Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[S:3][CH:4]=[C:5]([Cl:7])[N:6]=1.NC1C=C(C2SC([N:21]3[CH2:27][CH2:26][CH2:25][NH:24][C:23](=[O:28])[CH2:22]3)=NC=2)C=C(C)C=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].CS(C)=O>CC(O)C.C(Cl)(Cl)Cl.O>[Cl:7][C:5]1[N:6]=[C:2]([N:21]2[CH2:27][CH2:26][CH2:25][NH:24][C:23](=[O:28])[CH2:22]2)[S:3][CH:4]=1
Reactant: Cc1cc(N)cc(-c2cnc(N3CCCNC(=O)C3)s2)c1
Reactant: Clc1csc(Cl)n1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CC(C)O
Solvent: CS(C)=O
Product: O=C1CN(c2nc(Cl)cs2)CCCN1
Temperature: 150 °C
Yield: 29.4 %

Procedure:
Combined 2,4-dichlorothiazole (405 mg, 2.63 mmol), 3-oxo-1,4-diazepan-1-ium trifluoroacetate (preparation described in Intermediate XX, 600 mg, 2.63 mmol), potassium phosphate tribasic (1395 mg, 6.57 mmol) and DMSO (22.00 ml) in a round bottomed flask, fitted with water-cooled condenser, balloon and septum. The mixture was heated to 150° C. for 7 hours with stirring. The dark solution was diluted with 100 mL 10% IPA/CHCl3, 40 mL water, mL aq. NaHCO3(sat.). The resulting suspension was extracted with 10% IPA/CHCl3, and the organic layers were combined and washed successively with water and brine. The organic fractions were pooled and concentrated to dryness. The residue was then loaded directly onto silica gel and purified by preparative HPLC Normal phase, eluting with CH2Cl2/MeOH (0-30%). The 3rd peak was collected and concentrated to afford 4-(4-chloro-1,3-thiazol-2-yl)-1,4-diazepan-2-one (179 mg, 0.773 mmol, 29.4% yield) as a brown solid.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][C:4](O)=[O:5].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[NH:39]1[CH2:44][CH2:43][CH2:42][CH:41]([C:45]2[CH:50]=[CH:49][C:48]([C:51]3[O:52][C:53]4[C:59]([C:60]([NH2:62])=[O:61])=[CH:58][CH:57]=[CH:56][C:54]=4[N:55]=3)=[CH:47][CH:46]=2)[CH2:40]1>CN(C=O)C.O.C(OCC)(=O)C>[CH3:1][N:2]([CH3:7])[CH2:3][C:4]([N:39]1[CH2:44][CH2:43][CH2:42][CH:41]([C:45]2[CH:50]=[CH:49][C:48]([C:51]3[O:52][C:53]4[C:59]([C:60]([NH2:62])=[O:61])=[CH:58][CH:57]=[CH:56][C:54]=4[N:55]=3)=[CH:47][CH:46]=2)[CH2:40]1)=[O:5]
Reactant: NC(=O)c1cccc2nc(-c3ccc(C4CCCNC4)cc3)oc12
Reactant: CN(C)CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CC(=O)N1CCCC(c2ccc(-c3nc4cccc(C(N)=O)c4o3)cc2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 15.2 %

Procedure:
To a solution of 2-(dimethylamino)acetic acid (648 mg, 2.02 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (186 mg, 0.97 mmol), 1-hydroxybenzotriazole (131 mg, 0.97 mmol) in N,N′-dimethylformamide (50 ml) was added diisopropylethylamine (280 mg). The mixture was stirred at room temperature for 0.5 h. 2-(4-(Piperidin-3-yl)phenyl)benzo[d]oxazole-7-carboxamide (260 mg, 0.81 mmol) was added to the reaction mixture at 0° C. Then the mixture was stirred at room temperature for 4 h. Then ethyl acetate and water was added to the mixture and extracted. The organic phase was washed with water (50 mL×3), brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to give crude product which was purified by chromatography (silica gel, dichloromethane/methanol=10:1) to give 2-(4-(1-(2-(dimethylamino)acetyl)piperidin-3-yl)phenyl)benzo[d]oxazole-7-carboxamide (50 mg, Yield: 15%). 1H-NMR (400 MHz, DMSO-d6) δ: 1.41-1.58 (m, 1H), 1.76-1.84 (m, 2H), 1.96-1.98 (m, 1H), 2.10 (s, 6H), 2.54-2.88 (m, 2H), 2.93-3.09 (m, 2H), 3.14-3.26 (m, 2H), 4.11 (t, J=12 Hz, 1H), 4.44 (t, J=9.2 Hz, 1H), 7.48 (t, J=8.0 Hz, 1H), 7.54-7.57 (dd, J1=8.0 Hz, J2=2.4 Hz, 2H), 7.81 (d, J=8.0 Hz, 1H), 7.87 (brs, 1H), 7.90 (brs, 1H), 7.95 (d, J=7.6 Hz, 1H), 8.24-8.26 (dd, J1=8.0 Hz, J2=5.6 Hz, 2H); LC-MS (ESI) m/z: 407 (M+1)+.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:7][CH2:8][CH3:9])[CH:3]1[NH:6][C:4]1=[O:5].C(=O)([O-])O.[Na+].[CH2:15]([O:22][C:23](Cl)=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1COCC1.O>[CH2:15]([O:22][C:23]([NH:1][C@@H:2]([CH2:7][CH2:8][CH3:9])[CH:3]1[NH:6][C:4]1=[O:5])=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCC[C@H](N)C1NC1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCC[C@H](NC(=O)OCc1ccccc1)C1NC1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution obtained by dissolving 3(S)-amino-2-caprolactam (5.00 g, 39.01 mmol) in THF (20 ml) and water (40 ml), sodium hydrogen carbonate (4.92 g, 58.56 mol) and benzyloxycarbonyl chloride (5.57 ml, 39.01 mmol) were added under ice cooling, and the mixture was stirred at room temperature for 18 hours.
Reaction SMILES: C([O:5][C:6](=[O:39])[CH2:7][NH:8][C:9](=[O:38])[C@@H:10]([NH:15][C:16]([C:18]1[CH:37]=[CH:36][C:21]2[N:22]([CH:31]([CH2:34][CH3:35])[CH2:32][CH3:33])[C:23]([CH2:25][C:26]3[S:27][CH:28]=[CH:29][CH:30]=3)=[N:24][C:20]=2[CH:19]=1)=[O:17])[CH2:11][CH:12]([CH3:14])[CH3:13])(C)(C)C.Cl>O1CCOCC1>[CH2:32]([CH:31]([N:22]1[C:21]2[CH:36]=[CH:37][C:18]([C:16]([NH:15][C@@H:10]([CH2:11][CH:12]([CH3:13])[CH3:14])[C:9]([NH:8][CH2:7][C:6]([OH:39])=[O:5])=[O:38])=[O:17])=[CH:19][C:20]=2[N:24]=[C:23]1[CH2:25][C:26]1[S:27][CH:28]=[CH:29][CH:30]=1)[CH2:34][CH3:35])[CH3:33]
Reactant: CCC(CC)n1c(Cc2cccs2)nc2cc(C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)OC(C)(C)C)ccc21
Agent: Cl
Solvent: C1COCCO1
Product: CCC(CC)n1c(Cc2cccs2)nc2cc(C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)O)ccc21
Yield: 97.3 %

Procedure:
32 mg of ((S)-2-{[1-(1-ethyl-propyl)-2-thiophen-2-ylmethyl-1H-benzoimidazole-5-carbonyl]-amino}-4-methyl-pentanoylamino)-acetic acid tert.-butyl ester were reacted with 0.8 ml of 4 M hydrochloric acid in dioxane at rt over night. The reaction mixture was then concentrated in vacuo to yield 28 mg (91%) of ((S)-2-{[1-(1-Ethyl-propyl)-2-thiophen-2-ylmethyl-1H-benzoimidazole-5-carbonyl]-amino}-4-methyl-pentanoylamino)-acetic acid.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[CH3:9][N:10]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[C:14](=[O:21])[CH2:13][C:12]2[CH:22]=[CH:23][CH:24]=[CH:25][C:11]1=2>CN(C)C=O>[Br:8][C:19]1[CH:18]=[CH:17][C:16]2[N:10]([CH3:9])[C:11]3[CH:25]=[CH:24][CH:23]=[CH:22][C:12]=3[CH2:13][C:14](=[O:21])[C:15]=2[CH:20]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CN1c2ccccc2CC(=O)c2ccccc21
Solvent: CN(C)C=O
Product: CN1c2ccccc2CC(=O)c2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.5 %

Procedure:
22.81 g of N-bromosuccimide were added over 15 minutes at room temperature to a solution of 25 g of 5-methyl-10,11-dihydro [5H] dibenzo (b,f) azepine-10-one in 250 ml of dimethylformamide under a nitrogen atmosphere and the mixture was stirred for 30 minutes at room temperature. The reaction mixture was poured into 2 liters of ice water and was extracted with ether. The ether extracts were washed with water, dried over magnesium sulfate and evaporated to dryness to obtain 34 g of 2-bromo-5-methyl-10,11-dihydro [5H] dibenzo (b,f) azepine-11-one. The product was dissolved in 100 ml of refluxing ethyl acetate and the solution was filtered hot and concentrated to the start of crystallization. The mixture was iced for 30 minutes and vacuum filtered. The recovered precipitate was washed with ethyl acetate and dried under reduced pressure to obtain 29.5 g of the said product in the form of pale yellow crystals melting at 128°-129°C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20]Br)[NH:12][C:11]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)=[N:10]1.[NH:27]1[CH2:32][CH2:31][O:30][CH:29]([CH2:33][CH2:34][C:35]([NH2:37])=[O:36])[CH2:28]1>>[NH2:37][C:35](=[O:36])[CH2:34][CH2:33][CH:29]1[CH2:28][N:27]([CH2:20][C:13]2[NH:12][C:11]([C:22]3[S:23][CH:24]=[CH:25][N:26]=3)=[N:10][CH:9]([C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[Br:1])[C:14]=2[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:32][CH2:31][O:30]1
Reactant: CCOC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Reactant: NC(=O)CCC1CNCCO1
Product: CCOC(=O)C1=C(CN2CCOC(CCC(N)=O)C2)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Yield: 86.1 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (1.51 g, 3 mmol) was reacted with 3-(morpholin-2-yl)propanamide (0.47 g, 3 mmol) according to the procedure as described in Example 25, Step B to give the title compound as a yellow solid (1.5 g, 86%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [C:1]([C:7]1[CH:8]=[C:9]([O:13][CH2:14][C@@H:15]2[CH2:19][CH2:18][CH2:17][N:16]2[CH3:20])[CH:10]=[N:11][CH:12]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH3:6]>CO.[Pd].CC([O-])=O.CC([O-])=O.[Pb+2]>[CH:1]([C:7]1[CH:8]=[C:9]([O:13][CH2:14][C@@H:15]2[CH2:19][CH2:18][CH2:17][N:16]2[CH3:20])[CH:10]=[N:11][CH:12]=1)=[CH:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCC#Cc1cncc(OC[C@@H]2CCCN2C)c1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CO
Product: CCCCC=Cc1cncc(OC[C@@H]2CCCN2C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.5 %

Procedure:
To a solution of 5-(1-hexynyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine (from Example 4a, 100 mg, 0.37 mmol) in MeOH (3.0 mL) was added Lindlar's catalyst (10 mg). The mixture was stirred at room temperature overnight. The solvent was removed, and the residue was chromatographed on a silica gel column, eluting with NH4OH/MeOHTEtOAc 0:1:9 and 1:10:90 to afford a light yellowish oil (98 mg, 98%). MS (CI/NH3) m/z 277 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ0.88 (t, J=4.8 Hz, 3H), 1.23-1.37 (m, 6H), 1.53-1.62 (m, 2H), 1.70-2.08 (m, 4H), 2.26-2.36 (m, 1H), 2.48 (s, 3H), 2.56 (t, J=7.7 Hz, 2H), 2.58-2.71 (m, 1H), 3.07-3.14 (m, 1H), 3.88-4.05 (m, 2H), 7.03 (dd, J=3.0 Hz, J=J=2.1 Hz, 1H), 8.06 (d, J=2.1 Hz, 1H), 8.13 (d, J=3.0 Hz, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=[O:11])=[CH:4][CH:3]=1.[CH3:26][O:27][C:28](=[O:33])[CH2:29][CH2:30][C:31]#[CH:32]>>[CH3:26][O:27][C:28](=[O:33])[CH2:29][CH2:30][C:31]#[C:32][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=[O:11])=[CH:4][CH:3]=1
Reactant: C#CCCC(=O)OC
Reactant: Cc1cc(C(=O)CC(c2ccc(Br)cc2)c2ccccc2C)ccn1
Product: COC(=O)CCC#Cc1ccc(C(CC(=O)c2ccnc(C)c2)c2ccccc2C)cc1

Procedure:
In analogy to example 85, step 1, from 3-(4-bromo-phenyl)-1-(2-methyl-pyridin-4-yl)-3-o-tolyl-propan-1-one (example 74, step 5) and pent-4-ynoic acid methyl ester was prepared the title compound as a brown oil, MS (ESI+): m/z=426.2067 ([M+H]+).
Reaction SMILES: C1(C([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:54])[C@@H:24]([NH:25][C:26](=[O:53])/[C:27](/[C:40]4[N:41]=[C:42]([NH:45]C(OC(C)(C)C)=O)[S:43][CH:44]=4)=[N:28]\[O:29][C:30]([C:33]([O:35]C(C)(C)C)=[O:34])([CH3:32])[CH3:31])[C@H:21]3[S:20][CH2:19][C:18]=2[S:55][CH:56](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[S:57][C:58]2[N:59]=[N:60][NH:61][CH:62]=2)=[O:16])C2C=CC=CC=2)C=CC=CC=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>C1(OC)C=CC=CC=1.[N+](C)([O-])=O.O>[NH2:45][C:42]1[S:43][CH:44]=[C:40](/[C:27](=[N:28]/[O:29][C:30]([C:33]([OH:35])=[O:34])([CH3:31])[CH3:32])/[C:26]([NH:25][C@@H:24]2[C:23](=[O:54])[N:22]3[C:17]([C:15]([OH:16])=[O:14])=[C:18]([S:55][CH2:56][S:57][C:58]4[N:59]=[N:60][NH:61][CH:62]=4)[CH2:19][S:20][C@H:21]23)=[O:53])[N:41]=1
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(C)(C)C(=O)OC(C)(C)C)C(=O)N[C@@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(SC(Sc4c[nH]nn4)C(c4ccccc4)(c4ccccc4)c4ccccc4)CS[C@H]23)cs1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: COc1ccccc1
Solvent: O
Solvent: C[N+](=O)[O-]
Product: CC(C)(O/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(SCSc3c[nH]nn3)CS[C@H]12)c1csc(N)n1)C(=O)O
Reaction time: 1 h
Yield: 70.5 %

Procedure:
To a solution of 7β-[(Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-(1-t-butoxycarbonyl-1-methylethoxyimino)acetamido]-3-(trityl-1,2,3-triazol-4-ylthiomethylthio)-3-cephem-4-carboxylic acid diphenylmethyl ester (822 mg: 0.706 mMol.) in a mixture of anisole (3 ml) and nitro- methane (12 ml) at -40° C. is added a solution of aluminum chloride (0.75 g: 5.64 mMol.) in anisole (3 ml), and the mixture is stirred at -30° to -40° C. for 1 hour. The reaction mixture is mixed with 1N-hydrochloric acid (5.7 ml), diluted with water, washed with ethyl acetate, and concentrated under reduced pressure to remove remaining organic solvents. The residual solution is subjected to chromatography over styrene-divinylbenzene copolymer (methanol: water=4:1) and resulting powder is washed with ethyl acetate to give 7β-[(Z)-2-(2-aminothiazol-4-yl)-2-(1-carboxy-1-methylethoxyimino)acetamido]-3-(1,2,3-triazol-4-ylthiomethylthio)-3-cephem-4-carboxylic acid (299 mg) as pale yellowish white powder. Yield: 71%.
Reaction SMILES: CON(C)[C:4]([C:6]1[C:7]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:8]=2[S:9][CH:10]=1)=[O:5].[CH3:18][Li].[NH4+].[Cl-]>C1COCC1>[C:4]([C:6]1[C:7]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:8]=2[S:9][CH:10]=1)(=[O:5])[CH3:18]
Reactant: COc1ccc2c(C(=O)N(C)OC)csc2c1
Reactant: [Li]C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc2c(C(C)=O)csc2c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 48.3 %

Procedure:
6-Methoxy-benzo[b]thiophene-3-carboxylic acid methoxy-methyl amide (800 mg, 3.19 mmol) was stirred in dry THF (20 mL) under argon at −78° C. under argon. Methyl lithium (5.0 mL, 1.5 M in hexanes, 2.35 mmol) was added dropwise, and the reaction stirred 1 h at −78° C. and then 1 h while warning to −20° C. The reaction was poured over saturated NH4Cl (40 mL) and extracted with EtOAc (2×30 mL). Organics were washed with brine (25 mL), dried (Na2SO4), and concentrated in vacuo. Purification by silica gel chromatography gave 234 mg (36%) of 3-acetyl-6-methoxy-benzo[b]thiophene as an orange solid. 1H NMR (300 MHz, CDCl3) δ8.64 (d, 1H, J=9.0Hz), 8.11 (s, 1H), 7.30 (d, 1H, J=2.4Hz), 7.10 (dd, 1H, J=9.0, 2.4Hz), 3.89 (s, 3H), 2.63 (s, 3H) (C11H10O2S) C, H. S. Calculated C=64.06, H=4.89, S=15.54; found C=64.31, H=4.82, S=15.50.
Reaction SMILES: [CH2:1]([CH:4]1[O:8][C:7]([CH3:10])([CH3:9])[O:6][CH:5]1[CH2:11]O)[CH:2]=[CH2:3].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O.[C:44]1(=[O:54])[NH:48][C:47](=[O:49])[C:46]2=[CH:50][CH:51]=[CH:52][CH:53]=[C:45]12>C1COCC1>[CH2:1]([CH:4]1[O:8][C:7]([CH3:9])([CH3:10])[O:6][CH:5]1[CH2:11][N:48]1[C:44](=[O:54])[C:45]2[C:46](=[CH:50][CH:51]=[CH:52][CH:53]=2)[C:47]1=[O:49])[CH:2]=[CH2:3]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: C=CCC1OC(C)(C)OC1CO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=CCC1OC(C)(C)OC1CN1C(=O)c2ccccc2C1=O
Reaction time: 0.33 h
Yield: 96.3 %

Procedure:
To a stirred solution of compound 2 (2.8 g, 16.3 mmol) in THF (120 mL) were added PPh3 (6.4 g, 24.4 mmol) and DEAD (40% in toluene, 10.6 mL, 24.3 mmol) at 0° C. After 20 min stirring, phthalimide (3.59 g, 24.4 mmol). The reaction mixture was stirred overnight at room temperature, concentrated, diluted with EtOAc (300 mL) and extracted with aq. NaHCO3 solution (100 mL). The organic layer was dried (Na2SO4), filtered and concentrated. The residue was purified by silica gel column chromatography (Hex/EtOAc=2/1) to give compound 3 (4.74 g, 15.7 mmol, 97%) as an oil. 1H NMR (CDCl3, 300 MHz) δ 7.80-7.85 (m, 2H), 7.68-7.73 (m, 2H), 5.82 (m, 1H), 5.13-5.24 (m, 2H), 4.48 (m, 1H), 4.26 (m, 1H), 3.90 (dd, 1H, J=10.5, 13.5), 3.52 (dd, 1H, J=3.0, 13.5), 2.37-2.57 (m, 2H), 1.53, 1.30 (2s, 6H); 13C NMR (CDCl3, 75 MHz) δ 168.5, 134.1, 133.9, 132.4, 123.5, 118.0, 109.1, 76.5, 74.3, 39.1, 33.5, 28.2, 26.1.
Reaction SMILES: Br.C(O)(=O)C.[CH2:6]([S:10]([NH:13][CH:14]1[CH2:22][C:21]2[C:16](=[CH:17][CH:18]=[C:19]([C:23]3[CH2:24][CH2:25][C:26](=[O:29])[NH:27][N:28]=3)[CH:20]=2)[CH2:15]1)(=[O:12])=[O:11])[CH2:7][CH2:8][CH3:9]>CS(C)=O>[CH2:6]([S:10]([NH:13][CH:14]1[CH2:22][C:21]2[C:16](=[CH:17][CH:18]=[C:19]([C:23]3[CH:24]=[CH:25][C:26](=[O:29])[NH:27][N:28]=3)[CH:20]=2)[CH2:15]1)(=[O:11])=[O:12])[CH2:7][CH2:8][CH3:9]
Reactant: CCCCS(=O)(=O)NC1Cc2ccc(C3=NNC(=O)CC3)cc2C1
Agent: Br
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: CCCCS(=O)(=O)NC1Cc2ccc(-c3ccc(=O)[nH]n3)cc2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.2 %

Procedure:
In 100 ml of a 25% hydrogen bromide-acetic acid solution was suspended 17.44 g of 2-n-butylsulfonylamino-5-[4,5-dihydropyridazin-3(2H)-on-6-yl]indane, and 3.6 ml of dimethylsulfoxide was added thereto. The mixture was stirred at room temperature for 1 hour. Then, the reaction mixture was poured into ice water, and crystals precipitated were collected by filtration and recrystallized from methanol to obtain 14.60 g of 2-n-butylsulfonylamino-5-[pyridazin-3(2H)-on-6-yl]indane.
Reaction SMILES: [C:1]1([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([CH2:16][C:17]([O:19]CC)=[O:18])=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>C(O)C>[C:1]1([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([CH2:16][C:17]([OH:19])=[O:18])=[CH:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)Cc1cn(-c2ccccc2)c2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)Cc1cn(-c2ccccc2)c2ccccc12
Reaction time: 17 h
Yield: 98.6 %

Procedure:
A solution of 6.3 g (22.6 mmol) of ethyl 1-phenylindole-3-acetate in 20 ml of ethanol was treated with 20 ml (40 mmol) of 2M sodium hydroxide solution and left at room temperature for 17 hours. Ethanol was removed under reduced pressure and the aqueous solution was washed with two 20 ml portions of diethyl ether. The aqueous phase was acidified with concentrated hydrochloric acid and the suspension obtained was stored at 0° C. for 2 hours. The suspension was filtered and the solid was crystallized from methanol/water (2:1) to give 5.6 g 1-phenylindole-3-acetic acid as a blue-grey solid of melting point 131°-135° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:28])=[C:4]([CH2:8][S:9][C:10]2[N:15]=[C:14]([NH2:16])[C:13]([NH2:17])=[C:12]([S:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=3[F:27])[N:11]=2)[CH:5]=[CH:6][CH:7]=1.[CH:29]([N:32](C(C)C)CC)(C)[CH3:30].BrCC#N>O1CCOCC1>[NH2:16][C:14]1[C:13]([NH:17][CH2:30][C:29]#[N:32])=[C:12]([S:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=2[F:27])[N:11]=[C:10]([S:9][CH2:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=2[F:28])[N:15]=1
Reactant: Nc1nc(SCc2cccc(Cl)c2F)nc(SCc2cccc(Cl)c2F)c1N
Reactant: CCN(C(C)C)C(C)C
Agent: N#CCBr
Solvent: C1COCCO1
Product: N#CCNc1c(N)nc(SCc2cccc(Cl)c2F)nc1SCc1cccc(Cl)c1F
Temperature: 100 °C

Procedure:
To a solution of the product of example 13, step (a) (4.2 g) and diisopropylethylamine (1.2 ml) in dioxan (40 ml) was added bromoacetonitrile (1.2 g) and the mixture heated at 100° C. for 23 hours. After cooling, the red reaction solution was adsorbed onto silica and purified by silica gel flash column chromatography, eluting with dichloromethane then 95:5 dichloromethane:ethyl acetate, to give the subtitled compound as a pale orange solid (3.1 g).
Reaction SMILES: [Br-:1].[C:2]1([C:7](=[O:16])[CH2:8][N+:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:15])[CH2:6][CH2:5][CH2:4][CH:3]=1>CO.[Pd]>[Br-:1].[CH:2]1([C:7](=[O:16])[CH2:8][N+:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:15])[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: Cc1cccc[n+]1CC(=O)C1=CCCC1
Agent: [Pd]
Agent: [Br-]
Solvent: CO
Product: Cc1cccc[n+]1CC(=O)C1CCCC1
Yield: 92.7 %

Procedure:
A solution of 1-(2-cyclopent-1-enyl-2-oxo-ethyl)-2-methyl-pyridinium bromide salt (3.65 g, 12.9 mmol) in methanol (25 mL) was hydrogenated over 10% Pd/C (180 mg). After completion of the reaction the catalyst was removed by filtration, washing with methanol, and concentration of the filtrate gave 1-(2-cyclopentyl-2-oxo-ethyl)-2-methyl-pyridinium bromide salt (3.4 g, 93%).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[N:8]=[N:7][C:6]([NH2:9])=[CH:5][CH:4]=1.[Cl:12]N1C(=O)CCC1=O>C(#N)C>[Cl:12][C:5]1[CH:4]=[C:3]([C:2]([F:1])([F:10])[F:11])[N:8]=[N:7][C:6]=1[NH2:9]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Nc1ccc(C(F)(F)F)nn1
Solvent: CC#N
Product: Nc1nnc(C(F)(F)F)cc1Cl
Temperature: 70 °C
Yield: 33.1 %

Procedure:
A mixture of D6 (4.0 g, 24.5 mmol) and N-chlorosuccinimide (3.3 g, 24.5 mmol) in acetonitrile (160 ml) was heated at 70° C. for 18 h. After this period, the reaction was cooled to room temperature and the solvents evaporated in vacuo. The crude residue was purified by column chromatography (silica; 3%-5% methanol/dichloromethane) to give D7 (1.6 g, 33%). C5H3ClF3N3 requires 197; Found 198 (MH+)
Reaction SMILES: [C:1]([C:3]1[CH:20]=[CH:19][C:6]([C:7]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[O:8])=[CH:5][CH:4]=1)#[N:2].[H-].[Na+].[CH3:23]I.O>O1CCCC1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:7]([N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[CH3:23])=[O:8])=[CH:19][CH:20]=1)#[N:2]
Reactant: COc1ccc(CNC(=O)c2ccc(C#N)cc2)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CN(C)C(=O)c2ccc(C#N)cc2)cc1
Reaction time: 0.25 h

Procedure:
79 mg of 4-cyano-N-(4-methoxybenzyl)benzamide was dissolved in 2.5 ml of tetrahydrofuran, and 24 mg of 60% sodium hydride was added thereto, followed by heating under reflux for 5 minutes in an atmosphere of nitrogen. After cooling, 0.1 ml of methyl iodide was added thereto, followed by stirring for 15 minutes. Thereafter, the reaction was stopped by the addition of 1 ml of distilled water. After the product was extracted with ethyl acetate, the extract was successively washed with 2 N hydrochloric acid, a saturated aqueous solution of sodium hydrogen carbonate, and a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. After the solvent was distilled off, the resulting crude product was purified by TLC (using a 1:1 mixture of ethyl acetate and hexane as the developing solvent) to obtain 72 mg of 4-cyano-N-(4-methoxybenzyl)-N-methylbenzamide.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH:11]=O.[CH3:16][NH2:17]>C1COCC1.[Pd]>[CH3:16][NH:17][CH2:11][C:10]1[CH:9]=[C:8]([O:7][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])[CH:15]=[CH:14][CH:13]=1
Reactant: COCCOCOc1cccc(C=O)c1
Reactant: CN
Agent: [Pd]
Solvent: C1CCOC1
Product: CNCc1cccc(OCOCCOC)c1
Reaction time: 24 h

Procedure:
To a solution of 3-(2-methoxyethoxy-methoxy)-benzaldehyde (2.10 g, 10 mmol, example 8a) in THF (60 mL) is added methylamine (20 mL, 2M in THF) followed by palladium on carbon (210 mg, 10% Pd). The resulting mixture is stirred for 24 h under an atmosphere of hydrogen gas, then purged with nitrogen, filtered through celite and the filtrate concentrated. The residue is purified by flash chromatography (silica, 10% methanol in dichloromethane) to give the title compound as an oil.