Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](O)(=[O:3])[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[CH3:36][C:37]1[CH:46]=[CH:45][CH:44]=[C:43]2[C:38]=1[CH:39]=[C:40]([C:48]1[CH:53]=[CH:52][C:51]([CH2:54][N:55]3[CH2:60][CH2:59][NH:58][CH2:57][CH2:56]3)=[CH:50][CH:49]=1)[NH:41][C:42]2=[O:47]>C(Cl)Cl>[C:1]([N:58]1[CH2:59][CH2:60][N:55]([CH2:54][C:51]2[CH:50]=[CH:49][C:48]([C:40]3[NH:41][C:42](=[O:47])[C:43]4[C:38]([CH:39]=3)=[C:37]([CH3:36])[CH:46]=[CH:45][CH:44]=4)=[CH:53][CH:52]=2)[CH2:56][CH2:57]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O
Reactant: Cc1cccc2c(=O)[nH]c(-c3ccc(CN4CCNCC4)cc3)cc12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCN(Cc2ccc(-c3cc4c(C)cccc4c(=O)[nH]3)cc2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 7.8 %

Procedure:
To a stirred solution of acetic acid (0.005 mL, 0.068 mmol) in CH2Cl2 (5 mL) was added TBTU (22 mg, 0.068 mmol) and N,N-diisopropylethylamine (0.036 mL, 0.20 mmol) and the reaction stirred for 10 min at RT. 5-Methyl-3-(4-piperazin-1-ylmethylphenyl)-2H-isoquinolin-1-one (23 mg, 0.068 mmol) was then added and the reaction stirred for 2 h at RT. The reaction mixture was concentrated in vacuo and purified by reverse phase preparative HPLC-MS to afford 3-[4-(4-acetyl-piperazine-1-ylmethyl)-phenyl]-5-methyl-2H-isoquinolin-1-one as a white solid (2 mg, 9%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:29])=[C:4]([NH:10][C:11]([N:13]2[CH2:17][CH2:16][C@H:15]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[C@@:14]2([CH2:27]O)[CH3:26])=[O:12])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].CC(C)([O-])C.[K+].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C1COCC1.O.CCOC(C)=O>[Si:19]([O:18][C@@H:15]1[C@@:14]2([CH3:26])[N:13](/[C:11](=[N:10]/[C:4]3[CH:5]=[CH:6][C:7]([C:8]#[N:9])=[C:2]([Cl:1])[C:3]=3[CH3:29])/[O:12][CH2:27]2)[CH2:17][CH2:16]1)([C:22]([CH3:23])([CH3:25])[CH3:24])([CH3:20])[CH3:21].[Cl:1][C:2]1[C:3]([CH3:29])=[C:4]([N:10]2[CH2:26][C@@:14]3([CH3:27])[C@@H:15]([OH:18])[CH2:16][CH2:17][N:13]3[C:11]2=[O:12])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: Cc1c(NC(=O)N2CC[C@H](O[Si](C)(C)C(C)(C)C)[C@]2(C)CO)ccc(C#N)c1Cl
Agent: CC(C)(C)[O-]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(/N=C2\OC[C@@]3(C)[C@@H](O[Si](C)(C)C(C)(C)C)CCN23)ccc(C#N)c1Cl
Product: Cc1c(N2C[C@@]3(C)[C@@H](O)CCN3C2=O)ccc(C#N)c1Cl
Reaction time: 0.17 h

Procedure:
To a solution of (2S,3S)-3-(tert-butyldimethylsilanyloxy)-2-hydroxymethyl-2-methylpyrrolidine-1-carboxylic acid (3-chloro-4-cyano-2-methyl-phenyl)-amide (3D) (140 mg, 0.320 mmol) in THF (3 mL) at 0° C. was added a 1 M solution of potassium tert-butoxide in THF (1.12 mL, 1.12 mmol) followed by a solution of p-toluenesulfonyl chloride (152 mg, 0.800 mmol) in THF (1 mL). After 10 min, additional potassium tert-butoxide (200 μL) and p-toluenesulfonyl chloride (5 mg) were added. After another 10 min, additional potassium tert-butoxide (500 μL) was added and the reaction stirred for 2 h. The reaction was diluted with water and EtOAc and the layers were separated. The organic layer was washed with brine, dried (MgSO4), filtered and concentrated and purified via preparative HPLC (Luna C-18, 100×21.2 mm, eluting with 60-100% solvent B (A=90% H2O-10% MeOH-0.1% TFA and B=10% H2O-90% MeOH-0.1% TFA) over 12 min; Flow rate at 20 mL/min; UV detection at 220 nm) to provide compound 3E (8.0 mg, LC/MS m/z 420 [M+H]+), and (7S,7aS)-2-chloro-4-(7-hydroxy-7a-methyl-3-oxo-hexahydropyrrolo[1,2-c]imidazol-2-yl)-3-methylbenzonitrile (54.0 mg, LC/MS m/z 420 [M+H]+).
Reaction SMILES: C([NH:4][CH:5]([C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)[C:6]([OH:8])=[O:7])(=O)N.N(O)=O>>[S:10]1[CH:11]=[CH:12][CH:13]=[C:9]1[CH:5]([C:6]([OH:8])=[O:7])[NH2:4]
Reactant: NC(=O)NC(C(=O)O)c1cccs1
Agent: O=NO
Product: NC(C(=O)O)c1cccs1

Procedure:
Each thus obtained N-carbamoyl-2-(2-thienyl)glycine was subjected to decarbamoylation by reacting it with nitrous acid to give 2-(2-thienyl)glycine as follows: To a mixture of 5.0 g. of N-carbamoyl-D-(2-thienyl)glycine, 10 ml. of conc. HCl and a 100 ml. of a 50% aqueous acetic acid, 8.6 g. of a 20% aqueous solution of NaNO2 was added at 10° C. with stirring. After the completion of adding NaNO2, the reaction was carried out at 10° C. for 2 hours. The formed D-2-(2-thienyl)glycine was isolated by adsorption on an anion-exchange resin (commercially available under the registered trademark "Amberlite IR-120B" made by Rohm & Haas Co.) followed by elution with ammonia water. The fraction obtained was concentrated and neutralized with hydrochloric acid. D-2-(2-thienyl)glycine was collected and recrystallized from an aqueous ethanol. The amount of the obtained D-2-(2-thienyl)glycine was 2.9 g.
Reaction SMILES: C(N(C1C=C(OC)C=CC=1C1CCC2C(=CC=C(OC)C=2)C1)C(C1C=CC(OCC(O)=O)=CC=1)=O)C.[N:37]1([C:45](=O)[CH2:46][O:47][C:48]2[CH:78]=[CH:77][C:51]([C:52]([N:54]([CH2:75][CH3:76])[C:55]3[CH:60]=[C:59]([O:61][CH3:62])[CH:58]=[CH:57][C:56]=3[CH:63]3[CH2:72][CH2:71][C:70]4[C:65](=[CH:66][CH:67]=[C:68]([O:73][CH3:74])[CH:69]=4)[CH2:64]3)=O)=[CH:50][CH:49]=2)[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1>>[N:37]1([CH2:45][CH2:46][O:47][C:48]2[CH:49]=[CH:50][C:51]([CH2:52][N:54]([CH2:75][CH3:76])[C:55]3[CH:60]=[C:59]([O:61][CH3:62])[CH:58]=[CH:57][C:56]=3[CH:63]3[CH2:72][CH2:71][C:70]4[C:65](=[CH:66][CH:67]=[C:68]([O:73][CH3:74])[CH:69]=4)[CH2:64]3)=[CH:77][CH:78]=2)[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1
Reactant: CCN(C(=O)c1ccc(OCC(=O)N2CCCCCCC2)cc1)c1cc(OC)ccc1C1CCc2cc(OC)ccc2C1
Agent: CCN(C(=O)c1ccc(OCC(=O)O)cc1)c1cc(OC)ccc1C1CCc2cc(OC)ccc2C1
Product: CCN(Cc1ccc(OCCN2CCCCCCC2)cc1)c1cc(OC)ccc1C1CCc2cc(OC)ccc2C1
Yield: 90.6 %

Procedure:
Synthesized from {4-{ethyl[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]carbamoyl}phenoxy}acetic acid and heptamethyleneimine according to an analogous synthetic method to Example 378, 4-(2-azocan-1-yl-2-oxoethoxy)-N-ethyl-N-[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]benzamide (262 mg) was used according to an analogous synthetic method to Example 337 to provide [4-(2-azocan-1-ylethoxy)benzyl]ethyl[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]amine (226 mg). Synthesized from this compound (218 mg) according to an analogous synthetic method to Example 111, the title compound (168 mg) was obtained.
Reaction SMILES: [Cl-].[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[O:13][CH2:14][CH2:15][NH3+:16].[CH3:17][C:18]1[O:22][C:21]([C:23](=O)[CH3:24])=[CH:20][CH:19]=1>>[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[O:13][CH2:14][CH2:15][NH:16][CH:23]([C:21]1[O:22][C:18]([CH3:17])=[CH:19][CH:20]=1)[CH3:24]
Reactant: [NH3+]CCOc1ccc2ccccc2c1Cl
Reactant: CC(=O)c1ccc(C)o1
Agent: [Cl-]
Product: Cc1ccc(C(C)NCCOc2ccc3ccccc3c2Cl)o1
Yield: 34 %

Procedure:
Prepared from 2-[(1-chloronaphthalen-2-yl)oxy]ethanaminium chloride and 1-(5-methylfuran-2-yl)ethanone in 34% yield as a pale yellow oil.
Reaction SMILES: [CH3:1][CH:2]1[C:10]2[C:6](=[CH:7][NH:8][N:9]=2)[CH:5]([C:11]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=2)[CH2:4][CH2:3]1.C[C@@H]1C2C(=CNN=2)[C@@H](C2C=CC(C#N)=CC=2)CC1>CCO>[CH3:1][C@H:2]1[C:10]2[C:6](=[CH:7][NH:8][N:9]=2)[C@@H:5]([C:11]2[CH:12]=[CH:13][C:14]([C:15]#[N:16])=[CH:17][CH:18]=2)[CH2:4][CH2:3]1
Reactant: CC1CCC(c2ccc(C#N)cc2)c2c[nH]nc21
Agent: C[C@H]1CC[C@H](c2ccc(C#N)cc2)c2c[nH]nc21
Solvent: CCO
Product: C[C@@H]1CC[C@H](c2ccc(C#N)cc2)c2c[nH]nc21

Procedure:
(+/−)-(cis/trans)-4-[7-Methyl-4,5,6,7-tetrahydro-2H-indazol-4-yl]benzonitrile (0.36 g, 1.52 mmol) and (+/−)-(trans)-4-[7-methyl-4,5,6,7-tetrahydro-2H-indazol-4-yl]benzonitrile (0.18 g, 0.76 mmol) are combined and the single enantiomers are obtained by chiral chromatography (Chiralpak AD-H, 4.6×150 mm, 100% EtOH 0.2% DMEA, 225 mm) to give (cis)-4-[7-methyl-4,5,6,7-tetrahydro-2H-indazol-4-yl]benzonitrile-isomer 2, (0.05 g, 27%) as the second eluting isomer. ES/MS m/z 238 (M+H), Tr=2.988 min. (trans)-4-[7-Methyl-4,5,6,7-tetrahydro-2H-indazol-4-yl]benzonitrile-isomer 4, Example 61 (0.07 g, 19%). ES/MS m/z 238 (M+H).
Reaction SMILES: Cl.Cl.[C:3]([NH:11][NH2:12])(=O)[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[N:13]([O-])=O.[Na+].C(OCC)C.C(=O)(O)[O-].[Na+]>O>[CH2:3]([N:11]=[N+:12]=[N-:13])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1
Reactant: O=N[O-]
Reactant: NNC(=O)c1cccnc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: [N-]=[N+]=NCc1cccnc1
Yield: 86.1 %

Procedure:
To a solution of nicotinic acid hydrazide dihydrochloride (2 g) in water (10 ml) was added a solution of sodium nitrite (1.6 g) in water (10 ml), keeping the temperature below 20° C. Diethyl ether (50 ml) was then added and the mixture basified by the careful addition of solid sodium bicarbonate. The organic layer was separated, washed with water (20 ml), dried over anhydrous magnesium sulphate and evaporated to dryness under vacuum to give nicotinyl azide (1.1 g) m.pt. 54° C. This azide (1.1 g) was stirred in dry toluene (10 ml) and heated at 100° C. under a nitrogen atmosphere for 8 hr to give a solution containing 3-pyridyl isocyanate. A portion of this solution (1 ml) was reacted with 5-oximino-25-cyclohexyl-22,23-dihydroavermectin B1 monosaccharide (Example 5) (100 mg), in toluene (10 ml) at room temperature for 1 hr before pouring into a diethyl ether-water mixture (1:1, 30 ml). The organic layer was separated, dried over anhydrous magesium sulphate and evaporated to dryness under vacuum to give a residue (130 mg) which was purified by high pressure liquid chromatography on a Dynamax (trade mark) column (41.4×250 mm, 8 μm, ODS-silica, Rainin) eluting at 45 ml per minute with a methanol-water 85:15 mixture, changing to 87:13 after 15 mins. Appropriate fractions were combined and evaporated under vacuum to yield the title compound as a white powder (52 mg). Mass and NMR spectra were fully consistent with the proposed structure.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)[S:5][C:6]=1[CH2:7][O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][NH:13]2.[C:28]([O:32][C:33](=[O:36])[CH2:34]Br)([CH3:31])([CH3:30])[CH3:29].[H-].[Na+]>CN(C=O)C>[C:28]([O:32][C:33](=[O:36])[CH2:34][N:13]1[C:14]2[C:10](=[C:9]([O:8][CH2:7][C:6]3[S:5][C:4]([C:18]4[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:25])[F:26])=[CH:20][CH:19]=4)=[N:3][C:2]=3[CH3:1])[CH:17]=[CH:16][CH:15]=2)[CH:11]=[CH:12]1)([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1COc1cccc2[nH]ccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1COc1cccc2c1ccn2CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 72 h
Yield: 76.2 %

Procedure:
To a solution of 4-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-1H-indole (50 mg, 130 μmol) and bromo-acetic acid tert-butyl ester (20 μl, 140 μmol) in DMF (4 ml) was added sodium hydride (55%, 8 mg, 176 μmol) under an argon atmosphere at 0° C. The mixture was naturally warmed to room temperature, stirred for 72 h, poured onto 1 N HCl/ice water 1/1 and extracted three times with dichloromethane. The combined organic layers were washed with water and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue purified by column chromatography (silica gel, heptane/AcOEt) to give 50 mg (99 μmol, 77%) of the title compound as light yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])[CH:5]=[CH:6][C:7]=1[C:8]([O:10]C)=[O:9].[OH-].[Na+]>C1COCC1>[NH2:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])[CH:5]=[CH:6][C:7]=1[C:8]([OH:10])=[O:9]
Reactant: COC(=O)c1ccc(-c2ccccc2F)cc1N
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Nc1cc(-c2ccccc2F)ccc1C(=O)O
Temperature: 25 °C
Yield: 84.5 %

Procedure:
Step 2 A solution of methyl 3-amino-2′-fluorobiphenyl-4-carboxylate (0.425 g, 1.73 mmol) in 1 M aqueous sodium hydroxide (6.9 mL, 6.9 mmol) and THF (3.5 mL) was heated at reflux overnight. The mixture was cooled to rt and concentrated almost to dryness. 6 M hydrochloric acid (0.1 mL) was added to the solution at 0° C. and the precipitate was collected by filtration, washed with water and dried to give 3-amino-2′-fluorobiphenyl-4-carboxylic acid (0.338 g, 84%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.87, d, 8.25, 1H), 7.50 (t, J=7.97, 1H), 7.47-7.55 (m, 1H), 7.25-7.36 (m, 2H), 6.92 (br s, 1H), 6.76 (s, 1H), 6.59 (d, J=7.70, 1H). Mass spectrum m/z 232.1 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][CH3:12])[CH:9]=2)[C:4]([C:13]([OH:15])=O)=[C:3]1[CH3:16].S(Cl)(Cl)=O.[CH2:21]([NH2:24])[CH2:22][CH3:23]>>[CH2:21]([NH:24][C:13]([C:4]1[C:5]2[C:10](=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=2)[N:2]([CH3:1])[C:3]=1[CH3:16])=[O:15])[CH2:22][CH3:23]
Reactant: CCCN
Reactant: COc1ccc2c(C(=O)O)c(C)n(C)c2c1
Solvent: O=S(Cl)Cl
Product: CCCNC(=O)c1c(C)n(C)c2cc(OC)ccc12

Procedure:
This material was prepared from 1,2-dimethyl-6-methoxy-1H-indole-3-carboxylic acid 16c, thionyl chloride and propylamine in a manner as previously described for example 9d. 1H NMR (300 MHz, CDCl3) δ7.55 (1H, d, J=8.6 Hz), 6.84 (1H, dd, J=2.2, 8.6 Hz), 6.78 (1H, d, J=2.2 Hz), 5.87 (1H, bs), 3.87 (3H, s), 3.63 (3H, s), 3.45 (2H, m), 2.69 (3H, s), 1.67 (2H, m), 1.02 (3H, t, J=7.4 Hz). LCMS (ESI+) [M+H]/z Calc'd 261, found 261.
Reaction SMILES: [F:1][CH:2]([F:42])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([N:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:33]=[CH:34][CH:35]=[C:36]([O:37][CH2:38][CH2:39][CH2:40]O)[C:5]=2[N:4]=1.C[CH2:44][N:45](CC)[CH2:46]C.CS(Cl)(=O)=O.N(C)C>C1COCC1>[F:1][CH:2]([F:42])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:11]=[C:10]([N:20]3[CH2:21][CH2:22][N:23]([C:26]([O:28][C:29]([CH3:31])([CH3:32])[CH3:30])=[O:27])[CH2:24][CH2:25]3)[N:9]=2)[C:6]2[CH:33]=[CH:34][CH:35]=[C:36]([O:37][CH2:38][CH2:39][CH2:40][N:45]([CH3:46])[CH3:44])[C:5]=2[N:4]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(N3CCOCC3)nc(-n3c(C(F)F)nc4c(OCCCO)cccc43)n2)CC1
Reactant: CCN(CC)CC
Agent: CNC
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Product: CN(C)CCCOc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N2CCN(C(=O)OC(C)(C)C)CC2)n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of tert-butyl 4-[4-[2-(difluoromethyl)-4-(3-hydroxypropoxy)-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1-piperazinecarboxylate from the previous step and 0.34 g (3.3 mmol) of Et3N in 20 mL of THF was cooled to 0° C. and 0.32 g (2.8 mmol) of methanesulfonyl chloride was added dropwise. After 1 hr, 6 g of 40% aqueous Me2NH was added, and the resulting mixture was stirred at room temperature for 36 hrs. The THF was removed under vacuum and the residue was diluted with water and extracted into CH2Cl2. Drying and removal of the solvent gave tert-butyl 4-[4-{2-(difluoromethyl)-4-[3-(dimethylamino)propoxy]-1H-benzimidazol-1-yl}-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1-piperazinecarboxylate as an oil: 1H NMR (CDCl3) δ 7.87 (dd, J=8.4. 0.6 Hz, 1H), 7.48 (t, JHF=53.5 Hz, 1H), 7.33 (t, J=8.2 Hz, 1H), 6.85 (d, J=7.8 Hz, 1H), 4.31 (t, J=6.7 Hz, 2H), 3.87 (m, 8H), 3.79 (m, 4H), 3.53 (m, 4H), 2.51 (t, J=7.2 Hz, 2H), 2.26 (s, 6H), 2.13 (pentet, J=7.0 Hz, 2H), 1.50 (s, 9H).
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]2)[N:5]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:4][NH:3]1.C(=O)([O-])[O-].[K+].[K+].[CH2:31]([O:33][C:34](=[O:39])[CH2:35][CH2:36][CH2:37]Br)[CH3:32]>CN(C)C=O.C(OCC)(=O)C>[CH2:31]([O:33][C:34](=[O:39])[CH2:35][CH2:36][CH2:37][N:3]1[C:2](=[O:1])[C:6]2([CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:10][CH2:11]2)[N:5]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:4]1)[CH3:32]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)C(=O)NCN2c1ccccc1
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCN1CN(c2ccccc2)C2(CCN(C(=O)OC(C)(C)C)CC2)C1=O
Temperature: 60 °C
Reaction time: 60 h

Procedure:
To a solution of tert-butyl 4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate (0.15 g, 0.45 mmol) and potassium carbonate (0.124 g, 0.9 mmol) in N,N-dimethylformamide (4 mL), was added ethyl-4-bromobutyrate (0.072 mL, 0.5 mmol, d=1.35). After stirring at 60° C. for 60 hours, the reaction mixture was diluted with ethyl acetate (25 mL), washed with dilute citric acid, water and brine. The organic phase was dried over MgSO4, filtered and concentrated in vacuo to obtain tert-butyl 3-(4-ethoxy-4-oxobutyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate.
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].Br[C:6]1[S:7][CH:8]=[CH:9][CH:10]=1>>[S:7]1[CH:8]=[CH:9][CH:10]=[C:6]1[C:3]#[C:2][CH2:1][OH:4]
Reactant: C#CCO
Reactant: Brc1cccs1
Product: OCC#Cc1cccs1

Procedure:
In a manner described in Example 18 above, propargyl alcohol was reacted with 2-bromothiophene to give the title compound as a brown oil which was used in the next step without further purification.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([NH:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([O:20]CC(OC(C)(C)C)=O)=[CH:12][CH:11]=1)(=[O:8])=[O:7].Br[CH:30]([CH2:36][CH3:37])[C:31]([O:33][CH2:34]C)=[O:32]>>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([NH:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([O:20][CH2:37][CH2:36][CH2:30][C:31]([O:33][CH3:34])=[O:32])=[CH:12][CH:11]=1)(=[O:7])=[O:8]
Reactant: CC(C)(C)OC(=O)COc1ccc(NS(=O)(=O)c2cccs2)c2ccccc12
Reactant: CCOC(=O)C(Br)CC
Product: COC(=O)CCCOc1ccc(NS(=O)(=O)c2cccs2)c2ccccc12
Reaction time: 0.5 h
Yield: 51.3 %

Procedure:
15b was synthesized according to the procedure for 15a except 15 eq. of ethyl bromobutanoate was used and reaction was carried out at 90° C. for 30 min×2. After flash chromatography, 43 mg product was obtained in the yield of 51.3%. 1H NMR (400 MHz, CDCl3) δ 7.84-7.79 (m, 1H), 7.77 (m, 1H), 7.62 (dd, J=5.0, 1.3 Hz, 1H), 7.58 (dd, J=3.8, 1.3 Hz, 1H), 7.44-7.36 (m, 2H), 7.14 (d, J=8.4 Hz, 0H), 7.00 (dd, J=5.0, 3.9 Hz, 1H), 6.44 (d, J=8.4 Hz, 1H), 4.15 (q, J=7.1 Hz, 1H), 3.31 (t, J=6.7 Hz, 1H), 2.52 (t, J=6.8 Hz, 1H), 2.11 (p, J=6.7 Hz, 1H), 1.25 (t, J=7.1 Hz, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)=[CH:12][N:11]=[N:10][C:9]=2[NH:21][NH2:22])=[CH:4][CH:3]=1.[OH2:23]>CC(O)=O>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([C:13]2[CH:12]=[N:11][N:10]3[C:2](=[O:23])[C:3]([CH2:4][CH:5]([CH3:8])[CH3:6])=[N:22][N:21]=[C:9]3[C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[CH:15][CH:16]=1
Reactant: O
Reactant: NNc1nncc(-c2ccc(Cl)cc2)c1-c1ccc(Cl)cc1
Solvent: CC(=O)O
Product: CC(C)Cc1nnc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)cnn2c1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-(4,5-bis(4-chlorophenyl)pyridazin-3-yl)hydrazine (50.0 mg, 0.15 mmol) in AcOH (1 mL) was added (CH3)2CH2COCO2H (40.0 mg, 0.3 mmol). The solution was stirred at RT for 30 min then was heated at 120° C. for 5 h. The reaction mixture was cooled to RT and then poured into water (20 mL). The resultant solution was extracted with EtOAc (20 mL). The organic laer was dried over Na2SO4, filered and concentrate to give the a brown solid. The solid was purified by reverse phase preparative HPLC to give the title compound 9-bis-(4-chloro-phenyl)-3-isobutyl-pyridazino[6,1-c][1,2,4]triazin-4-one, (23.0 mg, 0.054 mmol) as a solid. HPLC retention time=3.87 min; MS observed=425 (M+H); 1H NMR (CDCl3, 500 MHz) δ 8.72 (s, 1H), 7.37–7.33 (m, 4H), 7.24 (d, J=8.8 Hz, 2H), 7.11 (d, J=8.8 Hz, 2H), 2.96 (d, J=7.1 Hz, 2H), 2.34 (m, 1H), 0.99 (d, J=9.3 Hz, 6H).
Reaction SMILES: [OH-].[K+].Cl.[NH2:4][CH2:5][CH2:6][SH:7].Cl.Cl[CH2:10][C:11]1[N:12]=[C:13]([CH2:16][OH:17])[S:14][CH:15]=1>C(O)(C)C>[NH2:4][CH2:5][CH2:6][S:7][CH2:10][C:11]1[N:12]=[C:13]([CH2:16][OH:17])[S:14][CH:15]=1
Reactant: OCc1nc(CCl)cs1
Reactant: NCCS
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Product: NCCSCc1csc(CO)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Potassium hydroxide (10.6 g) was added to a suspension of 6.82 g of cysteamine hydrochloride and 10.0 g of 4-chloromethyl-2-hydroxymethylthiazole hydrochloride in 100 ml isopropanol. The resulting suspension was stirred an room temperature for 2 hours and filtered through a pad of celite to remove insoluble inorganics and concentrated under reduced pressure. The residue was taken up in dichloromethane and filtered through a pad of celite and concentrated under reduced pressure. The oil (12.54 g) represents a quantitative yield of 4-[[(2-aminoethyl)thio]methyl]-2-hydroxymethylthiazole contaminated only with inorganic salts.
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10](=[O:31])[CH2:11][C@H:12]([C:22]1[O:23][C:24]([CH3:30])=[C:25]([C:27](O)=[O:28])[N:26]=1)[CH2:13][CH2:14][CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.Cl.[CH3:63][O:64][C:65](=[O:68])[CH2:66][NH2:67]>ClCCl>[CH2:1]([O:8][NH:9][C:10](=[O:31])[CH2:11][C@H:12]([C:22]1[O:23][C:24]([CH3:30])=[C:25]([C:27]([NH:67][CH2:66][C:65]([O:64][CH3:63])=[O:68])=[O:28])[N:26]=1)[CH2:13][CH2:14][CH2:15][CH:16]1[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1oc([C@H](CCCC2CCCCC2)CC(=O)NOCc2ccccc2)nc1C(=O)O
Reactant: COC(=O)CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: O
Product: COC(=O)CNC(=O)c1nc([C@H](CCCC2CCCCC2)CC(=O)NOCc2ccccc2)oc1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 60.4 %

Procedure:
A solution 2-((1R)-1-{2-[(benzyloxy)amino]-2-oxoethyl}-4-cyclohexylbutyl)5-methyl-1,3-oxazole-4-carboxylic acid (Preparation 72) (230 mg, 0.53 mmol), N-methylmorpholine (61 l, 0.56 mmol), 1-hydroxybenzotriazole hydrate (68 mg, 0.53 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (107 mg, 0.56 mmol) in dichloromethane (10 ml) was treated with a solution of glycine methyl ester hydrochloride (70 mg, 0.56 mmol) and N-methylmorpholine (61 l, 0.56 mmol) in dichloromethane (2 ml) and stirred at room temperature for 18 hours. The reaction mixture was diluted with dichloromethane and washed with water, saturated sodium hydrogen carbonate solution and brine, dried over anhydrous magnesium sulphate, filtered and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient system of 100:0:0 (dichloromethane:methanol:ammonia) gradually changing to 98:2:0.2 (dichloromethane:methanol:ammonia) to afford the title compound as a white solid (160 mg).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([NH2:14])[CH:5]=[CH:4][C:3]1=2.[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>N1C=CC=CC=1.O1CCCC1>[CH3:1][C:2]1([CH3:15])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([NH:14][C:16](=[O:23])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: O=C(Cl)c1ccccc1
Reactant: CC1(C)CCC(C)(C)c2cc(N)ccc21
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC1(C)CCC(C)(C)c2cc(NC(=O)c3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.7 %

Procedure:
2.5 g of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylamine were dissolved in 50 ml of pyridine and treated at room temperature with a solution of 1.7 g of benzoyl chloride in 20 ml of tetrahydrofuran. After stirring at room temperature for two hours the reaction mixture was poured on to ice-water and, after acidification with 3N hydrochloric acid, extracted with ethyl acetate. The oil obtained after drying and evaporating the organic phase was crystallized from hexane/ethyl acetate and gave 3 g of N-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)benzamide in white crystals, m.p. 146°-148° C.