N1C=CC=CC=1.C(Cl)(Cl)Cl>[CH3:10][C:3]1[C:2]2[N:1]=[C:11]([CH2:12][CH2:13][CH3:14])[O:8][C:7](=[O:9])[C:6]=2[S:5][N:4]=1
Reactant: CCCC(=O)Cl
Reactant: Cc1nsc(C(=O)O)c1N
Agent: Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CCCc1nc2c(C)nsc2c(=O)o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-amino-3-methyl-isothiazole-5-carboxylic acid (method 57) (2.91 g, 15 mmol) in pyridine (20 mL) at 0° C., was added dropwise a solution of butyryl chloride (3.18 g, 30 mmol) in chloroform (30 mL). The reaction mixture was allowed to warm to room temperature and stirred overnight. Chloroform (200 mL) was added to the reaction mixture followed by 2M HCl (200 mL) and the mixture was stirred. The chloroform layer was further washed with 2M HCl (100 mL), water (100 mL), brine (100 mL) and concentrated. Column purification of the thus obtained crude product provided the pure product as light brown solid. Yield 2 g (64%). 1H NMR (300 MHz) δ 1.03 (t, 3H), 1.80-1.92 (m, 2H), 2.65 (s, 3H), 2.76 (t, 2H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][C:10]=1[CH:23]=[O:24])([CH3:4])([CH3:3])[CH3:2].CC(=CC)C.[O-:31]Cl=O.[Na+]>C(O)(C)(C)C.O>[CH2:16]([O:15][C:12]1[CH:13]=[CH:14][C:9]([CH:8]=[CH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:25])=[C:10]([CH:11]=1)[C:23]([OH:31])=[O:24])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC(C)(C)OC(=O)C=Cc1ccc(OCc2ccccc2)cc1C=O
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: CC(C)(C)OC(=O)C=Cc1ccc(OCc2ccccc2)cc1C(=O)O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 96.6 %

Procedure:
A solution of 3-(4-benzyloxy-2-formyl-phenyl)-acrylic acid tert-butyl ester (6.70 g, 19.8 mmol) in tert-butanol (150 mL) was treated with 2-methyl-2-butene (50 mL) and cooled to 0° C. A solution of NaClO2 (17.0 g, 188 mmol) and NaH2PO4 (17.0 g, 142 mmol) in H2O (200 mL) was added, and the mixture was stirred at 0° C. for 15 min. The ice bath was removed, and the mixture was stirred at room temperature for 2 h. The organic layer was separated, and the aqueous layer was extracted with EtOAc (2×100 mL). The combined organic layers were dried (Na2SO4) and concentrated. The residue was purified using silica gel chromatography (hexanes/EtOAc 9/1 to 0/10) to afford the title compound as white solid (6.78 g, 96%). 1H NMR (400 MHz, CDCl3): δ 1.52 (s, 9H), 5.12 (s, 2H), 6.20 (d, 1H, J=16.2 Hz), 7.13 (dd, 1H, J=3.6, 9.0 Hz), 7.34-7.45 (m, 5H), 7.58 (d, 1H, J=8.8 Hz), 7.64 (d, 1H, J=2.4 Hz), 8.41 (d, 1H, J=16.2 Hz).
Reaction SMILES: [CH3:1][NH:2][NH2:3].[Cl:4][C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:6]=1[C:12](=O)[C:13]([CH3:19])=[C:14](SC)[S:15][CH3:16]>C(#N)C>[Cl:4][C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:6]=1[C:12]1[C:13]([CH3:19])=[C:14]([S:15][CH3:16])[N:2]([CH3:1])[N:3]=1
Reactant: CNN
Reactant: CSC(SC)=C(C)C(=O)c1ccc(Cl)cc1Cl
Solvent: CC#N
Product: CSc1c(C)c(-c2ccc(Cl)cc2Cl)nn1C
Temperature: 80 °C

Procedure:
0.138 g (0.003 mol) of methyl hydrazine is added to a solution of 0.614 g (0.002 mol) of 1-(2,4-dichlorophenyl)-3,3-bis(methylthio)-2-methyl-2-propen-1-one in 10 ml of acetonitrile and the reaction mixture is heated at 80° C. for 8 hours. The mixture is then concentrated in vacuo and the residue is taken up in ether, washed with water and dried over sodium sulfate. After the ether phase has been concentrated by evaporation, the residue is purified by column chromatography over silica gel with hexane/ethyl acetate 2/1 as eluant. The desired product is obtained in a yield of 0.425 g (74.0%) in the form of a white solid having a melting point of 65-66° C. (recrystallised from hexane).
Reaction SMILES: [C:1]1([CH2:7][NH:8][CH2:9][C@H:10]2[CH2:15][O:14][CH2:13][CH2:12][N:11]2[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)C(C)C)(C)C.Cl[C:33](=[O:39])[C:34]([O:36][CH2:37][CH3:38])=[O:35]>C1COCC1>[O:39]=[C:33]([N:8]([CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH2:9][C@H:10]1[CH2:15][O:14][CH2:13][CH2:12][N:11]1[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:34]([O:36][CH2:37][CH3:38])=[O:35]
Reactant: c1ccc(CNC[C@H]2COCCN2Cc2ccccc2)cc1
Reactant: CCOC(=O)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(=O)N(Cc1ccccc1)C[C@H]1COCCN1Cc1ccccc1
Temperature: 25 °C

Procedure:
A solution of 1-phenyl-N-{[(3S)-4-(phenylmethyl)-3-morpholinyl]methyl}methanamine (assumed 87.79 g, 296.2 mmol) and N,N-diisopropylethylamine (67.1 mL, 385.2 mmol) in THF (1000 mL) was cooled to 0° C. To the solution was added ethyl chloro(oxo)acetate (36.3 mL, 326.2 mmol) dropwise via addition funnel. The resulting mixture was allowed to stir and warm to room temperature for 1 h. The solvent was then removed in vacuo to approximately 20% volume, and the residue was partitioned between EtOAc (600 mL), water (100 mL) and sat. aqueous NaHCO3 (500 mL). The aqueous phase was extracted with a fresh portion of EtOAc (200 mL), and the combined organic phase was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was then azeotroped with EtOH (100 mL) to provide ethyl oxo((phenylmethyl){[(3S)-4-(phenylmethyl)-3-morpholinyl]methyl}amino)acetate as a yellow oil that was used without further purification. LCMS: (M+H)+: 397.2.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([C:12]2[C:13]([CH3:43])([CH3:42])[C@H:14]3[C@:27]([CH3:30])([CH2:28][CH:29]=2)[C@@H:26]2[C@:17]([CH3:41])([C@@:18]4([CH3:40])[C@H:23]([CH2:24][CH2:25]2)[C@H:22]2[C@H:31]([C:34]([CH3:36])=[CH2:35])[CH2:32][CH2:33][C@:21]2([N:37]=C=O)[CH2:20][CH2:19]4)[CH2:16][CH2:15]3)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[ClH:44]>C1COCC1.O>[ClH:44].[ClH:44].[NH2:37][C@:21]12[CH2:33][CH2:32][C@@H:31]([C:34]([CH3:36])=[CH2:35])[C@@H:22]1[C@@H:23]1[C@@:18]([CH3:40])([CH2:19][CH2:20]2)[C@@:17]2([CH3:41])[C@@H:26]([C@:27]3([CH3:30])[C@@H:14]([CH2:15][CH2:16]2)[C:13]([CH3:42])([CH3:43])[C:12]([C:10]2[CH:9]=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([F:1])[CH:11]=2)=[CH:29][CH2:28]3)[CH2:25][CH2:24]1
Reactant: C=C(C)[C@@H]1CC[C@]2(N=C=O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)c(F)c6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: C=C(C)[C@@H]1CC[C@]2(N)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)c(F)c6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reaction time: 24 h
Yield: 86.8 %

Procedure:
To a solution of crude methyl 2-fluoro-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-isocyanato-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (2.93 g, 4.99 mmol) in THF (35 mL) was added 12N HCl (10 mL, 121 mmol). After stirring the mixture for 24 h, the mixture was diluted with water (100 mL) until solids precipitated. The solids were collected by filtration and were washed with water to afford the title compound (2.75 g, 4.33 mmol, 87% yield), as an off-white solid that was used in the next step with no additional purification. LCMS: m/e 562 (M+H)+, 1.96 min (method 2).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[C:5](=[O:8])[C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:26][CH2:27][CH:28]=[C:29]([F:31])[F:30])[CH:20]=2)([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH:16]([F:18])[F:17])=[CH:11][CH:10]=2)[N:3]=1>C(Cl)(Cl)Cl>[NH2:1][C:2]1[N:6]([CH3:7])[C:5](=[O:8])[C@@:4]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:26][CH2:27][CH:28]=[C:29]([F:31])[F:30])[CH:20]=2)([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH:16]([F:17])[F:18])=[CH:11][CH:10]=2)[N:3]=1
Reactant: CN1C(=O)C(c2ccc(OC(F)F)cc2)(c2cccc(OCCC=C(F)F)c2)N=C1N
Solvent: ClC(Cl)Cl
Product: CN1C(=O)[C@](c2ccc(OC(F)F)cc2)(c2cccc(OCCC=C(F)F)c2)N=C1N

Procedure:
A racemic mixture of 2-amino-5-{3-[(4,4-difluorobut-3-en-1-yl)oxy]phenyl}-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one was separated by chiral HPLC using column type Chiralcel AD, 2×25 cm; the mobile phase was 14% ethanol in hexane with 0.1% diethylamine at 20 mL/min to obtain the title S-isomer as a glass, identified by NMR and mass spectral analyses [mp glass; [α]D25=−31.0° (c=1% SOLUTION, CHCl3); MS (ES) m/z 436.2].
Reaction SMILES: [CH:1]([N:14]1[C:18]2=[N:19][C:20]([CH3:24])=[CH:21][C:22]([CH3:23])=[C:17]2[C:16]([C:25]#[N:26])=[C:15]1/[CH:27]=[CH:28]/[C:29]([O:31]CC)=[O:30])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].O.Cl>C(O)C.C1COCC1>[CH:1]([N:14]1[C:18]2=[N:19][C:20]([CH3:24])=[CH:21][C:22]([CH3:23])=[C:17]2[C:16]([C:25]#[N:26])=[C:15]1/[CH:27]=[CH:28]/[C:29]([OH:31])=[O:30])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)/C=C/c1c(C#N)c2c(C)cc(C)nc2n1C(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: Cc1cc(C)c2c(C#N)c(/C=C/C(=O)O)n(C(c3ccccc3)c3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
To a solution of ethyl (2E)-3-(1-benzhydryl-3-cyano-4,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-2-yl)propenoate (1.52 g, 3.59 mmol) in ethanol (14 ml) and THF (10 ml) was added a 1 N aqueous sodium hydroxide solution (7.2 ml) and the mixture was stirred at room temperature for 7 hours. The reaction solution was poured into water, neutralized with 1 N hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure to give the objective product as a solid material.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10](=[O:33])(=[O:32])[NH:11][C:12]1[CH:31]=[CH:30][C:15]2[N:16]([CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:17]([CH2:19][CH2:20][CH3:21])=[N:18][C:14]=2[CH:13]=1.CCN(CC)CC>CO>[C:26]([O:25][C:23](=[O:24])[CH2:22][N:16]1[C:15]2[CH:30]=[CH:31][C:12]([N:11]3[C:3](=[O:2])[C:4]4[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=4[S:10]3(=[O:33])=[O:32])=[CH:13][C:14]=2[N:18]=[C:17]1[CH2:19][CH2:20][CH3:21])([CH3:29])([CH3:28])[CH3:27]
Reactant: CCCc1nc2cc(NS(=O)(=O)c3ccccc3C(=O)OC)ccc2n1CC(=O)OC(C)(C)C
Solvent: CO
Solvent: CCN(CC)CC
Product: CCCc1nc2cc(N3C(=O)c4ccccc4S3(=O)=O)ccc2n1CC(=O)OC(C)(C)C
Temperature: 110 °C

Procedure:
The product of step b.) (33 mg, 0.069 mmol) was stirred in methanol (2 mL) with Et3N (10 μL, 0.069 mmol) at 65° C. for two hours without change. The reaction was concentrated to dryness and redissolved in toluene (2 mL). Et3N (10 μL, 0.069 mmol) was added to the solution and the reaction was heated to 110° C. overnight. Additional Et3N (35 μL, 0.242 mmol) was added and the reaction was heated overnight to complete reaction. The reaction was then concentrated to give the sub-title compound that was used in crude form without purification. MS: ESI (positive): 456 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:28])=[C:4]([NH:10][C@H:11]([C@@H:25]([OH:27])[CH3:26])[C:12]([NH:14][NH:15][C:16](=[O:24])[C:17]2[CH:22]=[CH:21][C:20]([I:23])=[CH:19][CH:18]=2)=[O:13])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].N1C=CN=C1.[CH3:34][C:35]([Si:38](Cl)([CH3:40])[CH3:39])([CH3:37])[CH3:36]>CN(C=O)C>[Si:38]([O:27][C@@H:25]([CH3:26])[C@@H:11]([NH:10][C:4]1[CH:5]=[CH:6][C:7]([C:8]#[N:9])=[C:2]([Cl:1])[C:3]=1[CH3:28])[C:12]([NH:14][NH:15][C:16](=[O:24])[C:17]1[CH:22]=[CH:21][C:20]([I:23])=[CH:19][CH:18]=1)=[O:13])([C:35]([CH3:37])([CH3:36])[CH3:34])([CH3:40])[CH3:39]
Reactant: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc(I)cc2)[C@H](C)O)ccc(C#N)c1Cl
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc(I)cc2)[C@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.6 %

Procedure:
To a solution of N′-((2R,3S)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoyl)-4-iodobenzohydrazide (7.3 g, 14.2 mmol) in DMF (60 mL) were added imidazole (3.9 g, 57.3 mmol) and TBSCl (4.3 g, 28.5 mmol) at 0° C. After addition, the mixture was allowed to warm to room temperature gradually and stirred overnight. The reaction was quenched by adding ice-water and extracted with EtOAc. The EtOAc extracts were washed with water, brine and dried over Na2SO4. Removal of the solvent gave a residue, which was purified by SiO2 column to give the title compound (8.6 g, 97%), which was used directly in the next step.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]3[O:15][CH2:14][C@H:13]([CH2:16]OS(C4C=CC(Br)=CC=4)(=O)=O)[O:12][C:8]3=2)[N:3]=1.[NH:28]1[CH2:31][CH:30]([CH2:32][C:33]2[C:41]3[C:36](=[CH:37][CH:38]=[C:39]([CH3:42])[CH:40]=3)[NH:35][CH:34]=2)[CH2:29]1>>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]3[O:15][CH2:14][CH:13]([CH2:16][N:28]4[CH2:31][CH:30]([CH2:32][C:33]5[C:41]6[C:36](=[CH:37][CH:38]=[C:39]([CH3:42])[CH:40]=6)[NH:35][CH:34]=5)[CH2:29]4)[O:12][C:8]3=2)[N:3]=1
Reactant: Cc1ccc2c3c(ccc2n1)OC[C@H](COS(=O)(=O)c1ccc(Br)cc1)O3
Reactant: Cc1ccc2[nH]cc(CC3CNC3)c2c1
Product: Cc1ccc2[nH]cc(CC3CN(CC4COc5ccc6nc(C)ccc6c5O4)C3)c2c1

Procedure:
This compound was prepared as described for Example 10, using (2R)-4-bromobenzenesulfonic acid 8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-2-ylmethyl ester (0.4 g, 0.9 mmol), 3-azetidin-3-ylmethyl-5-methyl-1H-indole (0.19 g, 0.9 mmol), to afford 0.15 g of the (S)-enantiomer of the title compound as a light brown oil. The hydrochloride salt was prepared in ethyl acetate and collected as a yellow solid, m.p. 150° C. (dec).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([Br:16])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[C:24]([CH3:31])([CH3:30])[C:25]([O:27][CH2:28][CH3:29])=[O:26]>CN(C=O)C>[CH2:28]([O:27][C:25](=[O:26])[C:24]([O:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:10][C:11]=1[Br:16])([CH3:31])[CH3:30])[CH3:29]
Reactant: Oc1ccc(OCc2ccccc2)cc1Br
Reactant: CCOC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Oc1ccc(OCc2ccccc2)cc1Br
Temperature: 55 °C
Yield: 34.7 %

Procedure:
A mixture of 4-benzyloxy-2-bromo-phenol (9.37 g, 33.6 mmol) and Cs2CO3 (21.9 g, 67.2 mmol) in DMF (80 mL) was treated with ethyl bromoisobutyrate (15 mL, 100 mmol) and heated at 55° C. for 18 h. The reaction mixture was cooled and partitioned between ethyl acetate (250 mL) and H2 (100 mL). The organic layer was washed with brine (75 mL), dried (Na2SO4), and concentrated. The crude product was purified by flash chromatography using CH2Cl2:hexanes (2:3 to 3:2) to give a pale yellow oil (4.58 g, 35%): 1H NMR (400 MHz, CDCl3) δ1.29 (t, 3H, J=7.1 Hz), 1.57 (s, 6H), 4.25 (q, 2H, J=7.1 Hz), 4.98 (s, 2H), 6.79 (dd, 1H, J=3.2, 9.1 Hz), 6.89 (d, 1H, J=8.8 Hz), 7.17 (d, 1H, J=3.4 Hz), 7.32-7.40 (m, 5H); MS (ES) m/e #[M+1].
Reaction SMILES: C([O:4][C:5]1[CH:9]=[N:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][CH:11]=2)[N:6]=1)(=O)C.CO.[OH-].[Li+].Cl>O1CCOCC1.O>[Br:16][C:13]1[CH:12]=[CH:11][C:10]([N:7]2[N:6]=[C:5]([OH:4])[CH:9]=[N:8]2)=[CH:15][CH:14]=1
Reactant: CC(=O)Oc1cnn(-c2ccc(Br)cc2)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Solvent: CO
Product: Oc1cnn(-c2ccc(Br)cc2)n1
Temperature: 25 °C
Reaction time: 36 h

Procedure:
2-(4-bromophenyl)-2H-1,2,3-triazol-4-yl acetate (520 mg, 1.84 mmol) was treated with methanol (10 ml) and water (10 ml) followed by 1,4-dioxane (5 ml). The resulting solution was treated with lithium hydroxide (265 mg, 11.1 mmol). The reaction mixture was stirred at RT for 36 hours. 1N HCl (40 ml) was added to the reaction mixture and the product was extracted with ethyl acetate (3×100 ml). The combined organic phases were dried over potassium carbonate, filtered, and concentrated. The crude material was purified by chromatography on silica gel (4:1 heptane:EtOAc 1:4 heptane:EtOAc) to furnish a light tan solid (440 mg, 98% TY). MS (LC/MS) m/z 240.21 (M+1). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.33 (s, 1H) 7.58 (d, J=8.98 Hz, 2H) 7.78 (d, J=8.98 Hz, 2H).
Reaction SMILES: Cl.[NH:2]=[C:3]=[O:4].[CH3:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[CH2:7].C(Cl)(=O)N.C(Cl)(C1C=CC=CC=1)(C)C>C1(C)C=CC=CC=1.C(C(CC(C)C)=O)C(C)C.[Cl-].[Zn+2].[Cl-]>[C:6]([N:2]=[C:3]=[O:4])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:7])[CH3:5]
Reactant: N=C=O
Reactant: C=C(C)c1ccccc1
Agent: CC(C)(Cl)c1ccccc1
Agent: Cl
Agent: NC(=O)Cl
Solvent: CC(C)CC(=O)CC(C)C
Solvent: Cc1ccccc1
Product: CC(C)(N=C=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 75 %

Procedure:
0.365 grams of dry hydrogen chloride (0.010 mole) was introduced into a solution of 0.43 grams of isocyanic acid (0.010 mole) in 3.44 grams of toluene at 0° under a nitrogen atmosphere. 1.18 gram of α-methylstyrene (0.010 mole) was added to the resultant carbamoyl chloride solution over a period of ten minutes while maintaining the temperature at 0° C. After fifteen minutes, cumyl chloride was present in 75% yield. 11.5 ml of 20.4% isocyanic acid in toluene (0.050 mole) was then added at 0° C. followed by addition of 0.50 ml of 1 M zinc chloride (0.00050 mole) in diisobutyl ketone over a period of 2 minutes at 0° C. After 5 minutes, cumyl isocyanate (b.p 50° C./1 mm was formed in 75% yield based α-methylstyrene.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][C@:18]([CH:21]4[CH2:26][CH2:25][N:24]([C:27]#[N:28])[CH2:23][CH2:22]4)([CH3:20])[O:17][C:14]3=[CH:15][N:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[OH:29][NH:30][C:31](=N)[CH2:32][CH2:33][CH3:34]>>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][C:18]([CH3:20])([CH:21]4[CH2:22][CH2:23][N:24]([C:27]5[O:29][N:30]=[C:31]([CH2:32][CH2:33][CH3:34])[N:28]=5)[CH2:25][CH2:26]4)[O:17][C:14]3=[CH:15][N:16]=2)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: C[C@@]1(C2CCN(C#N)CC2)Cc2cc(-c3ccc(S(C)(=O)=O)cc3)ncc2O1
Reactant: CCCC(=N)NO
Product: CCCc1noc(N2CCC(C3(C)Cc4cc(-c5ccc(S(C)(=O)=O)cc5)ncc4O3)CC2)n1

Procedure:
The title compound is prepared from (S)-4-[5-(4-methanesulfonyl-phenyl)-2-methyl-2,3-dihydro-furo[2,3-c]pyridin-2-yl]-piperidine-1-carbonitrile (Intermediate 33; the configuration of the stereocenter is arbitrarily assigned) and N-hydroxy-butyramidine following a procedure analogous to that described in Example 2. LC (method 6): tR=1.25 min; Mass spectrum (ESI+): m/z=483 [M+H]+.
Reaction SMILES: Cl[C:2]1C=[C:11]([NH:13][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][N:3]=1.COS(OC)(=O)=O.C(N(CC)CC)C.CC(O)=O.[CH3:42][CH2:43][OH:44]>C(Cl)(Cl)Cl>[CH3:2][N:3]1[C:43](=[O:44])[CH:42]=[C:11]([NH:13][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4]1
Reactant: CCOC(=O)c1cnc(Cl)cc1Nc1ccc2ccccc2c1
Reactant: CCO
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cn(C)c(=O)cc1Nc1ccc2ccccc2c1
Yield: 57 %

Procedure:
Ethyl 6-chloro-4-(2-naphthylamino)nicotinate was dissolved in CHCl3 and reacted with Me2SO4, followed by triethylamine, AcOH and EtOH as described for example 33, step B. Purification by recrystallisation (EtOAc/Hexane) afforded ethyl 1-methyl-4-(2-naphthylamino)-6-oxo-1,6-dihydro-3-pyridinecarboxylate as a white solid (57%); m.p. (EtOAc/Hexane) 160-163° C. 1H NMR [400 MHz, (CD3)2SO] δ 9.55 (s, 1H), 8.57 (s, 1H), 7.97 (d, J=8.8 Hz, 1H), 7.91 (dd, J=7.7, 4.7 Hz, 2H), 7.81 (d, J=1.8 Hz, 1H), 7.55-7.43 (m, 3H), 5.79 (s, 1H), 4.32 (q, J=7.1 Hz, 2H), 3.43 (s, 3H), 1.35 (t, J=7.1 Hz, 3H). Anal. Calcd for C19H18N2O3: C, 70.8; H, 5.6; N, 8.7. Found C, 70.8; H, 5.5; N, 8.7.
Reaction SMILES: C(N(CC)CC)C.I[CH2:9][C:10]([NH2:12])=[O:11].[C:13]1([C:19]2[C:20]3[N:21]([CH2:36][CH2:37][N:38]=3)[C:22]3[C:27]([N+:28]=2[O-:29])=[CH:26][CH:25]=[C:24]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:23]=3)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(O)C>[O-:29][N+:28]1[C:27]2[C:22](=[CH:23][C:24]([N:30]3[CH2:35][CH2:34][N:33]([CH2:9][C:10]([NH2:12])=[O:11])[CH2:32][CH2:31]3)=[CH:25][CH:26]=2)[N:21]2[CH2:36][CH2:37][N:38]=[C:20]2[C:19]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: [O-][N+]1=C(c2ccccc2)C2=NCCN2c2cc(N3CCNCC3)ccc21
Reactant: NC(=O)CI
Solvent: CCO
Solvent: CCN(CC)CC
Product: NC(=O)CN1CCN(c2ccc3c(c2)N2CCN=C2C(c2ccccc2)=[N+]3[O-])CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.7 %

Procedure:
Triethylamine (0.75 g, 0.0072 mol.) was added to a solution of iodoacetamide (0.59 g, 0.0032 mol.) and 1,2-dihydro-4-phenyl-8-piperazinylimidazo[1,2-a]quinoxaline 5-oxide (1.0 g, 0.0029 mol.) in ethanol (50 ml) and the reaction mixture stirred overnight at room temperature. The resulting precipitate was removed by filtration, washed with ethanol and then ether. Recrystallization from ethanol yielded 2-[4-(1,2-dihydro-5-oxido-4-phenylimidazo[1,2-a]-quinoxalin-8-yl)piperazinyl]acetamide, (0.63 g) as bright yellow crystals, m.p. 225°-227° C. (Found: C, 63.50; H, 5.89; N, 19.72%; C22H24N6O6.O.75H2O requires C, 63.23; H, 6.11; N, 20.12%) represented by the structural formula: ##STR32##