Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([F:8])=[N:4][CH:5]=[CH:6][CH:7]=1.CC1(C)C(C)(C)OB([C:17]2[CH2:22][CH2:21][N:20]([C:23](=[O:25])[CH3:24])[CH2:19][CH:18]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[F:8][C:3]1[C:2]([C:17]2[CH2:22][CH2:21][N:20]([C:23](=[O:25])[CH3:24])[CH2:19][CH:18]=2)=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: CC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: Fc1ncccc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CC(=O)N1CC=C(c2cccnc2F)CC1
Temperature: 100 °C
Reaction time: 16 h
Yield: 20.5 %

Procedure:
To a round-bottomed flask was added 3-bromo-2-fluoropyridine (0.54 g, 3.1 mmol), 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridin-1(2H)-yl)ethanone (0.96 g, 3.8 mmol), trans-dichlorobis(triphenylphosphine) palladium (II) (0.17 g, 0.25 mmol), and sodium carbonate (0.97 g, 9.2 mmol) in DME (7.5 mL) and Water (2.5 mL). The reaction mixture was stirred at 100° C. for 16 h. After cooling to RT, the reaction mixture was diluted with water (15 mL) and extracted with EtOAc (3×50 mL). The organic extract was washed with water, brine, dried with Na2SO4, filtered, and concentrated. The crude product was chromatographed through a Redi-Sep pre-packed silica gel column (40 g), eluting with a gradient of 10% to 100% EtOAc in hexane, to provide 1-(4-(2-fluoropyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)ethanone (0.14 g, 21% yield) as a yellow oil. MS (ESI, pos. ion) m/z: 221.0 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:22][OH:23])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[N:12]=[C:13]([N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[S:14][CH:15]=1.O[C:25]1[C:29]([CH:30]=[O:31])=[CH:28][N:27]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:26]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[N:12]=[C:13]([N:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)[S:14][CH:15]=1)[CH2:22][O:23][C:25]1[C:29]([CH:30]=[O:31])=[CH:28][N:27]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[N:26]=1
Reactant: O=Cc1cn(-c2ccccc2)nc1O
Reactant: COc1cc(CO)ccc1OCc1csc(N2CCCCC2)n1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: COc1cc(COc2nn(-c3ccccc3)cc2C=O)ccc1OCc1csc(N2CCCCC2)n1
Reaction time: 15 h
Yield: 66.3 %

Procedure:
To a mixture of {3-methoxy-4-[(2-piperidin-1-yl-1,3-thiazol-4-yl)methoxy]phenyl}methanol (1.15 g), 3-hydroxy-1-phenyl-1H-pyrazole-4-carbaldehyde (0.70 g), tributylphosphine (1.03 g) and tetrahydrofuran (100 mL) was added 1,1′-(azodicarbonyl)dipiperidine (1.29 g) at room temperature, and the mixture was stirred for 15 hrs. The precipitated crystals were removed by filtration and the filtrate was concentrated. The residue was subjected to silica gel column chromatography to give 3-({3-methoxy-4-[(2-piperidin-1-yl-1,3-thiazol-4-yl)methoxy]benzyl}oxy)-1-phenyl-1H-pyrazole-4-carbaldehyde as crystals (1.15 g, yield 67%) from a fraction eluted with ethyl acetate-hexane (2:3, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 123-124° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[O:15][C:14]([CH3:20])([CH3:19])[CH:13]([OH:21])[CH:12]2[N:22]([CH3:27])[S:23]([CH3:26])(=[O:25])=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28](OC(=O)C)(=[O:30])[CH3:29]>N1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[O:15][C:14]([CH3:20])([CH3:19])[CH:13]([O:21][C:28](=[O:30])[CH3:29])[CH:12]2[N:22]([CH3:27])[S:23]([CH3:26])(=[O:24])=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C1c2cc(OCc3ccccc3)ccc2OC(C)(C)C1O)S(C)(=O)=O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OC1C(N(C)S(C)(=O)=O)c2cc(OCc3ccccc3)ccc2OC1(C)C
Reaction time: 8 h

Procedure:
A solution of 4.5 g of N-(6-benzyloxy-3-hydroxy-2,2-dimethylchroman-4-yl)-N-methyl-methanesulfonamide and 37 ml of acetic anhydride in 74 ml of pyridine was left to stand at RT overnight. The batch was concentrated under reduced pressure and the residue was dissolved in EA, washed successively with dilute hydrochloric acid and saturated sodium bicarbonate solution and dried over magnesium sulfate. Removal of the solvent under reduced pressure gave 4.7 g of N-(6-benzyloxy-3-acetoxy-2,2-dimethylchroman-4-yl)-N-methyl-methanesulfonamide, m.p. 124-125° C.
Reaction SMILES: Cl.[NH2:2][OH:3].[CH3:4][C:5]1[CH:10]=[C:9]([C:11]#[N:12])[CH:8]=[C:7]([CH3:13])[N:6]=1>CO>[OH:3][NH:2][C:11](=[NH:12])[C:9]1[CH:8]=[C:7]([CH3:13])[N:6]=[C:5]([CH3:4])[CH:10]=1
Reactant: Cc1cc(C#N)cc(C)n1
Reactant: NO
Agent: Cl
Solvent: CO
Product: Cc1cc(C(=N)NO)cc(C)n1
Temperature: 60 °C
Reaction time: 15 h
Yield: 82.1 %

Procedure:
To an ice-cooled solution of potassium tert.-butylate (1.25 g, 11.1 mmol) in methanol (20 mL), hydroxylamine hydrochloride (773 mg, 11.1 mmol) is added. The suspension is stirred for 30 min before 2,6-dimethyl-4-cyano-pyridine (490 mg, 3.71 mmol) is added. The mixture is stirred at 60° C. for 15 h before it is filtered. The filtrate is evaporated to dryness and the resulting solid is washed with water and then dried under HV to give N-hydroxy-2,6-dimethyl-isonicotinamidine (503 mg) as a white powder; LC-MS: tR=0.23 min; [M+1]+=166.01; 1H NMR (D6-DMSO): δ 2.43 (s, 6H), 5.88 (s, 2H), 7.30 (s, 2H), 9.90 (s, 1H).
Reaction SMILES: [NH:1]([C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])[C@H:2]([C:13](O)=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[NH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29].C(=O)(O)[O-].[Na+].CP(OP(CC)(C)=O)(CC)=O>CN(C)C=O.O>[NH:1]([C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])[C@H:2]([C:13]([NH:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1
Reactant: COC(=O)CN
Reactant: O=C(N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O)OCc1ccccc1
Agent: CCP(C)(=O)OP(C)(=O)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CNC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the suspension of 3.35 g (0.01 mol) of Z-Trp-OH and 1.25 g (0.01 mol) of H-Gly-OCH3 in 15 ml of dimethyl formamide there were added portionwise altogether 7 ml of water and subsequently 5.1 g of a finely powdered sodium bicarbonate. The suspension was largely clarified by adding dropwise 4 ml of methylethyl phosphinic acid anhydride. A sample of the reaction solution diluted with water showed a neutral reaction. Upon heating to room temperature the solution was stirred overnight and the solvents were separated by distillation in a high vacuum at room temperature. The residue was taken up in a mixture of 25 ml of water and 70 ml of ethyl acetate, the ethyl acetate extract was separated and the aqueous phase was extracted twice using each time 10 ml of ethyl acetate. The combined ethyl acetate extracts were washed twice using each time 7 ml of water, a 5% potassium bisulfate solution (until an acid reaction took place) and a saturated sodium bicarbonate solution (until s slightly alkaline reaction took place). Upon drying over magnesium sulfate the ethyl acetate solution was largely separated by distillation in vacuo and the residue was digested with diisopropyl ether.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5](/[CH:10]=[CH:11]/[C:12](=[O:14])[CH3:13])=[CH:4][C:3]=2[O:2]1.O.[C:16]([OH:20])(=[O:19])[CH:17]=O>C(O)(=O)C.O>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5](/[CH:10]=[CH:11]/[C:12](=[O:14])/[CH:13]=[CH:17]/[C:16]([OH:20])=[O:19])=[CH:4][C:3]=2[O:2]1
Reactant: O=CC(=O)O
Reactant: CC(=O)/C=C/c1ccc2c(c1)OCO2
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)/C=C/C(=O)/C=C/c1ccc2c(c1)OCO2

Procedure:
A solution of 15 g (78.8 mmol) of (E)-4-[3,4-(methylenedioxy)phenyl]but-3-en-2-one and 7.2 g (78.8 mmol) of glyoxylic acid monohydrate in 20 ml of acetic acid was heated at reflux for 20 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was extracted twice with 3N sodium hydroxide solution. The combined aqueous phases were treated with 3N hydrochloric acid to produce a strongly acidic reaction and extracted twice with ethyl acetate. The combined organic phases were dried over magnesium sulphate and concentrated. Crystallization of the residue from ethyl acetate/ether yielded (E,E)-6-[3,4-(methylenedioxy)phenyl]-4-oxo-2,5-hexadienoic acid of melting point 170°-173°.
Reaction SMILES: [CH3:1][N:2]([CH3:37])[CH2:3][CH2:4][N:5]1[C:13](=[O:14])[C:12]2[CH:11]=[C:10]3[NH:15][C:16]([C:18]4[C:19]([O:34]C)=[N:20][CH:21]=[CH:22][C:23]=4[O:24][CH:25]([CH3:33])[CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[N:17][C:9]3=[CH:8][C:7]=2[C:6]1=[O:36].Cl>O1CCOCC1>[CH3:37][N:2]([CH3:1])[CH2:3][CH2:4][N:5]1[C:13](=[O:14])[C:12]2[CH:11]=[C:10]3[NH:15][C:16]([C:18]4[C:19](=[O:34])[NH:20][CH:21]=[CH:22][C:23]=4[O:24][CH:25]([CH3:33])[CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[N:17][C:9]3=[CH:8][C:7]=2[C:6]1=[O:36]
Reactant: COc1nccc(OC(C)Cc2ccccc2)c1-c1nc2cc3c(cc2[nH]1)C(=O)N(CCN(C)C)C3=O
Agent: Cl
Solvent: C1COCCO1
Product: CC(Cc1ccccc1)Oc1cc[nH]c(=O)c1-c1nc2cc3c(cc2[nH]1)C(=O)N(CCN(C)C)C3=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 75.2 %

Procedure:
6-(2-(Dimethylamino)ethyl)-2-(2-methoxy-4-((1-phenylpropan-2-yl)oxy)pyridine-3-yl)imidazo[4,5-f]isoindole-5,7(1H,6H)-dione (0.52 g, 1.04 mmol) was dissolved in 30 mL of 1,4-dioxane at rt. 5 mL of concentrated HCl was added. The reaction mixture was stirred at rt for 12 h. The volatile was removed under reduced pressure. The residue was washed with 20 mL of saturated K2CO3 solution. The pale-yellow precipitate was purified by column chromatography (silica-gel, CH2Cl2/MeOH=7/3 v/v) to give a pale-yellow solid product, 0.38 g, 75.2% yield. MS: 486.8 [M+H]+. 1H-NMR (DMSO-d6, 500 MHz): δ 13.24 (s, 1H), 11.98 (s, 1H), 8.03 (s, 2H), 7.60 (d, 1H, J=7.0 Hz), 7.34-7.32 (m, 2H), 7.12-7.09 (m, 3H), 6.46 (d, 1H, J=7.5 Hz), 4.93-4.87 (m, 1H), 3.70 (t, 2H, J=7.0 Hz), 3.03-2.91 (m, 2H), 2.52 (t, 2H, J=7.0 Hz), 2.19 (s, 6H), 1.27 (d, 3H, J=6.0 Hz).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:24]=[CH:23][C:6]([CH:7]=[C:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][CH2:11][C:10]3[CH:19]=[CH:20][CH:21]=[CH:22][C:9]2=3)=[CH:5][CH:4]=1.C(OCC)(=O)C.[H][H]>C(O)C.[Pd]>[F:1][C:2]([F:25])([F:26])[C:3]1[CH:4]=[CH:5][C:6]([CH2:7][CH:8]2[C:9]3[CH:22]=[CH:21][CH:20]=[CH:19][C:10]=3[CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]2=3)=[CH:23][CH:24]=1
Reactant: [H][H]
Reactant: FC(F)(F)c1ccc(C=C2c3ccccc3CCc3ccccc32)cc1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: FC(F)(F)c1ccc(CC2c3ccccc3CCc3ccccc32)cc1
Reaction time: 17 h

Procedure:
Add the 5-(4-trifluoromethyl-benzylidene)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (0.14 g, 0.45 mmol), to a mixture of 10% Pd/C (0.05 g) suspended in absolute ethanol (4.0 mL) and ethyl acetate (4.0 mL) and hydrogenate under a balloon of hydrogen at room temperature and pressure. Stir for 17 h, remove the catalyst via filtration through a pad of Celite. Evaporate the filtrate and pass through a plug of silica gel equilibrated with hexanes. Concentrate the filtrate to gives the title product. MS (m/e): 352 (M+); Analysis for C23H19F3: Calcd: C, 78.39 H, 5.43. Found: C, 78.70 H, 5.16.
Reaction SMILES: [CH2:1]([C:4]12[CH2:10][CH:7]([CH:8]=[CH:9]1)[CH:6]1[C:11]([O:13][C:14](=[O:15])[CH:5]21)=[O:12])[CH:2]=[CH2:3].[CH2:16]([CH:18]([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:19][NH2:20])[CH3:17]>>[CH2:16]([CH:18]([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:19][N:20]=[C:14]([CH:5]1[CH:6]([C:11]([OH:13])=[O:12])[CH:7]2[CH2:10][C:4]1([CH2:1][CH:2]=[CH2:3])[CH:9]=[CH:8]2)[OH:15])[CH3:17]
Reactant: CCCCC(CC)CN
Reactant: C=CCC12C=CC(C1)C1C(=O)OC(=O)C12
Product: C=CCC12C=CC(C1)C(C(=O)O)C2C(O)=NCC(CC)CCCC

Procedure:
The procedure described in Example 3 is repeated, except that 204 g of allyl-bicyclo[2.2.1]hept-5-ene-2,3-dicarboxylic acid anhydride and 129 g of 2-ethylhexylamine are used. 17 g of water are split off at 115° to 160° C. under 4,000 Pa in the course of 4.5 hours. 292.05 g (92.6% of theory) of a fraction of boiling point 160°-164° C. under 10.7 Pa, nD20 1.5038 and η25 0.68 Pa.s are obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:23]=[CH:22][C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]2[CH:20]=[CH:19][N:18]=[C:17]([NH2:21])[N:16]=2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]2[CH:20]=[CH:19][N:18]=[C:17]([NH2:21])[N:16]=2)=[CH:22][CH:23]=1
Reactant: Nc1nccc(-c2ccccc2Oc2ccc([N+](=O)[O-])cc2)n1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(Oc2ccccc2-c2ccnc(N)n2)cc1
Reaction time: 8 h

Procedure:
4-(2-(4-nitrophenoxy)phenyl)pyrimidin-2-amine (0.280 g, 0.908 mmol) and palladium, 10 wt. % (dry basis) on activated carbon 50% water wet (0.193 g, 0.182 mmol) were combined under nitrogen and diluted with 5 mL MeOH. The atmosphere was replaced with hydrogen, and the mixture was stirred rapidly overnight. The reaction was flushed with nitrogen and was filtered through celite, rinsing with MeOH. Concentration in vacuo afforded 4-(2-(4-aminophenoxy)phenyl)pyrimidin-2-amine MS m/z=279 [M+H]+. Calc'd for C16H14N4O: 278.3.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C:20]([CH3:24])([C:21](O)=[O:22])[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.Cl.C1C=NC2N(O)N=NC=2C=1.C(N(CC)CC)C.[NH2:54][C:55]1[C:63]([NH2:64])=[CH:62][CH:61]=[CH:60][C:56]=1[C:57]([NH2:59])=[O:58]>CN(C=O)C>[NH2:54][C:55]1[C:56]([C:57](=[O:58])[NH2:59])=[CH:60][CH:61]=[CH:62][C:63]=1[NH:64][C:21]([C:20]1([CH3:24])[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][N:11]1[C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])=[O:22]
Reactant: NC(=O)c1cccc(N)c1N
Reactant: CC1(C(=O)O)Cc2ccccc2CN1C(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC1(C(=O)Nc2cccc(C(N)=O)c2N)Cc2ccccc2CN1C(=O)OCc1ccccc1
Temperature: 55 °C
Reaction time: 0.17 h

Procedure:
Step-4: To a solution of 2-((benzyloxy)carbonyl)-3-methyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (620 mg, 1.91 mmol) in anhydrous DMF (5 ml) was added EDC.HCl (1.098 mg, 5.73 mmol), HOAt (390 mg, 2.87 mmol) and triethylamine (0.4 ml, 2.87 mmol) at RT and the mixture was stirred for 10 min. To this reaction mixture, 2,3-diaminobenzamide (346 mg, 2.29 mmol) was added and heated to 55° C. for 3 days. The reaction mixture was poured into ice cold water and stirred for 30 min. The precipitate formed was filtered and dried under vacuum and purified by preparative TLC using ethyl acetate as eluent to afford benzyl 3-((2-amino-3-carbamoylphenyl)carbamoyl)-3-methyl-3,4-dihydroisoquinoline-2(1H)-carboxylate. MS (ES+): m/z 481.2 [M+Na]+
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C@H:11]([NH:15][S:16]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][C:26]3=[O:31])[C:20]=2[O:32][CH:33]([F:35])[F:34])(=[O:18])=[O:17])[C:12](O)=[O:13])=[O:8])=[CH:4][CH:3]=1.[CH2:36]([O:38][C:39]([CH:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1)=[O:40])[CH3:37]>CN(C=O)C>[CH2:36]([O:38][C:39]([CH:41]1[CH2:46][CH2:45][N:44]([C:12](=[O:13])[C@@H:11]([NH:15][S:16]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][C:26]3=[O:31])[C:20]=2[O:32][CH:33]([F:34])[F:35])(=[O:18])=[O:17])[CH2:10][NH:9][C:7]([C:5]2[S:6][C:2]([Cl:1])=[CH:3][CH:4]=2)=[O:8])[CH2:43][CH2:42]1)=[O:40])[CH3:37]
Reactant: O=C(NC[C@H](NS(=O)(=O)c1cccc(N2CCCCC2=O)c1OC(F)F)C(=O)O)c1ccc(Cl)s1
Reactant: CCOC(=O)C1CCNCC1
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCN(C(=O)[C@H](CNC(=O)c2ccc(Cl)s2)NS(=O)(=O)c2cccc(N3CCCCC3=O)c2OC(F)F)CC1

Procedure:
Intermediate 34 (258 mg, 0.467 mmol) and Piperidine-4-carboxylic acid ethyl ester (81 mg, 0.514 mmol) were coupled in close analogy to the procedure described in 3.5) using DMF as solvent. The mixture was purified by prep. HPLC. Yield after lyophilization: 253 mg, 78%, colorless, amorphous solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[O:6][C@H:5]([CH2:7][O:8][C:9]2[C:16]([CH3:17])=[CH:15][C:12]([C:13]#[N:14])=[CH:11][C:10]=2[CH3:18])[CH2:4][O:3]1.Cl.[NH2:21][OH:22].C(=O)(O)[O-].[Na+]>CO>[CH3:1][C:2]1([CH3:19])[O:6][C@H:5]([CH2:7][O:8][C:9]2[C:16]([CH3:17])=[CH:15][C:12](/[C:13](=[N:21]/[OH:22])/[NH2:14])=[CH:11][C:10]=2[CH3:18])[CH2:4][O:3]1
Reactant: Cc1cc(C#N)cc(C)c1OC[C@@H]1COC(C)(C)O1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: Cc1cc(/C(N)=N/O)cc(C)c1OC[C@@H]1COC(C)(C)O1
Temperature: 60 °C
Yield: 79.9 %

Procedure:
Nitrogen was bubbled in a solution of (R)-4-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-3,5-dimethylbenzonitrile (8.1 g, 31.0 mmol) and hydroxylamine hydrochloride (4.31 g, 62.0 mmol) in MeOH (150 ml) at room temperature (the solution was made in a 500 ml flask w/3 necks fitted with a reflux condenser) for 10 min. To this was then added the sodium bicarbonate (10.42 g, 124 mmol) in one portion. Nitrogen was bubbled for an additional 10 minutes. The reaction mixture was set to stir at 60° C. It was heated for a total of 25 h. The reaction mixture was cooled, concentrated in vacuo and then chromatographed (330 g Redisep cartridge pre-saturated and then eluted with 10% EtOAc-hexanes). 7.29 g (Yield=82%) of the (R,Z)-4-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-N′-hydroxy-3,5-dimethylbenzimidamide was obtained as a white solid. 1H NMR (400 MHz, CCl3D) δ ppm 7.25 (2H, s), 4.80 (3H, br. s.), 4.49 (1H, qd, J=5.93, 5.71 Hz), 4.18 (1H, dd, J=8.35, 6.59 Hz), 3.94 (1H, dd, J=8.35, 5.93 Hz), 3.81-3.88 (1H, m), 3.73-3.80 (1H, m), 2.29 (6H, s), 1.46 (3H, s), 1.40 (3H, s).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]([NH:17][CH3:18])=[O:16])[CH2:10][CH2:9]1)C1C=CC=CC=1>[Pd].CCO>[CH3:18][NH:17][C:15](=[O:16])[CH2:14][N:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CNC(=O)CN1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: CCO
Product: CNC(=O)CN1CCNCC1
Reaction time: 8 h
Yield: 98.9 %

Procedure:
10% Palladium on carbon (115 mg, 10% by wt.) was placed under an inert atmosphere and suspended in EtOH (5 mL). A solution of 2-(4-benzyl-piperazin-1-yl)-N-methyl-acetamide (1.15 g, 4.65 mmol) dissolved in EtOH (18 mL) was added. The reaction mixture was placed under H2 atmosphere (1 Atm pressure) and stirred overnight. The resulting mixture was filtered through a pad of Celite® and the solvent was concentrated in vacuo to give 723 mg (98.9%) of the title compound as a white solid. 1H-NMR (300 MHz, DMSO-d6) 7.61 (broad s, 1H), 2.80 (s, 2H), 2.68 (t, 4H), 2.59 (d, 3H), 2.31 to 2.26 (m, 4H); ES-MS m/z 158.0 [M+H]+, RT (min) 1.13.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12][CH:13]1[CH2:16][C:15]([CH3:22])([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:14]1.[NH4+].[Cl-]>C(Cl)Cl>[CH:12]([CH:13]1[CH2:14][C:15]([CH3:22])([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:16]1)=[O:11]
Reactant: CCOC(=O)C1(C)CC(CO)C1
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CS(C)=O
Solvent: ClCCl
Product: CCOC(=O)C1(C)CC(C=O)C1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 22.5 %

Procedure:
To a solution of oxalyl chloride (0.549 mL, 6.27 mmol) in DCM (15 mL) was added DMSO (0.890 mL, 12.54 mmol) as a solution in DCM (5 mL) slowly at −78° C. The resultant solution was stirred for 30 min prior to dropwise addition of Intermediate 258B (0.5 g, 3.14 mmol) as solution in DCM (5 mL). The resultant mixture was stirred for an additional 2 h at −78° C. TEA (4.37 mL, 31.4 mmol) was added to the reaction and the reaction mixture was allowed to stir at −78° C. for 30 min. The mixture was then warmed to RT and a saturated aqueous NH4Cl solution was added and extracted with dichloromethane (3×10 mL). The combined organic layer was washed with brine, dried over Na2SO4, filtered and the filtrate concentrated under reduced pressure. The crude product was purified by silica gel chromatography (12 g REDISEP® column, eluting with 30% EtOAc in hexane). Fractions containing the product were combined and evaporated to afford Intermediate 258C as a pale yellow liquid (0.12 g, 22%, mixture of cis and trans isomers). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.63 (d, J=1.51 Hz, 1H), 3.95-4.15 (m, 2H), 3.08-3.28 (m, 1H), 2.53-2.61 (m, 2H), 2.16-2.28 (m, 1H), 1.93-2.14 (m, 2H), 1.37-1.43 (s, 1H), 1.21-1.30 (s, 2H), 1.13-1.21 (m, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([CH2:17]O)=[CH:13][C:11]=2[N:12]=1.[Cl:19]CC1C=CC2OC(C3C=CC=C(F)C=3)=NC=2C=1>>[Cl:19][CH2:17][C:14]1[CH:15]=[CH:16][C:10]2[O:9][C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])=[N:12][C:11]=2[CH:13]=1
Reactant: Fc1cccc(-c2nc3cc(CCl)ccc3o2)c1
Reactant: OCc1ccc2oc(-c3ccccc3F)nc2c1
Product: Fc1ccccc1-c1nc2cc(CCl)ccc2o1

Procedure:
Compound 75B was reacted in a manner analogous to Compound 69C to give the title product. MS m/z 262 (M+1).
Reaction SMILES: [CH2:1]([N:3]([CH2:32][CH3:33])[CH2:4][CH2:5]/[CH:6]=[CH:7]/[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14]([NH:17][C:18]1[CH:27]=[CH:26][C:25]2[CH2:24][CH2:23][CH2:22][CH2:21][C:20]=2[C:19]=1[C:28]([O:30][CH3:31])=[O:29])(=[O:16])=[O:15])[CH3:2]>CO.[Pd]>[CH2:32]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14]([NH:17][C:18]1[CH:27]=[CH:26][C:25]2[CH2:24][CH2:23][CH2:22][CH2:21][C:20]=2[C:19]=1[C:28]([O:30][CH3:31])=[O:29])(=[O:15])=[O:16])[CH3:33]
Reactant: CCN(CC)CC/C=C/c1ccccc1S(=O)(=O)Nc1ccc2c(c1C(=O)OC)CCCC2
Agent: [Pd]
Solvent: CO
Product: CCN(CC)CCCCc1ccccc1S(=O)(=O)Nc1ccc2c(c1C(=O)OC)CCCC2
Yield: 109.8 %

Procedure:
A mixture of Example 529D (300 mg, 0.64 mmol) in methanol (12 mL) was hydrogenated with H2 over 90 mg (30 wt %) of 10% Pd/C. After 4.5 hours the reaction was filtered through diatomaceous earth (Celite®). The pad was washed with methanol and the filtrates were combined with those from a 50 mg scale (0.11 mmol) reaction and concentrated to provide 332 mg (94%) of the desired product. MS (ESI(+)) m/e 473 (M+H)+; 1H NMR (400 MHz, CDCl3) δ 1.00 (t, J=7.14 Hz, 6H) 1.58 (m, 2H) 1.68 (m, 6H) 2.53 (m, 6H) 2.69 (m, 4H) 2.95 (m, 2H) 3.72 (s, 3H) 6.99 (d, J=8.51 Hz, 1H) 7.05 (d, J=8.37 Hz, 1H) 7.21 (t, J=7.68 Hz, 1H) 7.30 (d, J=7.55 Hz, 1H) 7.42 (t, J=7.14 Hz, 1H) 7.85 (d, J=7.82 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH2:9][N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]([C:19]([CH3:21])=[CH2:20])[C:11]1=[O:22].Cl.[NH2:25][OH:26].N1C=CC=CC=1>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[N:25][OH:26])[CH2:9][N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]([C:19]([CH3:21])=[CH2:20])[C:11]1=[O:22]
Reactant: C=C(C)n1c(=O)n(CC(=O)c2ccccc2F)c2ccccc21
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: C=C(C)n1c(=O)n(CC(=NO)c2ccccc2F)c2ccccc21
Temperature: 80 °C
Yield: 73.2 %

Procedure:
To a stirred solution of 1-[2-(2-fluoro-phenyl)-2-oxo-ethyl]-3-isopropenyl-1,3-dihydro-benzimidazol-2-one (1.3 g, 4.2 mmol) in ethanol (50 ml) was added hydroxylamine hydrochloride (0.84 g, 12.2 mmol) followed by pyridine (1.7 ml, 21.0 mmol) at ambient temperature. The resulting mixture was warmed to 80° C. for 6 h, cooled to ambient temperature and concentrated. The remaining residue was diluted with water, 1M HCl and ethyl acetate. The layers were separated and the aqueous phase was extracted once more with ethyl acetate. The combined organics were dried (MgSO4), filtered and concentrated to give the crude product which was purified via column chromatography (silica gel, 50% EtOAc/hexanes). The product-containing fractions were combined and concentrated to give 1.0 g (73%) of the desired product as an oil which solidified on standing.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[Cl:10][C:11]1[C:12](=[O:21])[CH:13]=[CH:14][C:15](OC)([O:17]C)[CH:16]=1>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:12]1([OH:21])[CH:13]=[CH:14][C:15](=[O:17])[CH:16]=[C:11]1[Cl:10]
Reactant: COC1(OC)C=CC(=O)C(Cl)=C1
Reactant: c1ccc2scnc2c1
Product: O=C1C=CC(O)(c2nc3ccccc3s2)C(Cl)=C1
Yield: 58 %

Procedure:
The title compound was synthesised according to Method A, described above, from benzothiazole and 2-chloro-4,4-dimethoxycyclohexa-2,5-dien-1-one (see, e.g., McKillop et al., 1993).