Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][CH:9]=[C:10]([C:13](=O)[C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)[C:11]([OH:12])=[C:6]2[CH:5]=[N:4]1)[CH3:2].Cl.[NH2:23]O>N1C=CC=CC=1>[CH2:1]([N:3]1[C:7]2=[N:8][CH:9]=[C:10]3[C:13]([C:14]4[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=4)=[N:23][O:12][C:11]3=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: NO
Reactant: CCn1ncc2c(O)c(C(=O)c3ccc(C)cc3)cnc21
Agent: Cl
Solvent: c1ccncc1
Product: CCn1ncc2c3onc(-c4ccc(C)cc4)c3cnc21

Procedure:
1-Ethyl-4-hydroxy-5-(4-methylbenzoyl)-1H-pyrazolo[3,4-b]pyridine (1.45 g) was refluxed overnight in 20 ml of pyridine containing 3.0 g of hydroxylamine hydrochloride. The pyridine was then evaporated and the residue triturated with 5% hydrochloric acid and then washed with methanol. In this manner 1.26 g of product was obtained, mp 173°-175° C. An analytical sample was recrystallized from dichloromethane/hexane and the melting point was unchanged.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][C:5](=[O:7])[NH:4][C:3]1=[O:8].[Br:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16]Br)=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:4]2[C:5](=[O:7])[CH2:6][N:2]([CH3:1])[C:3]2=[O:8])=[CH:12][CH:11]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: CN1CC(=O)NC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN1CC(=O)N(Cc2ccc(Br)cc2)C1=O

Procedure:
1-Methylimidazolidine-2,4-dione (0.876 mmol, 100 mg), 1-bromo-4-(bromomethyl)benzene (0.964 mmol, 241 mg) and potassium carbonate (1.75 mmol, 242 mg) in acetonitrile (3 ml) were heated in the microwave at 120° C. for 1 h. The mixture was partitioned between water and DCM and the organic phase separated using a hydrophobic frit and concentrated to afford 3-(4-bromobenzyl)-1-methylimidazolidine-2,4-dione (3D3); 1H NMR (400 MHz, CDCl3) δ 7.44 (d, 2H) 7.29 (d, 2H) 4.59 (s, 2H) 3.85 (s, 2H) 2.98 (s, 3H).
Reaction SMILES: C(N(CC)CC)C.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[F:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]2[CH:43]=[C:42]([C:44]([OH:46])=O)[CH:41]=[C:40]([C:47]3[CH:52]=[CH:51][C:50]([F:53])=[CH:49][CH:48]=3)[N:39]=2)=[CH:34][CH:33]=1.Cl.[NH:55]1[C:59]([C:60]2[CH:61]=[C:62]3[C:72](=[CH:73][CH:74]=2)[O:71][C:65]2([CH2:70][CH2:69][NH:68][CH2:67][CH2:66]2)[CH2:64][C:63]3=[O:75])=[N:58][N:57]=[N:56]1>CN(C)C=O>[F:53][C:50]1[CH:49]=[CH:48][C:47]([C:40]2[CH:41]=[C:42]([C:44]([N:68]3[CH2:69][CH2:70][C:65]4([CH2:64][C:63](=[O:75])[C:62]5[C:72](=[CH:73][CH:74]=[C:60]([C:59]6[NH:58][N:57]=[N:56][N:55]=6)[CH:61]=5)[O:71]4)[CH2:66][CH2:67]3)=[O:46])[CH:43]=[C:38]([C:35]3[CH:34]=[CH:33][C:32]([F:31])=[CH:37][CH:36]=3)[N:39]=2)=[CH:52][CH:51]=1
Reactant: O=C(O)c1cc(-c2ccc(F)cc2)nc(-c2ccc(F)cc2)c1
Reactant: O=C1CC2(CCNCC2)Oc2ccc(-c3nnn[nH]3)cc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: O=C1CC2(CCN(C(=O)c3cc(-c4ccc(F)cc4)nc(-c4ccc(F)cc4)c3)CC2)Oc2ccc(-c3nnn[nH]3)cc21
Temperature: 60 °C
Reaction time: 3 h

Procedure:
Triethylamine (71.0 μl, 0.51 mol), 1-hydroxybenzotriazole hydrate (35 mg, 0.26 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (49.0 mg, 0.26 mol) were added to an N,N-dimethylformamide solution (0.5 mL) of 2,6-bis(4-fluorophenyl)pyridine-4-carboxylic acid (53.0 mg, 0.17 mmol) and 6-(tetrazol-5-yl)spiro[chroman-2,4′-piperidin]-4-one hydrochloride (82.0 mg, 0.26 mol), and stirred at 60° C. for 3 hours. The reaction liquid was concentrated under reduced pressure, and the resulting residue was purified through high-performance preparative liquid chromatography (0.1% TFA, water/acetonitrile) to obtain the title compound as a white solid. 1H-NMR (400 MHz, DMSO-d6) δ: 8.42 (1H, d, J=2.0 Hz), 8.31 (4H, dd, J=8.7, 5.7 Hz), 8.25 (1H, dd, J=8.7, 2.3 Hz), 7.94 (2H, s), 7.39-7.33 (5H, m), 4.35-4.32 (1H, m), 3.46-3.32 (3H, m), 2.99 (2H, s), 2.13-2.10 (1H, m), 1.91-1.87 (3H, m). MS [M+H]+=579.
Reaction SMILES: [CH3:1][C:2]([CH3:25])([CH3:24])[CH2:3][N:4]([CH3:23])[C:5]1[N:10]=[CH:9][N:8]=[C:7]([NH:11][C:12]2[CH:13]=[C:14]([CH:19]=[CH:20][C:21]=2[CH3:22])[C:15]([NH:17][CH3:18])=[O:16])[CH:6]=1.C(=O)(O)[O-].[Na+].[Br:31]Br>C(Cl)Cl.O>[Br:31][C:6]1[C:7]([NH:11][C:12]2[CH:13]=[C:14]([CH:19]=[CH:20][C:21]=2[CH3:22])[C:15]([NH:17][CH3:18])=[O:16])=[N:8][CH:9]=[N:10][C:5]=1[N:4]([CH2:3][C:2]([CH3:25])([CH3:24])[CH3:1])[CH3:23]
Reactant: CNC(=O)c1ccc(C)c(Nc2cc(N(C)CC(C)(C)C)ncn2)c1
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CNC(=O)c1ccc(C)c(Nc2ncnc(N(C)CC(C)(C)C)c2Br)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 44.4 %

Procedure:
To a solution of 3-{6-[(2,2-dimethyl-propyl)-methyl-amino]-pyrimidin-4-ylamino}-4,N-dimethyl-benzamide (0.46 g, 1.34 mmol) in methylene chloride (10 mL), was added sat. aq. sodium bicarbonate (2 mL) and bromine (0.07 mL, 1.37 mmol). The resulting mixture was stirred at room temperature for 18 hours, and the reaction was then diluted with water (20 mL). The organic layer was separated and the aqueous layer was extracted with DCM (10 mL). The combined organic layer was dried (sodium sulfate), filtered and concentrated. The residue was purified by silica gel column chromatography using 2% methanol in DCM as eluent to afford the product (250 mg, yield 44%). MS (m/z): 420 (M+H).
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]1([C:13]2[CH:14]=[C:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[NH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Br[CH2:24][CH2:25][O:26][CH3:27]>CS(C)=O>[CH3:27][O:26][CH2:25][CH2:24][N:16]1[CH:17]=[C:13]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:14]=[C:15]1[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)c1cc(-c2ccccc2)c[nH]1
Reactant: COCCBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOC(=O)c1cc(-c2ccccc2)cn1CCOC
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.9 %

Procedure:
Potassium tert-butoxide (780 mg, 6.96 mmol) was added in three portions over a period of 10 min to a stirred solution of ethyl 4-phenyl-1H-pyrrole-2-carboxylate (1.0 g, 4.63 mmol) in dimethylsulfoxide (10 mL) at 10° C. and maintained at this temperature for 30 min. A solution of 1-bromo-2-methoxy-ethane (770 mg, 5.50 mmol) in dimethylsulfoxide (2 mL) was added dropwise to the reaction mixture at 10° C. and then stirred for 2 h at room temperature. The reaction mixture was poured into ice water (25 mL) and the aqueous layer extracted with diethyl ether (3×20 mL). The combined organic layer was washed with water, brine (2×20 mL), dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford ethyl 1-(2-methoxyethyl)-4-phenyl-pyrrole-2-carboxylate (1.15 g, 91%) as an oil.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[S:24][CH:25]=[CH:26][CH:27]=4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:28].[NH2:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][C:38]([OH:40])=[O:39])=[CH:32][CH:31]=1>C1COCC1>[O:28]=[C:4]1[C:3](=[CH:2][NH:29][C:30]2[CH:31]=[CH:32][C:33]([CH2:36][CH2:37][C:38]([OH:40])=[O:39])=[CH:34][CH:35]=2)[C:11]2[C:6](=[CH:7][C:8]([C:12](=[O:13])[C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([NH:20][C:21]([C:23]4[S:24][CH:25]=[CH:26][CH:27]=4)=[O:22])[CH:15]=3)=[CH:9][CH:10]=2)[NH:5]1
Reactant: O=C1Nc2cc(C(=O)c3cccc(NC(=O)c4cccs4)c3)ccc2C1=CO
Reactant: Nc1ccc(CCC(=O)O)cc1
Solvent: C1CCOC1
Product: O=C(O)CCc1ccc(NC=C2C(=O)Nc3cc(C(=O)c4cccc(NC(=O)c5cccs5)c4)ccc32)cc1
Temperature: 65 °C
Reaction time: 24 h
Yield: 74 %

Procedure:
A small screw cap test tube was charged with Thiophene-2-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (as prepared in Example 45, 80 mg, 0.2049 mmol) and THF (2 mL). To the resulting solution was added 3-(4-Amino-phenyl)-propionic acid (41 mg, 0.2482 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature. The room temperature reaction mixture was concentrated in vacuo. The solid residue was recrystallized from EtOAc (5 mL) and Hexanes (2 mL) yielding the title compound in 74% yield (0.082 g, 0.1525 mmol).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.P(=O)(O)(O)O>CC(O)C.[Pd]>[CH3:4][C:3]1[CH:6]=[CH:7][C:8]([OH:10])=[CH:9][C:2]=1[OH:1]
Reactant: O=Cc1ccc(O)cc1O
Agent: [Pd]
Agent: O=P(O)(O)O
Solvent: CC(C)O
Product: Cc1ccc(O)cc1O
Reaction time: 3 h
Yield: 98.1 %

Procedure:
2,4-Dihydroxybenzaldehyde (33.97 gm, 0.246 mol) (recrystallized from toluene) was dissolved in spectroscopic grade 2-propanol (3 L) in a round bottom flask fitted with a gas inlet and a bubbler outlet. 10% Palladium on carbon (1.35 gm) was added followed by phosphoric acid (3 mL) and the mixture was sparged with nitrogen. The nitrogen flow was switched to hydrogen and the mixture was rapidly stirred with ice cooling. After 3 hours hydrogen uptake was complete and the catalyst was removed by filtration. The filtrate was stripped down to 200 mL and 200 mL of ethyl acetate was added. The solution was washed with 4×200 mL of water and the combined water extracts back-extracted with ethyl acetate. These organic extracts were water washed and the combined organic layers dried over sodium sulfate and stripped down to afford the product as a colorless crystalline solid (29.95 gm, 98%). M.p.: 106° C. (Lit. 106°-107° C. [J. C. Bell, W. Bridge, and A. Robertson. J. Chem. Soc., 1542-45 (1937)]). NMR (DMSO-d6): δ 1.961 (s, Me), 6.076 (dd, H-6, J[5,6]=8 hz, J[2,6]=2 hz), 6.231 (d, H-2), 6.760 (d, H-5) 8.867 (s, OH), and 9.008 (s, OH).
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[CH:4][C:5]([F:15])=[C:6]([CH:14]=1)[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].C([O-])([O-])=O.[K+].[K+].[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][C:25]=1[C:31]([F:34])([F:33])[F:32].O>CS(C)=O.CCOC(C)=O>[Cl:1][C:2]1[C:3]([O:30][C:27]2[CH:28]=[CH:29][C:24]([Cl:23])=[C:25]([C:31]([F:34])([F:32])[F:33])[CH:26]=2)=[CH:4][C:5]([F:15])=[C:6]([CH:14]=1)[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8]
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(F)cc1F
Reactant: Oc1ccc(Cl)c(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)c1cc(Cl)c(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 72 %

Procedure:
To a stirred solution of tert-butyl 5-chloro-2,4-difluorobenzoate (Preparation 51, 200 mg, 0.80 mmol) in DMSO (4 mL) was added K2CO3 (333 mg, 2.41 mmol) followed by 4-chloro-3-(trifluoromethyl)phenol (190 mg, 0.97 mmol) and the reaction stirred at room temperature for 18 h. Water (10 mL) and EtOAc (15 mL) were added and the layers separated. The aqueous layer was extracted with EtOAc (15 mL). The combined organic extracts were washed with brine (15 mL), dried (MgSO4) filtered and the solvent removed under reduced pressure to give the title compound (245 mg, 72%) as a solid.
Reaction SMILES: C(OC([NH:11][C@H:12]([CH2:30][CH2:31][CH2:32][NH:33]C(OCC1C=CC=CC=1)=O)[CH2:13][C:14]([NH:16][CH2:17][CH2:18][NH:19]C(OCC1C=CC=CC=1)=O)=[O:15])=O)C1C=CC=CC=1.[H][H]>CO.O.[C].[Pd]>[NH2:11][C@H:12]([CH2:30][CH2:31][CH2:32][NH2:33])[CH2:13][C:14]([NH:16][CH2:17][CH2:18][NH2:19])=[O:15]
Reactant: [H][H]
Reactant: O=C(C[C@@H](CCCNC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1)NCCNC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: O
Product: NCCC[C@@H](N)CC(=O)NCCN
Yield: 98.9 %

Procedure:
In 180 ml of methanol were suspended 1.41 g (2.39 mmol) of (R)-3,6-bis(benzyloxycarbonylamino)-N-(2-benzyloxycarbonylaminoethyl)hexanamide. To the resulting suspension was added a suspension of 718 mg of 10% palladium-carbon in 20 ml of water. After stirring, hydrogen gas was passed through the resulting mixture at room temperature for 3 hours to effect the reaction. The palladium-corbon was filtered off from the reaction mixture obtained, and the filtrate was concentrated to dryness. The residue obtained was dissolved in 15 ml of water and then subjected to a chromatography on a column of "Amberlite CG-50" (trade name, NH4+ -form, 50 ml). After the column was washed with 200 ml of water, the column was eluted with aqueous ammonia at concentrations gradiently varying from 0.5% to 4.0% (0.5%-increased steps; 200 ml at each concentration). Fractions of the eluate as eluted with 2.5% to 3.5% aqueous ammonia were combined together and concentrated to dryness, to afford 445 mg of (R)-3,6-diamino-N-(2-aminoethyl)hexanamide as a colorless paste.
Reaction SMILES: [O:1]([CH2:9][CH2:10][CH:11]1[C:16](=[O:17])[NH:15][C:14]2[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=2[O:12]1)[Si](C(C)(C)C)(C)C.Cl[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].[K+].[Br-]>>[OH:1][CH2:9][CH2:10][CH:11]1[C:16](=[O:17])[N:15]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:14]2[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=2[O:12]1
Reactant: CC(C)(C)[Si](C)(C)OCCC1Oc2ccccc2NC1=O
Reactant: CCCCCCl
Agent: [Br-]
Agent: [K+]
Product: CCCCCN1C(=O)C(CCO)Oc2ccccc21
Yield: 32 %

Procedure:
Prepared from 2-(2-tert-butyldimethylsiloxyethyl)-3,4-dihydro-3-oxo-2H-1,4-benzoxazine by Methods F and G, alkylating with 1-chloropentane in 32% yield and isolated as a colorless oil; IR (KBr) 3424, 2956, 2932, 1680, 1500, 1272, 1062, 749 cm-1 ; 1H NMR (CDCl3) δ 0.91 (t, J=6.8 Hz, 3H), 1.31-1.38 (m, 4H), 1.66 (br t, J=5.5 Hz, 2H), 2.08-2.29 (m, 2H), 2.59 (br s, 1H), 3.87-3.94 (m, 2H), 4.69 (dd, J=7.3, 5.8 Hz, 1H), 6.92-7.08 (m, 4H); Anal. Calc'd for C15H21NO3 : C, 68.42; H, 8.04; N, 5.32. Found: C, 68.10; H, 7.88; N, 5.32.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[NH:5][C:4]([CH3:11])([CH3:10])N=1.[OH2:12].[ClH:13]>Cl.Cl.CNNC.CC(C)=O>[CH3:10][C:4]1([CH3:11])[NH:5][C:6]([CH3:9])([CH3:8])[CH2:7][C:2](=[O:12])[CH2:1]1.[ClH:13]
Reactant: CC1=NC(C)(C)NC(C)(C)C1
Reactant: O
Agent: CNNC
Agent: Cl
Solvent: CC(C)=O
Product: CC1(C)CC(=O)CC(C)(C)N1

Procedure:
A mixture of 83 g of acetonine, 167 g of acetone, 17 g of water and 4.2 g of N,N'-dimethylhydrazine dihydrochloride was reacted at 50°-55° C. for 15 hours and then stripped under reduced pressure, followed by addition of acetone to the light-red residue and hydrogen chloride gas to pH=7. The crystals precipitated were filtered, washed with acetone, and dried to give 72.2 g of triacetonamine hydrochloride.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][C:5](=O)[CH2:4][N:3]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:25])=CC=1>>[CH3:1][C@H:2]1[CH2:7][NH:6][C:5](=[S:25])[CH2:4][N:3]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: C[C@H]1CNC(=O)CN1C(=O)OC(C)(C)C
Product: C[C@H]1CNC(=S)CN1C(=O)OC(C)(C)C
Temperature: 80 °C
Yield: 148.2 %

Procedure:
To a suspension of (S)-tert-butyl 2-methyl-5-oxopiperazine-1-carboxylate (7.0 g, 32.7 mmol) was added Lawesson's reagent (6.9 g, 16.7 mmol) and the reaction mixture was heated to 80° C. for 2 hours. The reaction mixture was cooled to room temperature, concentrated onto silica gel and purified by flash column chromatography (0-100% 10% 4M NH3 in MeOH in DCM) to provide the desired compound (5.7 g, 76%). 1H NMR (400 MHz, DMSO) δ 10.64 (s, 1H), 4.48 (d, J=18.9 Hz, 1H), 4.31-4.14 (m, 1H), 4.06 (d, J=18.9 Hz, 1H), 3.49-3.41 (m, 1H), 3.13 (ddd, J=13.7, 4.8, 2.9 Hz, 1H), 1.43 (s, 9H), 1.07 (d, J=6.6 Hz, 3H).
Reaction SMILES: [CH:1]12[CH2:6][CH:5]1[CH2:4][NH:3][CH2:2]2.[CH:7]1([N:10]2[C:19]3[C:14](=[CH:15][C:16]([F:21])=[C:17](F)[CH:18]=3)[C:13](=[O:22])[C:12]([C:23]([OH:25])=[O:24])=[CH:11]2)[CH2:9][CH2:8]1.C(N(CC)CC)C>CS(C)=O>[CH:1]12[CH2:6][CH:5]1[CH2:4][N:3]([C:17]1[CH:18]=[C:19]3[C:14]([C:13](=[O:22])[C:12]([C:23]([OH:25])=[O:24])=[CH:11][N:10]3[CH:7]3[CH2:9][CH2:8]3)=[CH:15][C:16]=1[F:21])[CH2:2]2
Reactant: C1NCC2CC12
Reactant: O=C(O)c1cn(C2CC2)c2cc(F)c(F)cc2c1=O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=C(O)c1cn(C2CC2)c2cc(N3CC4CC4C3)c(F)cc2c1=O
Yield: 33 %

Procedure:
A solution of the hydrochloride salt of 3-azabicyclo[3.1.0]hexane (157 mg, 1.31 mmol), (prepared in a manner similar to that described in U.S. Pat. No. 4,183,857) in dimethylsulfoxide (13 ml) was treated with 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid (348 mg, 1.31 mmol) and triethylamine (0.58 ml, 3.9 mmol) and heated for 18 hours. Filtration of the reaction mixture provided a white solid, which was purified by column chromatography (eluant: 1% acetic acid in chloroform, then 5% acetic acid in chloroform, then methanol) to give the title product as a white solid, melting point 290° (186 mg, 0.43 mmol, 33% yield). 1H NMR (DMSO-d6): 8.54 (s, 1H), 7.75 (d, J=14 Hz, 1H), 7.08 (d, J=9 Hz, 1H), 3.83 (dd, J=4, 10 Hz, 2H), 3.73 (bs, 1H), 3.62 (bd, J=10 Hz, 2H), 1.77 (m, 2H), 1.30 (d, J=6 Hz, 2H), 1.14 (bs, 2H), 0.77 (m, 1H), 0.30 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([S:8]([NH2:11])(=[O:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[CH:12](=O)[CH3:13].Cl>C(O)(C)C.C(OCC)(=O)C>[CH3:12][CH:13]1[NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[N:4][C:3]=2[S:8](=[O:10])(=[O:9])[NH:11]1
Reactant: Nc1cccnc1S(N)(=O)=O
Reactant: CC=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CC1Nc2cccnc2S(=O)(=O)N1

Procedure:
A mixture of 1 g of 3-aminopyridine-2-sulfonamide (Preparation 1) and 0.28 g of acetaldehyde in 10 cm3 of isopropanol to which 10 drops of ethyl acetate saturated with gaseous HCl have been added is brought to reflux for 1 to 2 hours. After cooling, a crystalline precipitate of the title compound is collected on a filter and washed with isopropanol. The 3-methyl-2,3-dihydro-4H-pyrido[3,2- e] [1,2,4]thiadiazine 1,1-dioxide is recrystallized from a CH3OH/H2O (1/4) mixture.
Reaction SMILES: [C:1]([CH:4]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(=[O:3])[CH3:2].[C:24]1([N:30]2[CH:33]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:32](=O)[C:31]2=[O:41])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1C=CC=CC=1>[O:3]=[C:1]([CH3:4])/[CH:2]=[C:32]1/[C:31](=[O:41])[N:30]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:33]/1[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=C1C(=O)N(c2ccccc2)C1c1ccccc1
Reactant: CC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: CC(=O)/C=C1/C(=O)N(c2ccccc2)C1c1ccccc1
Reaction time: 8 h

Procedure:
To a solution of 0.67 g of acetylmethylene triphenylphosphorane in 70 ml of benzene was added at room temperature under a nitrogen atmosphere a solution of 0.50 g of 1,4-diphenyl-2,3-azetidinedione in 30 ml of benzene, and the mixture was stirred overnight. After completion of the reaction, the benzene was evaporated, and the residue was applied to silica gel column chromatography (eluent; methylene chloride). The desired fractions were combined, the solvent was evaporated, and the residue was recrystallized from ethanol to give the title compound as pale yellow needles. Yield 0.32 g, m.p. 157.5°-158.5° C.
Reaction SMILES: [H-].[Na+].OC1C=CC(C2C3C=C(N(C)C)C=C[C:15]=3[S:14](=[O:25])(=[O:24])CCC2)=CC=1.I[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]I.CN(C=[O:37])C>>[S:14]([O:25][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])(=[O:37])(=[O:24])[CH3:15]
Reactant: CN(C)c1ccc2c(c1)C(c1ccc(O)cc1)CCCS2(=O)=O
Reactant: ICCCCCI
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: CCCCCOS(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 231 mg (5.79 mmol, 60% disp.) of NaH in 22 mL of DMF was added 2.05 g (4.45 mmol) of 5-(4′-hydroxyphenyl)-7-(dimethylamino)tetrahydrobenzothiepine-1,1-dioxide (obtained from Example 1402, Step 10), and the resulting solution was stirred at ambient temperature for 1 hour. To the mixture was added 18.02 g (55.63 mmol) of 1,5-diiodopentane and the solution was stirred overnight at ambient temperature. DMF was removed by high vacuum and the residue was extracted with ethyl acetate and washed with brine. The extract was dried over MgSO4, and the concentrated residue was purified by column chromatography to give the pentyl mesylate intermediate: 1H NMR (CDCl3) δ 0.90(q, 6H), 1.05-2.0 (m, 17H), 2.2 (t, 1H), 2.8 (s, 6 h), 3.0 (q, 2H), 3.22 (t, 2H), 3.95 (t, 2H), 4.1 (s, 1H), 5.42 (s, 1H), 6.1 (d, 1H), 6.6 (d, 1H), 6.9 (d, 2H), 7.4 (d, 2H), 7.9 (d, 1H).
Reaction SMILES: ClC1C=C(C=CC=1)N.ClC1C=CC2C(=C([C:20]3[NH:28][C:27]4[CH2:26][CH2:25][NH:24][C:23](=[O:29])[C:22]=4[CH:21]=3)C=CC=2)N=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.C1COCC1>>[NH:28]1[C:27]2[CH2:26][CH2:25][NH:24][C:23](=[O:29])[C:22]=2[CH:21]=[CH:20]1
Reactant: O=C1NCCc2[nH]c(-c3cccc4ccc(Cl)nc34)cc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: Nc1cccc(Cl)c1
Solvent: C1CCOC1
Product: O=C1NCCc2[nH]ccc21
Yield: 47.2 %

Procedure:
Prepared according to Example 102, using 3-chloroaniline (220 μl, 2.099 mmol, Sigma Aldrich), 2-(2-chloroquinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 1; 125 mg, 0.420 mmol). and 1.0 M LHMDS, 1.0M in THF (2099 μl, 2.099 mmol, Sigma Aldrich) and stirring at 25° C. for 30 min. Purification by column chromatography (silica gel 1 to 5% MeOH/DCM) provided 2424(3-chlorophenyl)amino)-8-quinolinyl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one (27 mg, 16.5%). 1H NMR (400 MHz, CDCl3) δ ppm 12.09-12.31 (1H, m) 8.03 (2H, d, J=1.00 Hz) 7.57-7.60 (1H, m) 7.50-7.55 (1H, m) 7.33-7.41 (4H, m) 7.17-7.22 (1H, m) 7.12-7.15 (1H, m) 6.88-6.93 (1H, m) 5.23-5.28 (1H, m) 3.55-3.62 (2H, m) 2.67-2.73 (2H, m). m/z (ESI, +ve) 389.1 (M+H)+.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]3[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=3)=[CH:26][CH:25]=2)[C:7](=[O:22])[C:8]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH:19]([CH3:21])[CH3:20])=[CH:14][CH:13]=2)=[C:9]([CH3:11])[N:10]=1)[CH2:2][CH2:3][CH3:4].Cl.[NH2:39]O.[C:41](=[O:44])([O-])[OH:42].[Na+]>CS(C)=O.C(OCC)(=O)C>[CH2:1]([C:5]1[N:6]([CH2:23][C:24]2[CH:25]=[CH:26][C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[C:36]3[NH:39][C:41](=[O:44])[O:42][N:37]=3)=[CH:28][CH:29]=2)[C:7](=[O:22])[C:8]([C:12]2[CH:13]=[CH:14][C:15]([O:18][CH:19]([CH3:20])[CH3:21])=[CH:16][CH:17]=2)=[C:9]([CH3:11])[N:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C([O-])O
Reactant: NO
Reactant: CCCCc1nc(C)c(-c2ccc(OC(C)C)cc2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)c(-c2ccc(OC(C)C)cc2)c(=O)n1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 78.1 %

Procedure:
4′-{[2-Butyl-5-(4-isopropoxyphenyl)-4-methyl-6-oxopyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile (0.56 g) was dissolved in dimethyl sulfoxide (5 mL), and hydroxylamine hydrochloride (0.79 g) and sodium hydrogen carbonate (1.2 g) were added. The mixture was stirred overnight at 90° C. After cooling, the reaction mixture was diluted with ethyl acetate, washed with water, dried over sodium sulfate and concentrated. The residue was dissolved in tetrahydrofuran (5 mL), and N,N′-carbonyldiimidazole (0.28 g) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.26 mL) were added. After stirring for 30 min, the reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid, dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.49 g, 78%).
Reaction SMILES: [C:1]([O:5][CH2:6][CH:7]([CH3:9])[CH3:8])(=[O:4])[CH:2]=[CH2:3].CCC[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20].[CH2:22]([CH:24]([CH2:48]CCC)[C:25]([O:27]OC(C)(CCC(O[O:37][C:38](=[O:46])[CH:39]([CH2:44]C)[CH2:40]CCC)(C)C)C)=[O:26])C>>[CH3:48][C:24]([C:25]([O:27][CH:16]1[C@@:15]2([CH3:1])[C:19]([CH3:20])([CH3:21])[C@H:18]([CH2:13][CH2:14]2)[CH2:17]1)=[O:26])=[CH2:22].[C:38]([O:37][CH2:6][CH:7]([CH3:9])[CH3:8])(=[O:46])[C:39]([CH3:40])=[CH2:44].[C:1]([O:5][CH2:6][CH:7]([CH3:9])[CH3:8])(=[O:4])[CH:2]=[CH2:3]
Reactant: CCCCCCCCCC(C)C
Reactant: CCCCC(CC)C(=O)OOC(C)(C)CCC(C)(C)OOC(=O)C(CC)CCCC
Agent: C=CC(=O)OCC(C)C
Product: C=C(C)C(=O)OC1C[C@H]2CC[C@]1(C)C2(C)C
Product: C=C(C)C(=O)OCC(C)C

Procedure:
90 g of isobutyl acrylate, 90 g of isododecane and 1.2 g of 2,5-bis(2-ethylhexanoylperoxy)-2,5-dimethylhexane were then introduced into the above mixture, still at 90° C. and over 30 minutes.