Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[NH:10][C:11]([N:13]1[CH:17]=[CH:16]N=C1)=[S:12].[Cl:18][C:19]1[CH:20]=[C:21](CCN)[CH:22]=[CH:23][CH:24]=1.C(OCC)(=O)C>CN(C)C=O>[Cl:18][C:19]1[CH:24]=[C:23]([CH2:16][CH2:17][NH:13][C:11]([NH:10][C:2]2[NH:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=2)=[S:12])[CH:22]=[CH:21][CH:20]=1
Reactant: S=C(Nc1nc2ccccc2[nH]1)n1ccnc1
Reactant: NCCc1cccc(Cl)c1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: S=C(NCCc1cccc(Cl)c1)Nc1nc2ccccc2[nH]1
Temperature: 25 °C
Yield: 14.5 %

Procedure:
A solution of 1-[(2-benzimidazolyl)thiocarbamoyl]imidazole (1.22 g, 5.0 mmol) and 2-(3-chlorophenyl)ethylamine (0.79 g, 5.0 mmol) in N,N-dimethylformamide (20 mL) was stirred at 90° C. for 2 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, 1N aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the resultant solid was crystallized from EtOAc to provide 0.24 g (14%) of the titled product as a white solid: mp 171°-177° C.; IR (KBr, cm-1) 3387, 1574, 1539, 1461, 1426, 1237, 1175, 734, 699, 477; 1H NMR (300 MHz, DMSO-d6) δ 11.18 (m, 2H), 7.28 (m, 8H), 7.06 (m, 1H), 3.83 (m, 2H), 2.94 (t, J=7 Hz, 2H); MS (FD) m/e 330 (M+); UV (EtOH) 293 nm (ε=17219), 266 nm (ε=9969), 260 nm (ε=9196), 240 nm (ε=8196), 203 nm (ε=27483).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:11][CH2:12][CH:13]2[CH2:15][CH2:14]2)=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[NH2:16][CH:17]([CH:21]([CH3:23])[CH3:22])[CH2:18][CH2:19][OH:20]>>[OH:20][CH2:19][CH2:18][CH:17]([NH:16][C:8]([C:5]1[CH:4]=[C:3]([O:11][CH2:12][CH:13]2[CH2:15][CH2:14]2)[C:2]([Cl:1])=[CH:7][N:6]=1)=[O:10])[CH:21]([CH3:23])[CH3:22]
Reactant: O=C(O)c1cc(OCC2CC2)c(Cl)cn1
Reactant: CC(C)C(N)CCO
Product: CC(C)C(CCO)NC(=O)c1cc(OCC2CC2)c(Cl)cn1

Procedure:
The title compound was synthesized in analogy to Example 12d, using 5-chloro-4-cyclopropylmethoxy-pyridine-2-carboxylic acid and 3-amino-4-methyl-1-pentanol (CAN 26734-09-8) as starting materials and isolated (21 mg, 64%) as colorless oil; LC-MS (UV peak area, m/z) 100%, 327.1473 (MH+).
Reaction SMILES: [CH:1]([NH:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])([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.C(N(C(C)C)CC)(C)C.[C:32](Cl)(=[O:35])[CH2:33][CH3:34]>C1C=CC=CC=1>[C:32]([N:14]([CH:1]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])(=[O:35])[CH2:33][CH3:34]
Reactant: CCC(=O)Cl
Reactant: CCOC(=O)CCCNC(c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCCN(C(=O)CC)C(c1ccccc1)c1ccccc1
Yield: 92.6 %

Procedure:
Analogously to Example 19, 9.0 g of ethyl 4-benzhydrylaminobutyrate and 4.3 g of diisopropylethylamine in 100 ml of benzene are reacted with 3.1 g of propionyl chloride. The reaction product is recrystallized from ethyl acetate/ligroin (1:1) to obtain 9.9 g (92.5% of theory) of ethyl N-propionyl-4-benzhydrylaminobutyrate (M.P. 83° to 85°).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([NH:5][C:6](=[O:8])[CH3:7])[CH2:2]1.Br[CH2:10][CH2:11][O:12][C:13]1[C:18]([CH3:19])=[CH:17][C:16]([C:20]2[NH:29][C:28](=[O:30])[C:27]3[C:22](=[CH:23][C:24]([O:33][CH3:34])=[CH:25][C:26]=3[O:31][CH3:32])[N:21]=2)=[CH:15][C:14]=1[CH3:35].C(N(CC)CC)C>CN(C=O)C>[CH3:32][O:31][C:26]1[CH:25]=[C:24]([O:33][CH3:34])[CH:23]=[C:22]2[C:27]=1[C:28](=[O:30])[NH:29][C:20]([C:16]1[CH:17]=[C:18]([CH3:19])[C:13]([O:12][CH2:11][CH2:10][N:1]3[CH2:4][CH:3]([NH:5][C:6](=[O:8])[CH3:7])[CH2:2]3)=[C:14]([CH3:35])[CH:15]=1)=[N:21]2
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(OCCBr)c(C)c3)nc2c1
Reactant: CC(=O)NC1CNC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(OCCN4CC(NC(C)=O)C4)c(C)c3)nc2c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a suspension of N-azetidin-3-yl-acetamide (0.30 g crude, 1.99 mmol) and 2-[4-(2-bromo-ethoxy)-3,5-dimethyl-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one (0.43 g, 1.00 mmol) in anhydrous DMF (10 mL) was added triethylamine (3 mL). The reaction mixture was stirred at room temperature for 3 days under nitrogen. Solvent was evaporated under reduced pressure, water (50 mL) was added, and the precipitated solid was filtered. The aqueous phase was extracted with ethyl acetate (2×100 mL). The organic phase was dried over anhydrous Na2SO4. Solvent was evaporated, and crude compound was purified by the Simpliflash system (0-5% 7 N ammonia in methanol and CH2Cl2 as eluent) to give the title compound as a white solid. Yield: 0.30 g (63%). MP 111.8-113.6° C. 1H NMR (400 MHz, CDCl3): δ 9.60 (br s, 1H), 7.69 (s, 2H), 6.82 (d, J=2.34 Hz, 1H), 6.46 (d, J=2.34 Hz, 1H), 6.10 (d, J=7.81 Hz, 1H), 4.71-4.44 (m, 1H), 3.97 (s, 3H), 3.93 (s, 3H), 3.85-3.67 (m, 4H), 3.26-3.13 (m, 2H), 2.90 (t, J=5.46 Hz, 2H), 2.36 (s, 6H), 2.01 (s, 3H). MS (ES+) m/z: 467.20 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@:8]12[CH2:17][CH2:16][C@@H:15]([O:18][CH3:19])[CH2:14][C@H:13]1[CH2:12][S:11][C:10]([NH:20]C(=O)C1C=CC=CC=1)=[N:9]2.C1CCN2C(=NCCC2)CC1>CO>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@:8]12[CH2:17][CH2:16][C@@H:15]([O:18][CH3:19])[CH2:14][C@H:13]1[CH2:12][S:11][C:10]([NH2:20])=[N:9]2
Reactant: CO[C@@H]1CC[C@]2(c3ccccc3F)N=C(NC(=O)c3ccccc3)SC[C@@H]2C1
Solvent: CO
Solvent: C1CCC2=NCCCN2CC1
Product: CO[C@@H]1CC[C@]2(c3ccccc3F)N=C(N)SC[C@@H]2C1
Temperature: 25 °C

Procedure:
(±)-N-[(4aR*,6R*,8aS*)-8a-(2-Fluorophenyl)-6-methoxy-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-yl]benzamide obtained in Preparation Example 59-(8) (1.65 g) was dissolved in methanol (60 mL). Then, DBU (1.24 mL, specific gravity: 1.018 g/cm3) was added, and the mixture was stirred with heating under reflux for 13 hours and 30 minutes. The reaction solution was left to cool to room temperature and then concentrated under reduced pressure. The residue was purified by NH-silica gel column chromatography to obtain the title compound (1.16 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([C:8](Cl)=[O:9])=[N:6][CH:7]=1.[CH3:11][NH:12][CH3:13]>O1CCCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[N:4][C:5]([C:8]([N:12]([CH3:13])[CH3:11])=[O:9])=[N:6][CH:7]=1
Reactant: CNC
Reactant: O=C(Cl)c1ncc(Br)cn1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN(C)C(=O)c1ncc(Br)cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.5 %

Procedure:
The 5-Bromo-pyrimidine-2-carbonyl chloride (55 g, 250 mmol) was dissolved in tetrahydrofuran (828 ml) and dimethyl-amine (2M solution in tetrahydrofuran) (373 ml, 745 mmol) was added portionwise at room temperature. The reaction was stirred at room temperature under nitrogen for 16 hours, after which time, LCMS indicated completion. The mixture was diluted with ethyl acetate (500 ml) and washed with H2O (500 ml). The water layer was further extracted with CH2Cl2 (5×500 ml), all organics combined, and dried over magnesium sulfate. The filtrate was concentrated in vacuo and then suspended in methyl-t-butylether (650 ml). The solution was then heated to reflux. The hot solution was allowed to cool overnight to afford pink crystals. The crystals were filtered and washed with cold methyl-t-butylether (100 ml) the solid was dried in a vacuum oven at 55° C. for 12 hours to afford the title compound 5-bromo-N,N-dimethylpyrimidine-2-carboxamide (SM-2: 44 g, 77%) as a pink solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([OH:15])=O)=[CH:4][CH:3]=1.[NH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:15])=[CH:6][CH:7]=1
Reactant: O=C(O)c1cnoc1-c1ccc(Br)cc1
Reactant: C1CCNC1
Product: O=C(c1cnoc1-c1ccc(Br)cc1)N1CCCC1

Procedure:
The title compound was prepared from 5-(4-bromophenyl)isoxazole-4-carboxylic acid (13.4 mg, 0.050 mmol) and pyrrolidine (4.3 mg, 0.060 mmol) as described in synthetic method A and thereafter purified, first by preparative HPLC method A and then by method B, to give a solid (16.2 mg). MS (pos) m/z 321.0.
Reaction SMILES: [N:1]([C:4]1[CH:36]=[CH:35][C:7]2[NH:8][C:9]([C:14]3[C:15](=[O:34])[N:16]([CH2:26][C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=4)[C@@H:17]4[C@H:22]([C:23]=3[OH:24])[C@@H:21]3[CH2:25][C@H:18]4[CH2:19][CH2:20]3)=[N:10][S:11](=[O:13])(=[O:12])[C:6]=2[CH:5]=1)=[N+]=[N-]>CO.C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:36]=[CH:35][C:7]2[NH:8][C:9]([C:14]3[C:15](=[O:34])[N:16]([CH2:26][C:27]4[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=4)[C@@H:17]4[C@H:22]([C:23]=3[OH:24])[C@@H:21]3[CH2:25][C@H:18]4[CH2:19][CH2:20]3)=[N:10][S:11](=[O:12])(=[O:13])[C:6]=2[CH:5]=1
Reactant: [N-]=[N+]=Nc1ccc2c(c1)S(=O)(=O)N=C(C1=C(O)[C@@H]3[C@H]4CC[C@H](C4)[C@@H]3N(Cc3ccc(F)cc3)C1=O)N2
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1ccc2c(c1)S(=O)(=O)N=C(C1=C(O)[C@@H]3[C@H]4CC[C@H](C4)[C@@H]3N(Cc3ccc(F)cc3)C1=O)N2
Temperature: 25 °C
Yield: 48.2 %

Procedure:
(1R,2S,7R,8S)-5-(7-Azido-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-3-(4-fluoro-benzyl)-6-hydroxy-3-aza-tricyclo[6.2.1.02,7]undec-5-en-4-one (0.348 g, 0.684 mmol) was dissolved in a 1:1 mixture if methanol and ethyl acetate (15 mL) at 25° C. Palladium on carbon (0.40 g, 5%, “wet”) was added, resulting in a black suspension. The reaction was maintained under a hydrogen atmosphere (balloon) at 25° C. for 6 h, and then was filtered through Celite. The Celite was washed with ethyl acetate (2×30 mL) and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography (Teledyne Isco RediSep column; 50 to 100% ethyl acetate in hexanes) to afford the desired product, (1R,2S,7R,8S)-5-(7-amino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-3-(4-fluoro-benzyl)-6-hydroxy-3-aza-tricyclo[6.2.1.02,7]undec-5-en-4-one (0.159 g, 0.330 mmol, 48%), as a pale yellow solid. 1H NMR (400 MHz, CDCl3) δ: 1.08-1.19 (3H, m), 1.40-1.57 (3H, m), 2.99 (1H, d, J=7.2 Hz), 3.31 (3H, s), 3.36-3.37 (1H, m), 3.50 (1H, d, J=7.8 Hz), 4.39 (1H, d, J=14.6 Hz), 4.93 (1H, d, J=14.5 Hz), 6.86-6.91 (3H, m), 7.13-7.15 (2H, m), 7.21 (1H, d, J=8.8 Hz), 7.30 (2H, bs), 13.79 (1H, s). LC-MS (ESI) calcd for C24H23FN4O4S 482.14, found 483.4 [M+H+].
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:10]2[CH:11]=[C:12]([CH3:16])[CH:13]=[CH:14][CH:15]=2)=[C:5]([C:7]([OH:9])=O)[N:6]=1.[F:17][C:18]1([F:38])[CH2:25][C@H:24]2[C@H:20]([CH2:21][NH:22][C@@H:23]2[CH2:26][N:27]2[C:35](=[O:36])[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:28]2=[O:37])[CH2:19]1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][C:2]1[S:3][C:4]([C:10]2[CH:11]=[C:12]([CH3:16])[CH:13]=[CH:14][CH:15]=2)=[C:5]([C:7]([N:22]2[CH2:21][C@H:20]3[C@H:24]([CH2:25][C:18]([F:17])([F:38])[CH2:19]3)[C@H:23]2[CH2:26][N:27]2[C:28](=[O:37])[C:29]3[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:35]2=[O:36])=[O:9])[N:6]=1
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)O)c1
Reactant: O=C1c2ccccc2C(=O)N1C[C@H]1NC[C@@H]2CC(F)(F)C[C@@H]21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3CC(F)(F)C[C@@H]3[C@H]2CN2C(=O)c3ccccc3C2=O)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 28 %

Procedure:
A mixture of 2-methyl-5-m-tolyl-thiazole-4-carboxylic acid (208 mg), (1S,2S,5R)-2-(7,7-difluoro-3-azabicyclo[3.3.0]oct-2-ylmethyl)-isoindole-1,3-dione (273 mg), DIPEA (0.41 mL) in dry DMF (6 mL) was stirred at RT for 4 h. The reaction mixture was directly purified by preparative HPLC to give the title compound (130 mg, 28%) as an oil. LC-MS: tR=1.02 min; [M+H]+=521.99
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH:12]([C:14]2[N:18]3[N:19]=[C:20]([C:23]4[CH:24]=[N:25][N:26]([CH:28]5[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]5)[CH:27]=4)[CH:21]=[CH:22][C:17]3=[N:16][CH:15]=2)[CH3:13])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.C=O.[C:36]([BH3-])#N.[Na+].C(O)(=O)C>CO>[Cl:1][C:2]1[C:11]([CH:12]([C:14]2[N:18]3[N:19]=[C:20]([C:23]4[CH:24]=[N:25][N:26]([CH:28]5[CH2:29][CH2:30][N:31]([CH3:36])[CH2:32][CH2:33]5)[CH:27]=4)[CH:21]=[CH:22][C:17]3=[N:16][CH:15]=2)[CH3:13])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: [BH3-]C#N
Reactant: CC(c1ccc2ncccc2c1Cl)c1cnc2ccc(-c3cnn(C4CCNCC4)c3)nn12
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(c1ccc2ncccc2c1Cl)c1cnc2ccc(-c3cnn(C4CCN(C)CC4)c3)nn12
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To (rac)-5-chloro-6-{1-[6-(1-piperidin-4-yl-1H-pyrazol-4-yl)-imidazo[1,2-b]pyridazin-3-yl]-ethyl}-quinoline (131 mg, 0.287 mmol), a 37% aqueous solution of formaldehyde (0.107 mL, 1.434 mmol) and 85% sodium cyanoborohydride (106 mg, 1.434 mmol) in MeOH (5 mL) was added acetic acid to adjust pH at 5-6. The RM was stirred at rt for 2.5 h, filtered and purified by preparative HPLC with acetonitrile and water (+0.1% TFA) to yield the title compound as a white foam (tR 2.29 min (conditions 8), MH+=472).
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[CH2:12]([N:16]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[S:17]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N+:26]([O-:28])=[O:27])(=[O:19])=[O:18])[CH2:13][CH:14]=[CH2:15]>C(Cl)(Cl)Cl.O.C([O-])(O)=O.[Na+]>[N+:26]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[S:17]([N:16]([CH2:12][CH2:13][CH:14]1[CH2:15][O:9]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)(=[O:19])=[O:18])([O-:28])=[O:27]
Reactant: C=CCCN(c1ccccc1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)N(CCC1CO1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 97 %

Procedure:
mCPBA (77%, 0.0550 g, 0.246 mmol) was added to N-(but-3-enyl)-2-nitro-N-phenylbenzenesulfonamide (0.0653 g, 0.196 mmol) in 1 mL CHCl3 at 0° C. The mixture was stirred at 0° C. for 30 min, then gradually warmed up to room temperature and continued to stir for 18 hr. After TLC showed the disappearance of starting material, the reaction mixture was diluted with a 1:1 mixture of water and saturated NaHCO3 (2×10 mL) and water (10 mL). The organic layer was dried over anhydrous Na2SO4 and evaporated to afford the crude product, which was subjected to silica gel chromatography using Hexanes/EtOAc to afford 0.0662 g colorless oil as product, yield 96.9%.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:5]([CH3:16])=[N:6][N:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8]=1[NH2:9].[NH3:17]>O.C(O)C>[NH2:9][C:8]1[N:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:6]=[C:5]([CH3:16])[C:4]=1[N:3]=[C:4]1[C:8](=[NH:7])[NH:9][N:17]=[C:5]1[CH3:16]
Reactant: N
Reactant: Cc1nn(-c2ccccc2)c(N)c1N
Agent: Cl
Solvent: O
Solvent: CCO
Product: CC1=NNC(=N)C1=Nc1c(C)nn(-c2ccccc2)c1N
Reaction time: 17 h

Procedure:
2.6 g 4,5-diamino-3-methyl-1-phenyl-1H-pyrazole dihydrochloride were dissolved in a mixture of 30 ml water and 30 ml ethanol. The pH of the resulting solution was then adjusted to 9 with concentrated ammonia. Subsequently the reaction mixture was stirred for 17 hours with a gasifying stirrer. The precipitated dye compounds was separated by filtration, washed with water and dried. The yield amounted to 1.2 g.
Reaction SMILES: O=P(Cl)(Cl)Cl.CN([CH:9]=[O:10])C.[CH3:11][C:12]1[CH:16]=[CH:15][S:14][C:13]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C([O-])(=O)C.[Na+]>O>[CH:9]([C:15]1[S:14][C:13]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[C:12]([CH3:11])[CH:16]=1)=[O:10]
Reactant: CN(C)C=O
Reactant: Cc1ccsc1-c1ccccc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1cc(C=O)sc1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.35 mol (32 mL) of POCl3 was added at 0° C. to a 1.0 mol (77 mL) of DMF (excess of DMF used as solvent). At the end of the addition, the mixture was allowed to warm to room temperature and stirred for 1 h. Then it was cooled again to 0° C. and treated with 3-methyl-2-phenylthiophene (60 g, 0.35 mol). The resulting reaction mixture was allowed to reach room temperature and after 12 h stirring at the same temperature was heated at 80° C. for 2 days. Then it was poured into a mixture of ice and water, added of sodium acetate and extracted with CHCl3 (3×150 mL). The organic phase was separated, washed with water until neutral pH, dried over MgSO4 and evaporated off to dryness. The residue was crystallized. Yield 60.2 g (85%).
Reaction SMILES: [CH2:1]([NH2:12])[CH2:2][C:3]1[CH:11]=[CH:10][C:9]2[O:8][CH2:7][O:6][C:5]=2[CH:4]=1.C(N(CC)CC)C.[C:20]12([C:30](Cl)=[O:31])[CH2:29][CH:24]3[CH2:25][CH:26]([CH2:28][CH:22]([CH2:23]3)[CH2:21]1)[CH2:27]2>C(OCC)C>[CH2:7]1[O:8][C:9]2[CH:10]=[CH:11][C:3]([CH2:2][CH2:1][NH:12][C:30]([C:20]34[CH2:29][CH:24]5[CH2:23][CH:22]([CH2:28][CH:26]([CH2:25]5)[CH2:27]3)[CH2:21]4)=[O:31])=[CH:4][C:5]=2[O:6]1
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Reactant: NCCc1ccc2c(c1)OCO2
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: O=C(NCCc1ccc2c(c1)OCO2)C12CC3CC(CC(C3)C1)C2
Reaction time: 3 h

Procedure:
Dissolve 0.5 g. of homopiperonylamine in 5 ml. of ethyl ether and 2.5 ml. of triethylamine. The mixture is cooled in an ice-bath and a solution of 0.6 g. of 1-adamantane carboxylic acid chloride in 10 ml. of ethyl ether added dropwise. Stir the mixture for an additional 3 hours. Add water and extract the mixture with ethyl acetate. Wash the ethyl acetate extract with 2N hydrochloric acid, saturated sodium bicarbonate solution, and water. Dry over anhydrous sodium sulfate, filter and evaporate the filtrate to a residue. Crystallize the residue from ethyl acetate to obtain the product of this step, m.p. 146°-148°C.
Reaction SMILES: N#N.Br[C:4]1[CH:5]=[C:6]([C:9]2([CH3:14])[O:13][CH2:12][CH2:11][O:10]2)[S:7][CH:8]=1.[Li]CCCC.CN([CH:23]=[O:24])C>CCOCC.CCCCCC>[CH3:14][C:9]1([C:6]2[S:7][CH:8]=[C:4]([CH:23]=[O:24])[CH:5]=2)[O:13][CH2:12][CH2:11][O:10]1
Reactant: CC1(c2cc(Br)cs2)OCCO1
Reactant: CN(C)C=O
Agent: N#N
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: CC1(c2cc(C=O)cs2)OCCO1
Reaction time: 0.17 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of 2-(4-bromo-thiophen-2-yl)-2-methyl-[1,3]dioxolane (1.00 g, 4.01 mmol) in Et2O (36.0 mL) at −78° C. was added dropwise n-BuLi (2.5 mL of a 1.6M solution in hexane, 4.00 mmol) over 15 min. The reaction mixture was then stirred at −78° C. for 15 min before DMF (3.1 mL, 40.14 mmol) was added dropwise. The cooling bath was removed and the reaction mixture was stirred for 10 min. Sat. aq. NaH4Cl (40 mL) was added and the aqueous layer was extracted with EA (2×100 mL). The combined org. extracts were dried over MgSO4, filtered, and the solvent was removed under reduced pressure to give crude 5-(2-methyl-[1,3]dioxolan-2-yl)-thiophene-3-carbaldehyde as an yellow oil. LC-MS-conditions 02: tR=0.84 min. The crude material was dissolved, under inert atmosphere (N2) in MeOH (9.98 mL) and treated at 0° C., portionwise with NaBH4 (284 mg, 7.21 mmol). The reaction mixture was stirred at rt for 2 h. The reaction mixture was poured in water (16 mL) and the aq. layer was extracted with EA (2×100 mL). The combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (50:50 hept-EA) gave the title compound as a yellow oil. TLC:rf (50:50 EA-Hept)=0.21. LC-MS-conditions 02: tR=0.71 min; [M+H]+=201.49.
Reaction SMILES: [O:1]1CCCO[CH:2]1[C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][C:8]=1[S:15]([CH2:18][CH2:19][OH:20])(=[O:17])=[O:16].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.O>CC(C)=O.O>[OH:20][CH2:19][CH2:18][S:15]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:7]=1[CH:2]=[O:1])[C:11]#[N:12])(=[O:17])=[O:16]
Reactant: N#Cc1ccc(C2OCCCO2)c(S(=O)(=O)CCO)c1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CC(C)=O
Solvent: O
Product: N#Cc1ccc(C=O)c(S(=O)(=O)CCO)c1
Temperature: 160 °C
Reaction time: 0.08 h

Procedure:
In an Emrys microwave, 4-(1,3-dioxan-2-yl)-3-[(2-hydroxyethyl)sulfonyl]benzonitrile (1970 mg, 6.6 mmol) and pyridinium 4-toluenesulfonate (1249 mg, 4.97 mmol; 0.75 eq.) in acetone/water (1:1, 30 ml) were heated with stirring at 160° C. for 5 min. The reaction mixture was then added to water (200 ml) and extracted with ethyl acetate (8×50 ml). The combined organic phases were then washed with saturated sodium chloride solution (2×50 ml), dried over sodium sulfate, filtered and concentrated under reduced pressure. To increase the yield, the sodium chloride wash solution was reextracted with ethyl acetate. The title compound was obtained as a solid (1.57 g, 99% of theory).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:7]([OH:9])=O)[S:5][CH:6]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[N-]1C=CN=C1.[N:27]1([C:37]([NH2:39])=[O:38])[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:29][C:28]1=[O:36]>CN(C)C=O.CN(C1C=CN=CC=1)C.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:7]([CH:29]2[C:30]3[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=3)[N:27]([C:37]([NH2:39])=[O:38])[C:28]2=[O:36])=[O:9])[S:5][CH:6]=1
Reactant: O=C(O)c1cc(Cl)cs1
Reactant: NC(=O)N1C(=O)Cc2ccccc21
Agent: CN(C)c1ccncc1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: c1c[n-]cn1
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: NC(=O)N1C(=O)C(C(=O)c2cc(Cl)cs2)c2ccccc21

Procedure:
The title compound was prepared according to the procedure of Example 55. An 831 mg (5.11 mmole) portion of 4-chloro-2-thiophenecarboxylic acid (prepared according to Iriarte, J., et al., J. Het. Chem., 13, 393 (1976)) was combined with 897 mg (5.53 mmole) of 1,1'-carbonyldiimidazole in 5 ml of N,N-dimethylformamide and the intermediate imidazolide coupled directly with 750 mg (4.26 mmole) of 2-oxindole-1-carboxamide in the presence of 1.40 g (11.49 mmole) of 4-(N,N-dimethylamino)pyridine. The resulting crude yellow solid (803 mg, 59% yield) was recrystallized from acetic acid to furnish 376 mg (1.17 mmole, 27% yield) of fluffy yellow crystals, m.p. 221-3° C.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C@@H:9]([CH3:10])[CH2:8][CH2:7][C@H:6]1[C:11]#[N:12])=[O:4].[CH:13]1([NH2:18])[CH2:17][CH2:16][CH2:15][CH2:14]1>C(#N)C>[CH:13]1([NH:18][CH2:2][C:3]([N:5]2[C@@H:9]([CH3:10])[CH2:8][CH2:7][C@H:6]2[C:11]#[N:12])=[O:4])[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: NC1CCCC1
Reactant: C[C@H]1CC[C@@H](C#N)N1C(=O)CCl
Solvent: CC#N
Product: C[C@H]1CC[C@@H](C#N)N1C(=O)CNC1CCCC1
Reaction time: 8 h

Procedure:
(2S,5S)-1-(2-Chloro-acetyl)-5-methyl-pyrrolidine-2-carbonitrile (50 mg, 0.30 mmol) and cyclopentylamine (0.059 mL, 0.6 mmol) were dissolved in acetonitrile (2 mL) and stirred overnight. The product was purified by reverse phase HPLC eluting with 0% to 70% acetonitrile/0.1% aqueous trifluoroacetic acid. 1H NMR (300 MHz, methanol-d4) δ ppm 1.36 (d, J=6.44 Hz, 3H), 1.68 (m, 5H), 1.85 (m, 3H), 2.16 (m, 3H), 2.38 (m, 3H), 3.60 (m, 1H), 4.20 (m, 1H), 4.77 (m, 1H). MS (ESI) m/z 236 (M+H)+.
Reaction SMILES: O.CS[C:4]1[NH:9][C:8]2[CH:10]=[CH:11][N:12]=[CH:13][C:7]=2[S:6](=[O:15])(=[O:14])[N:5]=1.[NH2:16][CH:17]([CH3:20])[CH2:18][OH:19]>C(OCC)C>[OH:19][CH2:18][CH:17]([NH:16][C:4]1[NH:9][C:8]2[CH:10]=[CH:11][N:12]=[CH:13][C:7]=2[S:6](=[O:15])(=[O:14])[N:5]=1)[CH3:20]
Reactant: CSC1=NS(=O)(=O)c2cnccc2N1
Reactant: CC(N)CO
Solvent: O
Solvent: CCOCC
Product: CC(CO)NC1=NS(=O)(=O)c2cnccc2N1
Reaction time: 3 h

Procedure:
A suspension of 3-methylsulfanyl-4H-pyrido[4,3-e]-1,2,4-thiadiazine 1,1-dioxide monohydrate and 2-amino-1-propanol (0.75 mL) was refluxed for 90 min (until completion of the reaction; t.l.c.). After cooling, the addition of diethylether (20 mL) gave rise to the separation of an oily residue. After decantation of the etheral solution, the residue was solubilized in methanol (1 mL) and then supplemented with diethylether (15 mL). An oily residue separated again. After decantation of the supernatent, the oily residue was solubilized in acetone (6 mL). A fine precipitate readily appeared. After 3 h at +4° C., the resulting precipitate was collected by filtration, washed with acetone and dried (yield: 0.33 g); m.p. 213°-216° C. (Compound 19).