Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]12[CH2:20][C:19]3[CH:18]=[C:17]([O:21][CH3:22])[CH:16]=[CH:15][C:14]=3[C:13]1=[C:12]([CH3:23])[C:11](=[O:24])[CH2:10][CH2:9]2)(=O)=O.[I-:25].[Na+]>CC(C)=O>[I:25][CH2:6][CH2:7][C:8]12[CH2:9][CH2:10][C:11](=[O:24])[C:12]([CH3:23])=[C:13]1[C:14]1[C:19](=[CH:18][C:17]([O:21][CH3:22])=[CH:16][CH:15]=1)[CH2:20]2
Reactant: [I-]
Reactant: COc1ccc2c(c1)CC1(CCOS(C)(=O)=O)CCC(=O)C(C)=C21
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1ccc2c(c1)CC1(CCI)CCC(=O)C(C)=C21
Temperature: 60 °C
Yield: 63.6 %

Procedure:
A solution of 2-(2-methoxy-5-methyl-6-oxo-6,7,8,9-tetrahydro-8aH-fluoren-8a-yl)ethyl methanesulfonate (49.7 mg, 0.142 mmol) in acetone (2.0 mL) was treated with sodium iodide (85 mg, 0.57 mmol) and the resulting mixture was stirred and heated in an oil bath at 60° C. for 16 hours. After cooling, the mixture was diluted with acetone (2 mL) and filtered through a 0.45 Fm Acrodisc filter. The filtrate was evaporated under vacuum and the residue in CH2Cl2 (3 mL) was re-filtered. The filtrate was purified by chromatography on a Biotage Flash 12M KP-Sil column (12 mm×15 cm) which was eluted with 4:1 hexanes-EtOAc, collecting 6 mL fractions every 30 seconds. Fractions 9-11 gave 9a-(2-iodoethyl)-7-methoxy-4-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one (34.5 mg, 64% yield) as an oil.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]([NH:8][CH2:9][CH:10]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[CH3:11])=[N:6][CH:7]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:25]=[CH:26][C:27]([C:30]#[CH:31])=[N:28][CH:29]=2)=[CH:20][CH:19]=1>>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[CH:25]=[CH:26][C:27]([C:30]#[C:31][C:2]3[CH:3]=[CH:4][C:5]([NH:8][CH2:9][CH:10]([N:12]4[CH2:16][CH2:15][CH2:14][CH2:13]4)[CH3:11])=[N:6][CH:7]=3)=[N:28][CH:29]=2)=[CH:22][CH:23]=1
Reactant: CC(CNc1ccc(I)cn1)N1CCCC1
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Product: CC(CNc1ccc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)cn1)N1CCCC1

Procedure:
Prepared according to general working method I from (5-iodo-pyridin-2-yl)-(2-pyrrolidin-1-yl-propyl)-amine (250 mg, 0.76 mmol) and 5-(4-chloro-phenyl)-2-ethynyl-pyridine (165 mg, 0.77 mmol).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:10]([O:12][C:13](=[O:16])[CH:14]=[CH2:15])[CH3:11]>CCO>[CH2:10]([O:12][C:13](=[O:16])[CH2:14][CH2:15][NH:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:11]
Reactant: NCCc1ccccc1
Reactant: C=CC(=O)OCC
Solvent: CCO
Product: CCOC(=O)CCNCCc1ccccc1

Procedure:
Phenylethyl amine (10 g) was dissolved in EtOH (50 ml) and then treated with acrylic acid ethyl ester (8.3 g) dropwise under argon at RT. The resulting mixture was allowed to stir over night and was evaporated and dried in vacuo. The residue (18.9 g) was used without further purification. Colorless liquid, MS (ESI): 222.3 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:33])[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15](=[O:32])[C@H:16]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[NH:17]C(OC(C)(C)C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:34]>O1CCOCC1.O>[ClH:34].[CH2:1]([O:8][C:9](=[O:33])[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15](=[O:32])[C@H:16]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[NH2:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: N[C@@H](Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 100 %

Procedure:
N-t-butyloxycarbonyl-L-phenylalanyl-L-proline benzylester (29.87 g, 66 mmole) was dissolved in 4.5N hydrochloric acid in dioxane solution (220 ml), and stirred for 1.5 hours at room temperature. The solvent was distilled off under reduced pressure, and gelatinous solid material thus obtained was dissolved in water (250 ml). The solution was washed with diethyl ether and the water layer was freeze-dried to obtain L-phenylalanyl-L-proline benzylester hydrochloride(yield: 26.53 g, 100%).
Reaction SMILES: O.O.C([C@@](C(O)=O)(O)[C@@](C(=O)C1C=CC=CC=1)(O)C(O)=O)(=O)C1C=CC=CC=1.[O:29]=[C:30]([N:44]1[CH2:49][CH2:48][N:47]2[C:50]([C:53]([F:56])([F:55])[F:54])=[N:51][N:52]=[C:46]2[CH2:45]1)[CH2:31][CH:32]([NH2:43])[CH2:33][C:34]1[CH:39]=[C:38]([F:40])[C:37]([F:41])=[CH:36][C:35]=1[F:42]>CC(O)C>[O:29]=[C:30]([N:44]1[CH2:49][CH2:48][N:47]2[C:50]([C:53]([F:56])([F:55])[F:54])=[N:51][N:52]=[C:46]2[CH2:45]1)[CH2:31][C@@H:32]([NH2:43])[CH2:33][C:34]1[CH:39]=[C:38]([F:40])[C:37]([F:41])=[CH:36][C:35]=1[F:42]
Reactant: NC(CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Agent: O=C(O)[C@@](O)(C(=O)c1ccccc1)[C@@](O)(C(=O)O)C(=O)c1ccccc1
Solvent: CC(C)O
Solvent: O
Product: N[C@H](CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Temperature: 42.5 °C
Reaction time: 1 h

Procedure:
In a 50 mL three neck flask IPA (5 mL), water (2 mL) and Dibenzoyl-L-tartaric acid monohydrate (1.84 g) were taken. It was heated to 40-45° C. 4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine (2.0 g, % purity-94%) dissolved in IPA (5 mL) was added into reaction mixture at 60-65° C. It was stirred for 1 h at 60-65° C. It was gradually cooled to room temperature. Then it was further cooled to 0-5° C. and stirred for 1 h. The salt was filtered and washed with cold IPA. An enantiomerically enriched desired Dibenzoyl-L-tartaric acid salt of mixture of (2R) and (2S)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine was obtained (Wt.-1.1 g, % Y-28.7%, Purity by HPLC-99.1%, % Chiral purity by HPLC of R-isomer 74%).
Reaction SMILES: [C:1]1([NH:7][C:8]2[C:13](=[O:14])[NH:12][C:10](=[O:11])[CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:15](Cl)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C>CC(C)=O>[C:1]1([NH:7][C:8]2[C:13](=[O:14])[N:12]([C:15](=[O:22])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:10](=[O:11])[CH:9]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1C=C(Nc2ccccc2)C(=O)N1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: O=C1C=C(Nc2ccccc2)C(=O)N1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
1.88 g. (0.01 mole) of 3-phenylamino-maleinimide are dissolved in 70 ml. of acetone under stirring. To this mixture 2.1 g. (0.015 mole) of benzoyl chloride and 1.51 g. (0.015 mole) of triethylamine are added dropwise under simultaneous stirring. The temperature is maintained at 25°-30° C. during the addition. The mixture is then stirred for 2.5 hours at room temperature and heated for 1.5 hours. The mixture is allowed to stand overnight. The product is precipitating together with triethylaminechlorohydrate. The crystalline mixture is filtered and washed with 2×10 ml. of water. After drying a yellow crystalline product is obtained, which can be recrystallized from chloroform or acetone, if desired. 3-Phenylamino-N-benzoyl-maleinimide is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[CH2:18][C:17]2[C:12](=[N:13][C:14](S(C)(=O)=O)=[N:15][CH:16]=2)[N:11]([CH3:23])[C:10]1=[O:24].[CH2:25]([NH2:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.Cl>C(OCC)(=O)C>[CH2:25]([NH:32][C:14]1[N:13]=[C:12]2[N:11]([CH3:23])[C:10](=[O:24])[N:9]([C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=3[Cl:8])[CH2:18][C:17]2=[CH:16][N:15]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: NCc1ccccc1
Reactant: CN1C(=O)N(c2c(Cl)cccc2Cl)Cc2cnc(S(C)(=O)=O)nc21
Agent: Cl
Solvent: CCOC(C)=O
Product: CN1C(=O)N(c2c(Cl)cccc2Cl)Cc2cnc(NCc3ccccc3)nc21
Temperature: 180 °C
Yield: 77.4 %

Procedure:
A mixture of 110 mg (0.29 mmol) of 3-(2,6-dichlorophenyl)-7-methanesulfonyl-3,4-dihydro-1-methylpyrimido[4,5-d]pyrimidin-2(1H)-one and 0.31 ml (2.9 mmol) of benzylamine was heated at 180° C. for 10 minutes and then cooled. 30 ml of ethyl acetate and 30 ml of 2M aqueous hydrochloric acid were added to the residue. The phases were separated and the organic phase was washed in sequence with 20 ml of 5% aqueous sodium bicarbonate solution and 20 ml of brine, dried over magnesium sulfate, filtered and evaporated to give 93 mg (79%) of 7-benzylamino-3-(2,6-dichlorophenyl)-3,4-dihydro-1-methylpyrimido[4,5-d]pyrimidin-2(1H)-one as a white solid of melting point 195-198° C.
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH2:2][OH:3].[OH-].[Na+].Cl[C:11]1[N:21]=[CH:20][CH:19]=[CH:18][C:12]=1[C:13](OCC)=[O:14]>COCCOC>[OH:14][C:13]1[C:12]2[C:11](=[N:21][CH:20]=[CH:19][CH:18]=2)[O:3][C:2]=1[C:1]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)CO
Reactant: CCOC(=O)c1cccnc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Product: CCOC(=O)c1oc2ncccc2c1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41 %

Procedure:
Ethyl glycolate (35.5 mL, 375 mmol) is slowly added (over 20 min) to a slurry of NaOH (15.8 g, 394 mmol) in 1,2-dimethoxyethane (400 mL) in a dry flask under N2 with the flask being in an ice bath. The mixture is allowed to warm to rt, is stirred for 30 min, and ethyl 2-chloronicotinate (27.84 g, 150 mmol) in 1,2-dimethoxyethane (50 mL) is added over 10 min. The reaction is warmed to 65° C. for 15 h in an oil bath. The mixture is concentrated to dryness, the residue is dissolved in water (500 mL), washed with hexane (500 mL), acidified to pH 3 with 5% HCl, and extracted with CHCl3 (4×400 mL). The combined organic layer is dried over MgSO4, filtered, and concentrated to a yellow solid. The solid is suspended in ether (200 mL) and heated on a steam bath until concentrated to a volume of 40 mL. The material is allowed to crystallize overnight, then filtered to afford ethyl 3-hydroxyfuro[2,3-b]pyridine-2-carboxylate as a pale orange solid (41% yield). Additional material is obtained by concentrating the filtrate. Recrystallization in ether a second time affords ethyl 3-hydroxyfuro[2,3-b]pyridine-2-carboxylate (C40) as a pale yellow solid (7.3% yield). MS (EI) for C10H9NO4, m/z: 207 (M)+.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:38]([O:40][C:41]([CH:43]1[C@@H:48]2[C@H:44]1[CH2:45][NH:46][CH2:47]2)=[O:42])[CH3:39]>>[CH2:38]([O:40][C:41]([CH:43]1[C@@H:48]2[C@H:44]1[CH2:45][N:46]([C:32]([N:12]1[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=[C:11]1[C:8]1[CH:9]=[N:10][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:6][C:7]=1[O:35][CH2:36][CH3:37])=[O:33])[CH2:47]2)=[O:42])[CH3:39]
Reactant: CCOC(=O)C1[C@H]2CNC[C@@H]12
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOC(=O)C1[C@H]2CN(C(=O)N3C(c4cnc(C(C)(C)C)cc4OCC)=N[C@@](C)(c4ccc(Cl)cc4)[C@@]3(C)c3ccc(Cl)cc3)C[C@@H]12

Procedure:
In a manner analogous to the method described in examples 8, (4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 51) was coupled with (1S,5R)-3-aza-bicyclo-[3.1.0]hexane-6-carboxylic acid ethyl ester (Tyger Scientific) to give the title compound. HR-MS (ES, m/z) calculated for C37H43Cl2N4O4 [(M+H)+] 677.2656, observed 677.2655.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([S:12]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)(=[O:14])=[O:13])[CH2:8][CH2:7]1)=[O:5])C.[OH-].[Na+]>CO>[N:15]1([S:12]([N:9]2[CH2:10][CH2:11][CH:6]([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]2)(=[O:14])=[O:13])[CH2:16][CH2:17][O:18][CH2:19][CH2:20]1
Reactant: CCOC(=O)C1CCN(S(=O)(=O)N2CCOCC2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C1CCN(S(=O)(=O)N2CCOCC2)CC1
Temperature: 85 °C
Yield: 79.4 %

Procedure:
1-(Morpholine-4-sulfonyl)-piperidine-4-carboxylic acid ethyl ester (1.9 g) dissolved in methanol (80 ml) was treated at RT with 2M NaOH (15.5 ml) and the mixture was then heated at 85° C. for 12 h. The solvent was then evaporated off, the residue partitioned between methylene chloride and 1N HCL, the layers were separated and the organic layer washed with 2M aqueous KHCO3, dried over Na2SO4 and concentrated in vacuo to give 1-(morpholine-4-sulfonyl)-piperidine-4-carboxylic acid (1.37 g) as a white solid. MS (ESI): 277.08 ([M-H]−).
Reaction SMILES: C([O:3][C:4](=[O:28])[CH2:5][CH2:6][C:7]([C:9]1[CH:14]=[C:13]([I:15])[C:12]([O:16][CH2:17][CH2:18][CH3:19])=[C:11]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:10]=1)=O)C.[BH4-].[Na+]>C(O)C>[CH2:21]([O:20][C:11]1[CH:10]=[C:9]([CH:7]2[O:3][C:4](=[O:28])[CH2:5][CH2:6]2)[CH:14]=[C:13]([I:15])[C:12]=1[O:16][CH2:17][CH2:18][CH3:19])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CCCOc1c(I)cc(C(=O)CCC(=O)OCC)cc1OCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCCOc1c(I)cc(C2CCC(=O)O2)cc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.21 h
Yield: 79.2 %

Procedure:
To a stirring solution of ethyl-4-(3-benzyloxy 4-propoxy-5-Iodophenyl)-4-oxo-1-butanoate (15.8 g, 0.031 ml) in ethanol (80 ml) at 0° C., was added sodium borohydride (0.90 g, 0.023 mol) slowly. The reaction mixture stirred for 10-15 mins at 0° C. The ethanol was removed and water was added and extracted with ethyl acetate (300 ml) dried, filtered and concentrated. The crude containing hydroxyester 6 and lactone 7 were purified on silica gel column using (1:5) EtoAc:light petroleum. The mixture was dissolved in dichloromethane (60 ml); to it PTSA (catalytic, 680 mg) was added at 0° C. and stirred at room temperature over night under nitrogen atmosphere. The dichloromethane solution was washed with water and aqueous NaHCO3 (50 ml), dried (Na2SO4), filtered and concentrated. The crude product was purified on silica gel column using EtOAc: light petroleum (1:5) to give 4-(3-benzyloxy-4-propoxy-5-Iodophenyl) butyrolactone (11.4 g, 79%). TLC: Ethyl acetate:light petroleum (1:3), Rf=0.25; 1H NMR: δ 1.03 (t, J=7.90 Hz, 3H), 1.75-1.90 (m, 2H), 2.0-2.3 (m, 1H), 2.45-2.65 (m,3H), 3.96 (t, J=6.04 Hz, 2H), 5.08 (s, 2H), 5.35 (t, J=6.97 Hz, 1H), 6.88 (d, J=1.62 Hz, 1H), 7.28 (d, J=1.62 Hz, 1H), 7.30-7.40 (m, 5H); EI Mass: 452 (M+), IR (neat): 3070, 2960, 2895, 1760, 1600, 1585 cm−1
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1Br)[C:5]([O:7]CC1C=CC=CC=1)=[O:6].[Br-].[CH:20]1([Zn+])[CH2:24][CH2:23][CH2:22][CH2:21]1>C1COCC1.CO.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[CH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1)[C:5]([OH:7])=[O:6]
Reactant: [Zn+]C1CCCC1
Reactant: O=C(OCc1ccccc1)c1ccc(Br)c(F)c1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Pd]
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc(C2CCCC2)c(F)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 0.45 g (1.45 mmol) of benzyl 3-fluoro-4-bromobenzoate (0.45 g, 1.45 mmol) in 4.4 mL of 0.5 M cyclopentylzinc bromide solution in THF was treated with ˜5 mg of bis(tri-t-butylphosphine)palladium(0) and the resulting mixture was stirred at rt for 24 h. The reaction mixture was directly purified on a Biotage 40S cartridge using 1:1 hexanes/EtOAc as the eluant. A mixture of the resulting solid (0.27 g, 0.91 mmol) and 10% Pd/C in 5 mL of MeOH was stirred under 1 atm of H2 for 3 h. The reaction was filtered and concentrated. Purification by HPLC B afforded the title compound: 1H NMR δ 1.58-1.90 (m, 6H), 2.05-2.14 (m, 2H), 3.30 (m, 1H), 7.36 (t, J=7.7, 1H), 7.72 (dd, J=1.6, 10.5, 1H), 7.83 (dd, J=1.6, 8.0, 1H).
Reaction SMILES: [C:1]([C:5]1[N:6]([CH3:18])[S:7](=[O:17])(=[O:16])[C:8]2[C:9](=[CH:12][S:13][C:14]=2[Cl:15])[C:10]=1[OH:11])([O:3]C)=O.[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1>CC1C=CC=CC=1C>[Cl:15][C:14]1[S:13][CH:12]=[C:9]2[C:8]=1[S:7](=[O:17])(=[O:16])[N:6]([CH3:18])[C:5]([C:1](=[O:3])[NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1)=[C:10]2[OH:11]
Reactant: COC(=O)C1=C(O)c2csc(Cl)c2S(=O)(=O)N1C
Reactant: Nc1ccccn1
Solvent: Cc1ccccc1C
Product: CN1C(C(=O)Nc2ccccn2)=C(O)c2csc(Cl)c2S1(=O)=O
Temperature: 25 °C

Procedure:
A mixture of 2.2 g. of 3-carbomethoxy-7-chloro-4-hydroxy-2-methyl-2H-thieno-[3,4-e]-1,2-thiazine-1,1-dioxide, 0.9 g. of 2-aminopyridine and 240 ml. of absolute o-xylene is boiled under reflux for 7 hours while stirring, approximately 80 ml. of the o-xylene being slowly distilled during the first 2 hours. After the reaction mixture has been cooled to room temperature, it is concentrated to approximately 60 ml. by evaporation in vacuo and cooled in an ice bath. The product that crystallizes out is suction filtered, washed with ether, dried and recrystallized from acetonitrile, and 7-chloro-4-hydroxy-2-methyl-3-(2-pyridylcarbamoyl)-2H-thieno[3,4-e]-1,2-thiazine-1,1-dioxide having a melting point of 218°-220° (with decomposition) is obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:13][C:12](=[O:14])[C:11]2[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=2[N:9]=1.[C:19]([O:23][C:24]([NH:26][CH2:27][C:28](O)=[O:29])=[O:25])([CH3:22])([CH3:21])[CH3:20]>>[C:19]([O:23][C:24]([NH:26][CH2:27][C:28]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:13][C:12](=[O:14])[C:11]2[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=2[N:9]=1)=[O:29])=[O:25])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: Nc1ccccc1-c1nc2ccccc2c(=O)o1
Product: CC(C)(C)OC(=O)NCC(=O)Nc1ccccc1-c1nc2ccccc2c(=O)o1

Procedure:
Using identical reaction conditions as described for the synthesis of the compounds of formula VII of Scheme 2 above, 480 mg (2.0 mmole) of 2-(2-aminophenyl)-3,1-benzoxazin-4-one was reacted with 525 mg (3.0 mmole) of tert-butyloxycarbonylglycine to give 170 mg of the chromatographically-homogeneous tilted compound in 60% overall yield after three cycles.
Reaction SMILES: [Br:1][C:2]1[C:23]([Br:24])=[CH:22][C:5]2[NH:6][C:7]([N:9]3[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]3)=[N:8][C:4]=2[C:3]=1[N+:25]([O-:27])=[O:26].[OH-].[Na+].I[CH:31]([CH3:33])[CH3:32].[ClH:34]>C(#N)C.CO.O1CCOCC1>[ClH:34].[Br:1][C:2]1[C:23]([Br:24])=[CH:22][C:5]2[N:6]([CH:31]([CH3:33])[CH3:32])[C:7]([N:9]3[CH2:10][CH2:11][NH:12][CH2:13][CH2:14]3)=[N:8][C:4]=2[C:3]=1[N+:25]([O-:27])=[O:26]
Reactant: CC(C)I
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc3c([N+](=O)[O-])c(Br)c(Br)cc3[nH]2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: C1COCCO1
Solvent: CO
Product: CC(C)n1c(N2CCNCC2)nc2c([N+](=O)[O-])c(Br)c(Br)cc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Tert-butyl 4-(5,6-dibromo-4-nitro-1H-1,3-benzodiazol-2-yl)piperazine-1-carboxylate (Method 4A) (0.4 mmol, 200 mg) was dissolved in acetonitrile (5 ml). Next, NaOH (0.5 mmol, 19 mg) was added. The mixture was stirred at RT for 0.5 h. Then 2-Iodopropane (32 mmol, 538 mg) was added dropwise. The resulting mixture was stirred at 85° C. in a sealed tube until the reaction was complete (18 hours) by LC/MS. The mixture was allowed to cool to RT and concentrated in-vacuo. The product was taken up into ethyl acetate and washed with water. The organic extract was dried over MgSO4, filtered and concentrated. The product was purified on silica gel using EA/hex (1:4). The obtained product (0.3 mmol, 180 mg) was dissolved in MeOH (3 ml), then hydrogen chloride, (4M in 1,4-dioxane, 1 ml) was added dropwise. The resulting mixture was stirred at RT overnight. Solid was filtered and washed with Et2O to afford 5,6-dibromo-4-nitro-2-(piperazin-1-yl)-1-(propan-2-yl)-1H-1,3-benzodiazole hydrochloride (130 mg). 1H NMR (600 MHz, DMSO) δ 9.37 (s, 2H), 8.28 (s, 1H), 4.62 (hept, J=6.9 Hz, 1H), 3.47-3.44 (m, 4H), 3.28-3.26 (m, 4H), 1.54 (d, J=6.9 Hz, 6H); m/z 472; rt 2.4.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:10][CH3:11])[N:5]=[C:4]([N:12]2[CH2:17][CH2:16][S:15][CH2:14][CH2:13]2)[N:3]=1.[NH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.O>C(O)C>[C:8]([C:7]1[C:2]([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[N:3][C:4]([N:12]2[CH2:17][CH2:16][S:15][CH2:14][CH2:13]2)=[N:5][C:6]=1[O:10][CH3:11])#[N:9]
Reactant: COc1nc(N2CCSCC2)nc(Cl)c1C#N
Reactant: C1CNCCN1
Solvent: CCO
Solvent: O
Product: COc1nc(N2CCSCC2)nc(N2CCNCC2)c1C#N
Temperature: 130 °C

Procedure:
18 gm (0.067 mol) of 4-chloro-5-cyano-6-methoxy-2-thiomorpholino-pyrimidine (m.p. 218°-219°C) were admixed with 60.3 gm (0.7 mol) of piperazine, and the mixture was heated at 130°C for 3 hours. After cooling, water was added, and the aqueous mixture was extracted with chloroform. The chloroform phase was dried, and the chloroform was removed in vacuo. The residue, the free base reaction product, was dissolved in hot ethanol, and the hydrochloride was precipitated by addition of ethanolic hydrochloric acid, suction-filtered off and washed with ethanol. Yield: 13 gm (54.8% of theory); m.p. 261°C.
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[O:5]=[C:6]1[CH2:10][CH2:9][S:8](=[O:12])(=[O:11])[CH2:7]1>O.Cl>[OH:3][N:1]=[C:7]1[C:6](=[O:5])[CH2:10][CH2:9][S:8]1(=[O:12])=[O:11]
Reactant: O=N[O-]
Reactant: O=C1CCS(=O)(=O)C1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=C1CCS(=O)(=O)C1=NO
Reaction time: 1 h
Yield: 60.8 %

Procedure:
A solution of 8.4 g (120 mmol) of sodium nitrite in 25 ml of water is added dropwise at 0° C. to a suspension of 15.5 g (116 mmol) of 3-oxotetrahydrothiophene dioxide (M. A. Smith et al., J. Chem. Soc. (c) 1967, 2171) in 70 ml of water and 10 ml of conc. hydrochloric acid. After 1 hour at 0° C., the product is filtered off with suction, washed with water and dried in vacuo. 11.5 g (61%) of 2-hydroxyimino-3-oxotetrahydrothiophene dioxide, m.p. 148° C., are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([CH3:12])[N:8]=[CH:9]2)=[C:4]([N+:13]([O-])=O)[CH:3]=1.[H][H]>CO.[Pd].CC([O-])=O.CC([O-])=O.[Pb+2].[Pd]>[Cl:1][C:2]1[CH:3]=[C:4]([NH2:13])[C:5]2[CH:6]=[C:7]([CH3:12])[N:8]=[CH:9][C:10]=2[CH:11]=1
Reactant: [H][H]
Reactant: Cc1cc2c([N+](=O)[O-])cc(Cl)cc2cn1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CO
Product: Cc1cc2c(N)cc(Cl)cc2cn1
Yield: 73.1 %

Procedure:
To a nitrogen flushed solution of 7-chloro-3-methyl-5-nitroisoquinoline (Description 85; 300 mg, 1.35 mmol) in methanol (30 ml) was added a spatula end of Palladium 5% on calcium carbonate poisoned with lead (lindlar catalyst), and the resulting mixture stirred under a balloon of hydrogen overnight. The catalyst was removed by filtration and the filtrate evaporated. The residue was dissolved in methanol (20 ml) and silica gel (2 g) added and evaporated to dryness. Loaded onto a silica gel column and eluted with 1% MeOH in DCM+0.5% NH4OH to give the title compound (190 mg, 73%) as an orange solid.
Reaction SMILES: OC1C(=O)N=C(CC2(C3C4C(=CC=CC=4)C=CC=3)CCCC2)N2CCNC(=O)C=12.C([O:37][C:38]1[C:43](=[O:44])[N:42]=[C:41]([CH2:45][C:46]2([C:51]3[C:60]4[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=4)[CH:54]=[CH:53][CH:52]=3)[CH2:50][CH2:49][CH2:48][CH2:47]2)[N:40]2[CH2:61][CH2:62][N:63]([CH3:66])[C:64](=[O:65])[C:39]=12)C1C=CC=CC=1>>[OH:37][C:38]1[C:43](=[O:44])[N:42]=[C:41]([CH2:45][C:46]2([C:51]3[C:60]4[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=4)[CH:54]=[CH:53][CH:52]=3)[CH2:50][CH2:49][CH2:48][CH2:47]2)[N:40]2[CH2:61][CH2:62][N:63]([CH3:66])[C:64](=[O:65])[C:39]=12
Reactant: CN1CCn2c(CC3(c4cccc5ccccc45)CCCC3)nc(=O)c(OCc3ccccc3)c2C1=O
Agent: O=C1NCCn2c(CC3(c4cccc5ccccc45)CCCC3)nc(=O)c(O)c21
Product: CN1CCn2c(CC3(c4cccc5ccccc45)CCCC3)nc(=O)c(O)c2C1=O

Procedure:
This compound was prepared by following the same method as described for pure 9-hydroxy-6-(1-naphthalen-1-yl-cyclopentylmethyl)-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (349) from 9-benzyloxy-2-methyl-6-(1-naphthalen-1-yl-cyclopentylmethyl)-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (352) (85 mg, 0.17 mmol). The yield was 35 mg, 50% (white solid).