Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH2:10][N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[C:6]([CH:9]=1)[C:7]#[N:8].[CH3:17][C:18]1[CH:23]=[C:22]([CH3:24])[NH:21][C:20](=[O:25])[C:19]=1[CH2:26][NH:27][C:28](=[O:54])[C:29]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[C:31]([N:44]([CH2:51][CH3:52])[CH:45]2[CH2:50][CH2:49][O:48][CH2:47][CH2:46]2)[C:30]=1[CH3:53].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:7]([C:6]1[CH:9]=[C:2]([C:33]2[CH:32]=[C:31]([N:44]([CH2:51][CH3:52])[CH:45]3[CH2:50][CH2:49][O:48][CH2:47][CH2:46]3)[C:30]([CH3:53])=[C:29]([C:28]([NH:27][CH2:26][C:19]3[C:20](=[O:25])[NH:21][C:22]([CH3:24])=[CH:23][C:18]=3[CH3:17])=[O:54])[CH:34]=2)[CH:3]=[CH:4][C:5]=1[CH2:10][N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)#[N:8]
Reactant: CCN(c1cc(B2OC(C)(C)C(C)(C)O2)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Reactant: N#Cc1cc(Br)ccc1CN1CCOCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCN(c1cc(-c2ccc(CN3CCOCC3)c(C#N)c2)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Temperature: 100 °C
Yield: 5.9 %

Procedure:
To a stirred solution of 5-bromo-2-(morpholinomethyl)benzonitrile (190 mg, 0.68 mmol) and N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (200 mg, 0.45 mmol) in dioxane (6 mL), aqueous 2M Na2CO3 solution (0.81 mL, 1.63 mmol) was added and solution was purged with argon for 15 min. Then Pd(PPh3)4 (52 mg, 0.04 mmol) was added and argon was purged again for 15 min. Reaction mass was heated at 100° C. for 4 h. On completion, reaction mixture was diluted with water and extracted with 10% MeOH/DCM (3 times). Combined organic layer was dried over sodium sulphate. Removal of the solvent under reduced pressure followed by column chromatographic purification afforded the title compound (16 mg, 6%). LCMS: 598.20 (M+1)+; HPLC: 89/15% (@254 nm) (Rt; 4.039; Method: Column: YMC ODS-A 150 mm×4.6 mm×5μ; Mobile Phase; A; 0.05% TFA in water/B; 0.05% TFA in acetonitrile; Inj. Vol: 10 μL, Col. Temp.: 30° C.; Flow rate: 1.4 mL/min.; Gradient: 5% B to 95% B in 8 min, Hold for 1.5 min, 9.51-12 min 5% B); 1H NMR (DMSO-d6, 400 MHz) δ 11.46 (bs, 1H), 8.20 (t, 1H), 8.15 (s, 1H), 7.94 (d, 1H, J=6.8 Hz), 7.63 (d, 1H, J=8.4 Hz), 7.51 (s, 1H), 7.31 (s, 1H), 5.86 (s, 1H), 4.29 (m, 2H), 3.84-3.82 (m, 2H), 3.66-3.58 (m, 6H), 3.32 (m, 5H), 3.11-3.03 (m, 4H), 2.25 (s, 3H), 2.21 (s, 3H), 2.11 (s, 3H), 1.65-1.51 (m, 4H), 0.82 (t, 3H, J=6 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[CH:3]=1.CO[CH:13](OC)[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([S:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)(=[O:23])=[O:22])[CH:15]=1>>[C:24]1([S:21]([C:16]2[CH:15]=[C:14]([CH:13]3[C:3]4[C:4](=[O:10])[CH2:5][C:6]([CH3:9])([CH3:8])[CH2:7][C:2]=4[NH:1][C:2]4[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[C:3]3=4)[CH:19]=[CH:18][C:17]=2[Cl:20])(=[O:22])=[O:23])[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: COC(OC)c1ccc(Cl)c(S(=O)(=O)c2ccccc2)c1
Reactant: CC1(C)CC(=O)C=C(N)C1
Product: CC1(C)CC(=O)C2=C(C1)NC1=C(C(=O)CC(C)(C)C1)C2c1ccc(Cl)c(S(=O)(=O)c2ccccc2)c1

Procedure:
Reaction of 3-amino-5,5-dimethyl-2-cyclohexen-1-one with 4-chloro-3-phenylsulphonylbenzaldehyde dimethyl acetal in an analogous manner to that described in Example 1 gave 9-[3-benzenesulphonyl-4-chlorophenyl]-3,4,6,7,9,10-hexahydro-3,3,6,6-tetramethyl-1,8(2H,5H)-acridinedione. Crystallization from dimethylformamide/water gave a yellow crystalline solid of melting point 252-254° C. (decomposition).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:10]=[CH:9][C:7](=[O:8])[NH:6][C:4]1=[O:5].[CH3:11][Si:12]([CH3:19])([CH3:18])[CH2:13][CH2:14][O:15][CH2:16]Cl>CN(C=O)C.O>[CH3:11][Si:12]([CH3:19])([CH3:18])[CH2:13][CH2:14][O:15][CH2:16][N:3]1[CH:10]=[CH:9][C:7](=[O:8])[NH:6][C:4]1=[O:5]
Reactant: O=c1cc[nH]c(=O)[nH]1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C[Si](C)(C)CCOCn1ccc(=O)[nH]c1=O
Temperature: 0 °C
Reaction time: 4 h
Yield: 14.8 %

Procedure:
A solution of 60% sodium hydride (2 g, 50 mmol) in mineral oil was washed with hexanes (2×20 mL) and cooled to 0° C. The solution was diluted with DMF (200 mL) and then uracil (5.6 g, 50 mmol) was added portionwise over 30 minutes. The mixture was treated with 2-(trimethylsilyl)ethoxymethyl chloride (8.8 mL, 50 mmol) and allowed to warm to 25° C. and stand 4 hours. The reaction mixture was diluted with water (500 mL) and extracted with diethyl ether (4×100 mL). The combined extract was washed with brine, dried (Na2SO4), filtered and concentrated. The residue was purified by chromatography on silica gel eluting with hexanes/ethyl acetate (2:1) to give 1-[2-(trimethylsilyl)ethoxymethyl]-2,4(1H,3H)-pyrimidinedione (1.8 g, 7.4 mmol), M.p. 120°-122° C.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([Br:14])=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11])(=[O:3])[CH3:2].ON1[C:20]2C=CC=C[C:19]=2N=N1.CN(C1C=CC=CN=1)C.Cl.CN(C)CCCC(N=C=N)C>ClCCl.C(O)C>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([Br:14])=[C:9]([CH:13]=1)[C:10]([O:12][CH2:19][CH3:20])=[O:11])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(Br)c(C(=O)O)c1
Reactant: On1nnc2ccccc21
Agent: CC(CCCN(C)C)N=C=N
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)c1cc(NC(C)=O)ccc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.2 %

Procedure:
A mixture of 5-(acetylamino)-2-bromobenzoic acid (2.58 g, 10 mmol), 1-hydroxybenzotriazole (1.68 g, 11 mmol), dimethylaminopyridine (1.22 g, 10 mmol) and 1-(3-dimethylaminopropyl)-ethylcarbodiimide hydrochloride (2.20 g, 11.5 mmol) in dichloromethane/ethanol (5:1, 30 ml) was stirred at room temperature for 2 hours then washed with saturated sodium bicarbonate solution, dried (magnesium sulphate) and chromatographed on silica eluting with ethyl acetate/iso-hexane (2:3) to give 2.18 g of white solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].CCC[CH2-].[Br:20]CCBr>O1CCCC1>[C:1]([O:5][C:6]([NH:8][C:9]1[C:14]([Br:20])=[CH:13][CH:12]=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccccn1
Reactant: BrCCBr
Agent: [CH2-]CCC
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ncccc1Br
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 32 %

Procedure:
2-t-Butoxycarbonylaminopyridine (10 g, 51.5 mmol) was dissolved in tetrahydrofuran (80 mL), and cooled to -78° C. N-butyllithium (120 mmol, 80 mL of 1.49M in hexanes) was added dropwise over a period of 1 h. After stirring for an additional 15 min at -78° C. and then for 2.5 h at -10° C., the solution was recooled back down to -78° C. and 1,2-dibromoethane (77.2 mmol, 6.65 mL) was added dropwise over a period of 15 min via syringe. The solution was allowed to warm to room temperature. The reaction was quenched with 100 mL of saturated ammonium chloride and was extracted with ethyl acetate (3×). The organic layers were collected, dried over magnesium sulfate, filtered, and concentrated. The resulting solid was purified by flash chromatography on silica gel (25% ethyl acetate/hexanes) giving 4.5 g (32%) of the titled product as a light brown solid:
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[C:12]2[C:20]3[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=3)[C:14]([CH2:23][C:24]([O:26][CH3:27])=[O:25])=[C:13]2[CH3:28])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[N+](=[CH2:31])=[N-].CCOCC>CO>[CH3:31][NH:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]=[C:12]2[C:20]3[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=3)[C:14]([CH2:23][C:24]([O:26][CH3:27])=[O:25])=[C:13]2[CH3:28])=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: COC(=O)CC1=C(C)C(=Cc2ccc(S(N)(=O)=O)cc2)c2ccc(OC)cc21
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Solvent: CO
Product: CNS(=O)(=O)c1ccc(C=C2C(C)=C(CC(=O)OC)c3cc(OC)ccc32)cc1
Yield: 29 %

Procedure:
A solution of 4a (100 mg) in methanol (20 ml) was treated with excess diazomethane ether solution to give two products. They are separated via preparative tlc using 1500 μm silica gel plates developed 3 times with 5% ethyl acetate in chloroform to give Z methyl 1-(4-(N-methylaminosulfonyl)phenyl)methylene-5-methoxy-2-methyl-1H-3-indenylacetate (6a) (30 mg, 29% yield): m.p. 167°-169° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].[CH3:12][N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.[Na+].[Cl-]>>[CH3:12][N:13]1[CH2:18][CH2:17][N:16]([C:2]2[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=2)[NH2:7])[CH2:15][CH2:14]1
Reactant: CN1CCNCC1
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Product: CN1CCN(c2ccc([N+](=O)[O-])c(N)c2)CC1
Temperature: 111 °C
Reaction time: 16 h
Yield: 96.3 %

Procedure:
A 1-L, 4-neck round bottom flask was equipped with a heating mantle, an overhead stirrer, condenser, nitrogen inlet, and thermocouple. The flask was charged with 5-chloro-2-nitroaniline (150 g, 869 mmol, 1 equiv), 1-methylpiperazine (348 mL, 386 g, 3.48 mol, 4 equiv) and 4M aqueous NaCl (247 mL). The contents of the flask were stirred and purged with N2 for at least 15 min. The reactor was then heated until an internal temperature of 110-112° C. was reached. The contents were stirred for 7-8 h until the reaction was complete as determined by HPLC. After completion, the reaction mixture was cooled to 20° C. over 2 h to precipitate the product as a slurry, and stirring was continued for an additional 16 h. The solid was vacuum filtered, and the mother liquor collected in the original reaction vessel. The solids were washed on the filter with H2O (2×250 mL), followed by soaking in heptane (200 mL) for 0.5 h. The slurry was again filtered via vacuum, and dried in vacuo (50° C., 30 in. Hg) to yield 5-(4-methyl-piperazin-1-yl)-2-nitroaniline (197.8 g, 96.3% yield). Residual N-methylpiperazine was not detected by 1H NMR.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([C:13]1[CH:18]=[CH:17][C:16]([CH2:19][NH2:20])=[CH:15][CH:14]=1)(=[O:12])=[O:11].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[N:56]1[CH:61]=[CH:60][CH:59]=[C:58](/[CH:62]=[CH:63]/[C:64](O)=[O:65])[CH:57]=1>O>[N:56]1[CH:61]=[CH:60][CH:59]=[C:58]([CH:62]=[CH:63][C:64]([NH:20][CH2:19][C:16]2[CH:17]=[CH:18][C:13]([S:10]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[O:3][C:2]([F:1])([F:21])[F:22])(=[O:12])=[O:11])=[CH:14][CH:15]=2)=[O:65])[CH:57]=1
Reactant: O=C(O)/C=C/c1cccnc1
Reactant: NCc1ccc(S(=O)(=O)c2ccccc2OC(F)(F)F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(C=Cc1cccnc1)NCc1ccc(S(=O)(=O)c2ccccc2OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
In a 50 ml of flask were added (4-(2-(trifluoromethoxy)phenylsulfonyl)phenyl)methanamine (100 mg, 0.302 mmol), 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (138 mg, 0.362 mmol DIEA (117 mg, 0.905 mmol), (E)-3-(pyridin-3-yl)acrylic acid (49.5 mg, 0.332 mmol) DMF (5 ml). The mixture was stirred at RT for 16 hours. The mixture was diluted with water and back extracted with ethyl acetate (3×20 mL). The organic layers were combined and washed with water (3×20 mL). The organic was separated, dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product The crude product was purified by Biotage to afford E)-3-(pyridin-3-yl)-N-(4-(2-(trifluoromethoxy)phenylsulfonyl)benzyl)acrylamide, 85 mg (61%). 1HNMR (DMSO-D6): δ 8.70 (t, 1H), 8.75 (d, 1H), 8.54 (dd, 1H), 8.21 (dd, 2H), 7.98 (dd, 1H), 7.83 (m, 2H), 7.66 (dt, 1H), 7.53 (m, 2H), 7.44 (m, 1H), 6.75 (d, 1H), 4.49 (d, 1H)
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[N:14]=[C:15]2[CH:20]=[C:19]([C:21]([OH:23])=O)[CH:18]=[CH:17][N:16]2[CH:24]=1.[CH2:25]([CH2:27][NH2:28])[OH:26]>>[OH:26][CH2:25][CH2:27][NH:28][C:21]([C:19]1[CH:18]=[CH:17][N:16]2[CH:24]=[C:13]([C:3]3[C:4]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)=[N:5][O:6][C:2]=3[CH3:1])[N:14]=[C:15]2[CH:20]=1)=[O:23]
Reactant: NCCO
Reactant: Cc1onc(-c2ccccc2)c1-c1cn2ccc(C(=O)O)cc2n1
Product: Cc1onc(-c2ccccc2)c1-c1cn2ccc(C(=O)NCCO)cc2n1
Yield: 72 %

Procedure:
As described for Example 11b, 2-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazo[1,2-a]pyridine-7-carboxylic acid (96 mg, 0.3 mmol) was converted, using ethanolamine instead of aminomethylcyclopropane, to the title compound (78 mg, 72%) which was obtained as a light yellow foam. MS: m/e=363.3 [M+H]+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[C:7]([NH2:11])[C:8]([NH2:10])=[CH:9][C:4]=2[O:3][CH2:2]1.[S:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[C:17](=O)[C:18](O)=[O:19]>>[S:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[C:17]1[C:18](=[O:19])[NH:10][C:8]2[CH:9]=[C:4]3[O:3][CH2:2][O:1][C:5]3=[CH:6][C:7]=2[N:11]=1
Reactant: O=C(O)C(=O)c1cccs1
Reactant: Nc1cc2c(cc1N)OCO2
Product: O=c1[nH]c2cc3c(cc2nc1-c1cccs1)OCO3

Procedure:
The quinoxalin-2-one of the present example is prepared with Benzo[1,3]dioxole-5,6-diamine and (thiophen-2-yl) oxo-acetic acid via the method described in Example 12 to afford 7-thiophen-2-yl-5H-1,3-dioxa-5,8-diaza-cyclopenta[b]naphthalen-6-one.
Reaction SMILES: C[Si](C)(C)C[CH2:4][O:5]COC[Sn](CCCC)(CCCC)CCCC.C([Li])CCC.[CH3:29][NH:30][C@H:31]([C:41]([NH:43][C@H:44]([C:49]([N:51]([C@@H:53]([CH:63]([CH3:65])[CH3:64])/[CH:54]=[C:55](\[CH3:62])/[C:56](N(OC)C)=[O:57])[CH3:52])=[O:50])[C:45]([CH3:48])([CH3:47])[CH3:46])=[O:42])[C:32]([CH3:40])([CH3:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>O1CCCC1>[OH:5][CH2:4][C:56](=[O:57])[C:55]([CH3:62])=[CH:54][CH:53]([N:51]([CH3:52])[C:49]([CH:44]([NH:43][C:41](=[O:42])[CH:31]([NH:30][CH3:29])[C:32]([CH3:39])([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH3:40])[C:45]([CH3:46])([CH3:48])[CH3:47])=[O:50])[CH:63]([CH3:65])[CH3:64]
Reactant: CN[C@H](C(=O)N[C@H](C(=O)N(C)[C@H](/C=C(\C)C(=O)N(C)OC)C(C)C)C(C)(C)C)C(C)(C)c1ccccc1
Reactant: CCCC[Sn](CCCC)(CCCC)COCOCC[Si](C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CNC(C(=O)NC(C(=O)N(C)C(C=C(C)C(=O)CO)C(C)C)C(C)(C)C)C(C)(C)c1ccccc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 21.3 %

Procedure:
To a solution of trimethyl-(2-tributylstannanylmethoxymethoxy-ethyl)-silane (933 mg, 2.07 mmole, E. Fernandez-Megia and S. V. Ley; Synlett 2000, 4, 455-8) in 6 mL tetrahydrofuran at −78° C. is added dropwise 1.6 M n-butyllithium solution in hexanes (1.25 mL, 2.0 mmole). The resulting yellow solution is stirred for 10 mins at −78° C. Then a solution of N,β,β-trimethyl-L-phenylalanyl-N1 {(1S,2E)-1-isopropyl-4-[methoxy(methyl)amino]-3-methyl-4-oxobut-2-enyl}-N1,3-dimethyl-L-valinamide (258 mg, 0.5 mmole, Example 52) in tetrahydrofuan (5 mL) at −78° C. is added dropwise and the reaction mixture stirred at −78° C. for 15 mins and then at −60° C. for 45 mins. The reaction is quenched with a saturated aqueous solution of ammonium chloride (2 mL), warmed to room temperature and partioned between ethyl acetate (50 mL) and saturated aqueous solution of ammonium chloride (50 mL). The aqueous layer is extracted with ethyl acetate (30 mL) and the combined organic layer is washed with water, brine, dried over sodium sulfate, filtered and the residue treated with a mixture of trifluoroacetic acid (10 mL) and dichloromethane (5 mL) at 0° C. and stirred for 1 hour, evaporated and then purified by HPLC to give 52 mg of an off-white solid, MS (ES): m/z 488.4 (M+H).
Reaction SMILES: [NH:1]1[C:12]2[C:4](=[CH:5][CH:6]=[C:7]3[C:11]=2[C:10](=[O:13])[C:9](=[O:14])[NH:8]3)[N:3]=[N:2]1.[CH:15]1[C:20]([NH:21][NH2:22])=[CH:19][CH:18]=[C:17]([S:23]([NH2:26])(=[O:25])=[O:24])[CH:16]=1.Cl>>[NH:1]1[C:12]2[C:4](=[CH:5][CH:6]=[C:7]3[C:11]=2[C:10](=[O:13])[C:9](=[O:14])[NH:8]3)[N:3]=[N:2]1.[O:14]=[C:9]1[C:10](=[N:22][NH:21][C:20]2[CH:19]=[CH:18][C:17]([S:23]([NH2:26])(=[O:24])=[O:25])=[CH:16][CH:15]=2)[C:11]2[C:7](=[CH:6][CH:5]=[C:4]3[C:12]=2[N:1]=[N:2][NH:3]3)[NH:8]1
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Agent: Cl
Agent: O=C1Nc2ccc3nn[nH]c3c2C1=O
Product: NS(=O)(=O)c1ccc(NN=C2C(=O)Nc3ccc4[nH]nnc4c32)cc1

Procedure:
1,6-Dihydro-1,2,3,6-tetraaza-as-indacene-7,8-dione was prepared according to Procedure A in 56% yield: 1H NMR (DMSO-d6): δ 6.93 (d, J=8.6 Hz, 1H), 8.32 (d, J=8.6 Hz, 1H), 11.14 (s, 1H); APCI−MS m/z 189 (M+1)+. Condensation of 1,6-dihydro-1,2,3,6-tetraaza-as-indacene-7,8-dione with 4-sulfonamidophenylhydrazine hydrochloride according to Procedure G gave the title compound in 15% yield: 1H NMR (DMSO-d6): δ 7.06 Z (d, J=8.4 Hz, 1H), 7.24 E (d, J=8.4 Hz, 1H), 7.30 Z (s, 2H), 7.30 E (s, 2H), 7.55 E (d, J=8.5 Hz, 2H), 7.82 Z (d, J=8.5 Hz, 2H), 7.82 E (d, J=8.5 Hz, 1H), 7.90 E (d, J=8.7 Hz, 2H), 7.90 Z (d, J=8.8 Hz, 2H), 7.98 Z (d, J=8.4 Hz, 1H), 10.86 E (s, 1H), 11.35 Z (s, 1H), 12.87 Z (s, 1H), 12.95 E (s, 1H), 16.00 Z (s, 1H), 16.25 E (s, 1H); APCI−MS m/z 356 (M−H)−. Anal. Calcd for C14H11N7O3S.H2O: C, 44.80, H, 3.49; N, 26.12; S, 8.54. Found C, 44.72, H, 3.46; N, 26.05; S, 8.48.
Reaction SMILES: [ClH:1].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[CH:4]([CH2:10][C:11]([O:13]C1C(F)=C(F)C(F)=C(F)C=1F)=O)[CH2:3]2.[Br:25][C:26]1[CH:35]=[CH:34][C:29]2[CH:30]=[C:31]([NH2:33])[S:32][C:28]=2[CH:27]=1.C(=O)([O-])[O-].Cl>CN(C=O)C.C(#N)C>[ClH:1].[N:2]12[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9]1)[CH:4]([CH2:10][C:11]([NH:33][C:31]1[S:32][C:28]3[CH:27]=[C:26]([Br:25])[CH:35]=[CH:34][C:29]=3[CH:30]=1)=[O:13])[CH2:3]2
Reactant: O=C(CC1CN2CCC1CC2)Oc1c(F)c(F)c(F)c(F)c1F
Reactant: Nc1cc2ccc(Br)cc2s1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CC#N
Solvent: CN(C)C=O
Product: O=C(CC1CN2CCC1CC2)Nc1cc2ccc(Br)cc2s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
89.2 mg (0.24 mmol) of pentafluorophenyl (1-azabicyclo[2.2.2]oct-3-yl)acetate hydrochloride are dissolved in 1 ml of DMF, mixed with 71.2 mg (0.31 mmol) of 6-bromo-1-benzothiophene-2-amine and stirred at room temperature overnight. 1 g of MP-carbonate (polymer-bound carbonate, capacity: 2.5-3.5 mmol/g; from Argonaut Technologies, USA) is added. After 3 h, the polystyrene resin is filtered off and washed with THF. The combined filtrates are concentrated in vacuo, and the crude product is purified by preparative HPLC. The hydrochloride is prepared by mixing the product with a mixture of 1 M hydrochloric acid and acetonitrile and again concentrating. Drying under high vacuum results in 14 mg (14% of theory) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:7]([O:8][CH3:9])=[CH:6][S:5][CH:4]=1.[CH2:10](O)C(O)C>>[CH3:10][CH:1]1[O:2][C:3]2=[CH:4][S:5][CH:6]=[C:7]2[O:8][CH2:9]1
Reactant: COc1cscc1OC
Reactant: CC(O)CO
Product: CC1COc2cscc2O1

Procedure:
Racemic 2-methyl-2,3-dihydro-thieno[3,4-b][1,4]dioxine was synthesized by transetherification of 3,4-dimethoxythiophene with racemic 1,2-propanediol as described in COMPARATIVE EXAMPLE 1. It was characterized by GC-MS and H-NMR-spectroscopy, and exhibited no optical rotation.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([C:13](=[O:17])[CH:14]([Br:16])[CH3:15])[CH:6]=[C:7](C(F)(F)F)[CH:8]=1.[F:20]C(F)(F)C1C=C(C(=O)CC)C=C(C(F)(F)F)C=1>>[Br:16][CH:14]([CH3:15])[C:13]([C:5]1[CH:4]=[C:3]([C:2]([F:19])([F:18])[F:1])[CH:8]=[C:7]([F:20])[CH:6]=1)=[O:17]
Reactant: CC(Br)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CCC(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: CC(Br)C(=O)c1cc(F)cc(C(F)(F)F)c1
Yield: 86 %

Procedure:
1-[3,5-Bis(trifluoromethyl)phenyl]-2-bromopropan-1-one: A stirred suspension of 1 g (3.7 mmol) of 1-[3,5-bis(trifluoromethyl)phenyl]-propan-1-one (Lancaster, Windham, N.J., USA) treated in a manner similar to that for Example 127, step (a) to give 2-bromo-1-[3-fluoro-5-(trifluoromethyl)phenyl]propan-1-one (1.1 g, 86%). 1H-NMR (DMSO-d6; 300 MHz) δ 8.46 (m, 2H), 8.09 (m, 1), 5.26 (q, 1H, J=6.6 Hz), 1.96 (d, 3H, J=6.5 Hz). Mass spectrum (MALDI-TOF, CHCA matrix, m/z): Calcd. for C11H7OBrF6, 349.0 (M+H), found 348.9.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([NH:15][C:16]([NH:18][NH2:19])=[O:17])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[C:20](O)(=O)C.C(=N)N>O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([N:15]3[CH:20]=[N:19][NH:18][C:16]3=[O:17])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1
Reactant: CC(=O)O
Reactant: COc1ccc(N2CCN(NC(=O)NN)CC2)cc1
Agent: N=CN
Solvent: O
Product: COc1ccc(N2CCN(n3cn[nH]c3=O)CC2)cc1
Yield: 68 %

Procedure:
6.5 Parts of N-[4-(4-methoxyphenyl)-1-piperazinyl]hydrazinecarboxamide and 6.5 parts of methanimidamide acetate (1:1) are melted together for 1 hour at 140° C. Water is added to the melt. The solid product is filtered off and crystallized from 1-butanol, yielding 4.5 parts (68%) of 2,4-dihydro-4-[4-(4-methoxyphenyl)-1-piperazinyl]-3H-1,2,4-triazol-3-one.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([S:9](Cl)(=[O:11])=[O:10])=[C:4]([CH3:13])[CH:3]=1.Cl.[CH2:15]([O:17][C:18](=[O:29])[CH:19](CC)[CH2:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][NH:22]1)[CH3:16].C(N(CC)CC)C>ClCCl>[CH2:15]([O:17][C:18](=[O:29])[CH2:19][CH2:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][N:22]1[S:9]([C:5]1[CH:6]=[C:7]([CH3:8])[C:2]([Cl:1])=[CH:3][C:4]=1[CH3:13])(=[O:11])=[O:10])[CH3:16]
Reactant: CCOC(=O)C(CC)CC1CCCCN1
Reactant: Cc1cc(S(=O)(=O)Cl)c(C)cc1Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CCC1CCCCN1S(=O)(=O)c1cc(C)c(Cl)cc1C
Temperature: 0 °C
Yield: 50 %

Procedure:
4-Chloro-2,5-dimethyl-benzenesulfonyl chloride (1 g, 3.8 mmol) was added to a solution of ethyl 3-(piperidin-2-yl)propionic acid ethyl ester hydrochloride (1.1 g, 4.6 mmol) in dichloromethane (15 ml) while stirring, the mixture was cooled to 0° C., and triethylamine (1.6 ml, 11.5 mmol) was added dropwise over 15 min. The mixture was stirred for 4 h at 0° C., then diluted with dichloromethane, washed with water and saturated sodium chloride solution, dried over sodium sulfate and concentrated to small volume under vacuum. The crude product was purified with ethyl acetate/hexane (9:1) by column chromatography. Yield: 50%
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]2[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:21]([C:28]4[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=4)=[CH:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26])[CH:18]=3)[CH2:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:34](=O)([O-])[O-].[K+].[K+]>CO.Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]2[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:21]([C:28]4[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=4)=[CH:22][CH2:23][CH2:24][C:25]([O:27][CH3:34])=[O:26])[CH:18]=3)[CH2:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(O)CCC=C(c1cccnc1)c1ccc2c(c1)CC(NS(=O)(=O)c1ccc(Cl)cc1)C2
Agent: Cl
Agent: [K+]
Solvent: CO
Product: COC(=O)CCC=C(c1cccnc1)c1ccc2c(c1)CC(NS(=O)(=O)c1ccc(Cl)cc1)C2
Reaction time: 8 h

Procedure:
3.7 g of 5-(2-(4-chlorobenzenesulphonylamino)indan-5-yl)-5-(3-pyridyl)pent-4-enoic acid are dissolved in 30 ml of methanol into which dry hydrogen chloride is introduced. The solution is stirred overnight and then rotary evaporated. Whilst cooling with ice, the base is liberated with aqueous potassium carbonate solution and then extracted with methylene chloride. The solution is rotary evaporated and the residue is chromatographed over a silica gel column.