Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([Si:15]([CH3:26])([CH3:25])[O:16][CH2:17][CH2:18][C:19]([CH3:24])([CH3:23])[CH2:20][CH2:21][OH:22])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>ClCCl.O>[C:11]([Si:15]([CH3:26])([CH3:25])[O:16][CH2:17][CH2:18][C:19]([CH3:24])([CH3:23])[CH2:20][CH:21]=[O:22])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(CCO)CCO[Si](C)(C)C(C)(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(CC=O)CCO[Si](C)(C)C(C)(C)C
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 71.6 %

Procedure:
Step C To a solution of oxalyl chloride (0.97 mL, 11 mmol) (Aldrich) in dichloromethane (20 mL) at −78° C. was added the solution of dimethyl sulfoxide (1.6 mL, 22 mmol) in dichloromethane (5 mL) dropwise. After 5 mins, the solution of 5-(tert-butyl-dimethyl-silanyloxy)-3,3-dimethyl-pentan-1-ol (2.5 g, 10 mmol) in dichloromethane (10 mL) was added dropwise. The reaction mixture was stirred at −78° C. for 15 min. Triethylamine (5 mL, 36 mmol) was added and the reaction mixture was slowly warmed up to room temperature and stirred at room temperature for 45 min. Then water was added. The organic layers were separated, and the aqueous layer was extracted with dichloromethane. The organic layers were combined, washed with 10% of HCl, saturated NaHCO3, brine, dried over MgSO4, and concentrated to give 5-(tert-butyl-dimethyl-silanyloxy)-3,3-dimethyl-pentanal as a light yellow oil (Yield: 1.75 g, 71%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[N:16][N:15]4[C:18]([C:21]5[CH:22]=[C:23]([NH:27][C:28]([NH:30][CH2:31][C:32]([F:35])([F:34])[F:33])=[O:29])[CH:24]=[CH:25][CH:26]=5)=[CH:19][N:20]=[C:14]4[CH:13]=3)[CH:9]=[N:8]2)[CH2:3][CH2:2]1.Cl.[CH3:37][N:38]([CH2:40][C:41](Cl)=[O:42])[CH3:39]>>[CH3:37][N:38]([CH2:40][C:41]([N:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[N:16][N:15]4[C:18]([C:21]5[CH:22]=[C:23]([NH:27][C:28]([NH:30][CH2:31][C:32]([F:33])([F:35])[F:34])=[O:29])[CH:24]=[CH:25][CH:26]=5)=[CH:19][N:20]=[C:14]4[CH:13]=3)[CH:9]=[N:8]2)[CH2:3][CH2:2]1)=[O:42])[CH3:39]
Reactant: CN(C)CC(=O)Cl
Reactant: O=C(NCC(F)(F)F)Nc1cccc(-c2cnc3cc(-c4cnn(C5CCNCC5)c4)cnn23)c1
Agent: Cl
Product: CN(C)CC(=O)N1CCC(n2cc(-c3cnn4c(-c5cccc(NC(=O)NCC(F)(F)F)c5)cnc4c3)cn2)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 30 (Step 6) starting from N-{3-[7-(1-piperidin-4-yl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-3-yl]phenyl}-N′-(2,2,2-trifluoroethyl)urea and dimethylaminoacetyl chloride hydrochloride (Lancaster, Cat. No. L18475). LCMS (M+H)+: m/z=570.2.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1C1C=C2C(=CC=1)C(=O)NC=C2.Br[C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[C:30](=[O:34])[NH:29][C:28]([CH3:35])=[CH:27]2>>[CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[C:27]1[C:26]2[C:31](=[CH:32][CH:33]=[CH:24][CH:25]=2)[C:30](=[O:34])[NH:29][C:28]=1[CH3:35]
Reactant: COC(=O)c1ccc(C)c(-c2ccc3c(=O)[nH]ccc3c2)c1
Reactant: Cc1cc2cc(Br)ccc2c(=O)[nH]1
Product: COC(=O)c1ccc(C)c(-c2c(C)[nH]c(=O)c3ccccc23)c1

Procedure:
The sub-title compound was prepared by the method of intermediate 3 using the product of step i).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:14][C:13]2[C:8](=[CH:9][C:10]([OH:18])=[C:11]([N+:15]([O-])=O)[CH:12]=2)[CH2:7][N:6]1[C:19]([O:21][CH:22]([CH3:24])[CH3:23])=[O:20])=[O:4]>CO.[Pd]>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:14][C:13]2[C:8](=[CH:9][C:10]([OH:18])=[C:11]([NH2:15])[CH:12]=2)[CH2:7][N:6]1[C:19]([O:21][CH:22]([CH3:24])[CH3:23])=[O:20])=[O:4]
Reactant: COC(=O)[C@@H]1Cc2cc([N+](=O)[O-])c(O)cc2CN1C(=O)OC(C)C
Agent: [Pd]
Solvent: CO
Product: COC(=O)[C@@H]1Cc2cc(N)c(O)cc2CN1C(=O)OC(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 98.8 %

Procedure:
(S)-7-Hydroxy-6-nitro-3,4-dihydro-1H-isoquinoline-2,3-dicarboxylic acid 2-isopropyl ester 3-methyl ester (2.0 g) was dissolved in MeOH and 200 mg Pd/C added. The flask was evacuated and placed under balloon pressure of hydrogen. The reaction stirred at r.t. for 1.5 h and was filtered over a plug of celite. The celite plug was washed with EtOAc and DCM. The filtrates were combined and evaporated to provide (S)-6-amino-7-hydroxy-3,4-dihydro-1H-isoquinoline-2,3-dicarboxylic acid 2-isopropyl ester 3-methyl ester (1.8 g). LC-MS (m/z) 310.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]3[C:14](=[O:17])[NH:15][N:16]=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[Cl:24][C:25]1[C:30]([CH2:31]Cl)=[CH:29][CH:28]=[C:27]([C:33]([F:36])([F:35])[F:34])[N:26]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:24][C:25]1[C:30]([CH2:31][N:15]2[C:14](=[O:17])[N:11]3[CH:12]=[CH:13][C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)=[C:9]([C:18]4[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=4)[C:10]3=[N:16]2)=[CH:29][CH:28]=[C:27]([C:33]([F:34])([F:35])[F:36])[N:26]=1
Reactant: O=c1[nH]nc2c(-c3ccncc3)c(-c3ccc(Cl)cc3)ccn12
Reactant: FC(F)(F)c1ccc(CCl)c(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1n(Cc2ccc(C(F)(F)F)nc2Cl)nc2c(-c3ccncc3)c(-c3ccc(Cl)cc3)ccn12
Temperature: 70 °C
Reaction time: 3 h
Yield: 81 %

Procedure:
To a solution of 7-(4-chlorophenyl)-8-(pyridin-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (200 mg, 0.62 mmol) and 2-chloro-3-(chloromethyl)-6-(trifluoromethyl)pyridine in anhydrous DMF (4.0 mL) at room temperature was added anhydrous K2CO3 (1.8 g, 13 mmol). The resulting yellow suspension was stirred at 70° C. for 3 h. Analysis by HPLC/MS indicated that starting 7-(4-chlorophenyl)-8-(pyridin-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one had been consumed. After cooling to room temperature, the reaction mixture was diluted with water and extracted with EtOAc (20 mL×2). The combined EtOAc extracts were washed with water, then saturated aqueous NaCl, dried (Na2SO4), filtered, and concentrated under reduced pressure to afford 260 mg (81%) of the title compound as a yellow foam. This product (25 mg) was further purified using preparative reverse phase HPLC (Phenomenex Luna 5 μm C-18 21.2×100 mm column eluted with a linear gradient of 40% to 80% B over 8 min (A=0.1% trifluoroacetic acid, 90% water, 10% methanol and B=0.1% trifluoroacetic acid, 90% methanol, 10% water) with flow rate at 20 mL/min and UV detection at 220 nm). The desired fractions were concentrated under reduced pressure. The residue was dissolved in EtOAc, washed with saturated aqueous NaHCO3 once, water twice, then saturated aqueous NaCl, dried over Na2SO4 and evaporated. The residue was dissolved in acetonitrile, frozen and lyophilized to afford 21 mg of the title compound as a light yellow powder. HPLC/MS: retention time=2.96 min, [M+H]+=516.1.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=[O:7].Cl[CH2:10]CCl.S(=O)(=O)(O)O>CO>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([O:8][CH3:10])=[O:7]
Reactant: O=C(O)c1cccs1
Reactant: ClCCCl
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)c1cccs1
Yield: 90 %

Procedure:
The synthesis was carried out according to the method of Example 7-(1). 2-Thiophenecarboxylic acid (25.0 g), : 1,2-dichloroethane (120 ml), methanol (23.7 ml) and concentrated sulfuric acid (0.8 ml) were used as reagents to give 24.9 g of a pale-yellow transparent liquid (yield 90%).
Reaction SMILES: Cl.FC1C=C(C=CC=1)CN1C=C(C2C3C(=NC=C(C4C=CC(C5CCNCC5)=CC=4)C=3)N(S(C3C=CC(C)=CC=3)(=O)=O)C=2)C=N1.[F:46][C:47]1[CH:48]=[C:49]([CH:92]=[CH:93][CH:94]=1)[CH2:50][N:51]1[CH:55]=[C:54]([C:56]2[C:64]3[C:59](=[N:60][CH:61]=[C:62]([C:65]4[CH:70]=[CH:69][C:68]([N:71]5[CH2:77][CH2:76][CH2:75][N:74]([CH2:78][C@@H:79]([OH:81])[CH3:80])[CH2:73][CH2:72]5)=[CH:67][CH:66]=4)[CH:63]=3)[N:58](S(C3C=CC(C)=CC=3)(=O)=O)[CH:57]=2)[CH:53]=[N:52]1.[OH-].[Li+]>C1COCC1.CO.O>[F:46][C:47]1[CH:48]=[C:49]([CH:92]=[CH:93][CH:94]=1)[CH2:50][N:51]1[CH:55]=[C:54]([C:56]2[C:64]3[C:59](=[N:60][CH:61]=[C:62]([C:65]4[CH:66]=[CH:67][C:68]([N:71]5[CH2:77][CH2:76][CH2:75][N:74]([CH2:78][C@@H:79]([OH:81])[CH3:80])[CH2:73][CH2:72]5)=[CH:69][CH:70]=4)[CH:63]=3)[NH:58][CH:57]=2)[CH:53]=[N:52]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCCN(C[C@H](C)O)CC5)cc4)cnc32)cc1
Agent: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(C5CCNCC5)cc4)cnc32)cc1
Agent: Cl
Agent: [Li+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: C[C@H](O)CN1CCCN(c2ccc(-c3cnc4[nH]cc(-c5cnn(Cc6cccc(F)c6)c5)c4c3)cc2)CC1
Yield: 42.8 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, (S)-1-(4-(4-(3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-1,4-diazepan-1-yl) propan-2-ol (100 mg, 0.147 mmol) was hydrolyzed with lithium hydroxide (31 mg, 0.736 mmol) in THF/methanol/water (2/2/1 mL) to yield 33 mg (42.8% yield) of desired product. 1H NMR (CDCl3, 300 MHz): δ 8.83 (s, 1H), 8.538-8.531 (d, 1H), 8.13-8.12 (d, 1H), 7.86 (s, 1H), 7.70 (s, 1H), 7.52-7.49 (d, 2H), 7.39-7.30 (m, 2H), 7.07-6.91 (m, 3H), 6.82-6.79 (d, 2H), 5.38 (s, 2H), 3.85-3.75 (m, 1H), 3.70-3.55 (m, 4H), 3.15-3.00 (m, 1H), 2.90-2.80 (m, 2H), 2.70-2.55 (m, 2H), 2.35-2.25 (m, 1H), 2.15-1.95 (m, 2H), 1.14-1.12 (d, 3H). MS: m/z=525.3 (M+1), HPLC: 92.75% in method A.
Reaction SMILES: CN(C)C=O.[CH2:6]([N:13]1[CH2:18][CH2:17][CH:16]([OH:19])[CH2:15][CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.N1C=CN=C1.[Si:25](Cl)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]>O>[CH2:6]([N:13]1[CH2:18][CH2:17][CH:16]([O:19][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])[CH2:15][CH2:14]1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: OC1CCN(Cc2ccccc2)CC1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OC1CCN(Cc2ccccc2)CC1
Reaction time: 1.5 h

Procedure:
To a N,N-dimethylformamide (10 mL) solution of N-benzyl-4-hydroxypiperidine (1.90 g, 9.93 mmol) was added imidazole (1.35 g, 19.9 mmol) and tert-butyldimethylsilyl chloride (1.57 g, 10.4 mmol). After 1.5 hours, the reaction mixture was diluted with water and extracted with ethyl acetate (3×50 mL). The combined organic extracts were washed with brine (50 mL), dried (magnesium sulfate), filtered, and concentrated in vacuo. Chromatography over silica gel, eluting with hexanes/ethyl acetate, afforded the title compound. 1H NMR (500 MHz, CDCl3) δ 7.36-7.21 (m, 5H), 3.75-3.65 (m, 1H), 3.49 (s, 2H), 2.72-2.63 (m, 2H), 2.26-2.12 (m, 2H), 1.78-1.71 (m, 2H), 1.62-1.53 (m, 2H), 0.88 (s, 9H), 0.04 (s, 6H); LC-MS: m/z 306.1 (M+H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.Cl.[NH2:10][C:11]12[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:19][CH:13]([CH2:14]3)[CH2:12]1)[CH2:18]2.CCN(C(C)C)C(C)C>CC(O)C>[C:11]12([NH:10][C:2]3[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=3)[CH2:18][CH:17]3[CH2:16][CH:15]([CH2:14][CH:13]([CH2:19]3)[CH2:12]1)[CH2:20]2
Reactant: NC12CC3CC(CC(C3)C1)C2
Reactant: Clc1cc(Cl)ncn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Clc1cc(NC23CC4CC(CC(C4)C2)C3)ncn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
200 mg of 4,6-dichloropyrimidine, 252 mg of 1-aminoadamantane hydrochloride and 452 mg of DIPEA were dissolved in 2 mL of i-PrOH and the mixture obtained was charged into a screw cap vial and the vial was kept overnight in a heating block at 90° C. The reaction was monitored by TLC and was completed after 12 hours. The mixture obtained was cooled to r.t., solvent was evaporated and N-adamant-1-yl-6-chloropyrimidin-4-amine was obtained by column chromatography using PE:EtOAc 10:1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH:6]=[C:5]2[S:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1.[CH:27]1([CH2:30]Br)[CH2:29][CH2:28]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:30][CH:27]1[CH2:29][CH2:28]1)[CH:6]=[C:5]2[S:13][CH:14]1[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19]1
Reactant: CC(C)(C)OC(=O)N1CCC(Sc2c[nH]c(=O)c3ccc(Br)cc23)CC1
Reactant: BrCC1CC1
Product: CC(C)(C)OC(=O)N1CCC(Sc2cn(CC3CC3)c(=O)c3ccc(Br)cc23)CC1

Procedure:
The subtitle compound was prepared from tert-butyl 4-[(6-bromo-1-oxo-1,2-dihydroisoquinolin-4-yl)sulfanyl]piperidine-1-carboxylate (Example 58b) and cyclopropylmethylbromide using the method of example 58c.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:12][C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2.C([O-])([O-])=O.[K+].[K+].[CH2:25]([NH:27][CH2:28][CH3:29])[CH3:26]>C(#N)C.O>[CH2:25]([N:27]([CH2:28][CH3:29])[CH2:2][CH2:3][CH2:4][N:5]1[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:12][C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH3:26]
Reactant: CCNCC
Reactant: ClCCCN1c2ccccc2Oc2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCN(CC)CCCN1c2ccccc2Oc2ccccc21

Procedure:
1 g (4.31 mmol) of the product of Example 1 was dissolved in 150 mL of anhydrous acetonitrile, and 1.5 g KI, 2.13 g K2CO3 and 1.6 mL (15.4 mmol) of N,N-diethylamine were added. The mixture was refluxed overnight until a substantial amount of product was formed (TLC, System B, Rf =0.40). The reaction mixture was diluted with water and extracted with ether three times. The ether layer was washed with water and dried over anhydrous Na2SO4 and evaporated. The crude oil was subjected to column chromatography for purification. Ethylacetate-petroleum ether (50 mL+50 mL) eluted the title compound as the free base as a colorless oil, which was dried and used for NMR studies. An ethereal solution of the free base was treated with an excess of tartaric acid to separate the hygroscopic tartrate salt (1.2 g). UV-λmax (MeOH) 215, 238 and 320 nm; IR (CHCl3) 3378, 2974, 2838, 1453, 1375, 1155, 973 and 722 cm-1 ; 1H-NMR (`δ`) 6.51-6.80 (m, 8H, ArH, H1 -H4 and H6 -H9), 1.16 (t, 6H, Hc and Hd), 1.70 (m, 2H, H1), 2.50 (q, 4H, Ha and Hb, J=7 Hz), 3.42-3.63 (m, 4H, Hk and Hm); 13C-NMR 111.54 (C1 and C9), 115.49 (C4 and C6), 121.21 (C3 and C7), 123.85 (C2 and C8), 132.72 (C1' and C9'), 144.95 (C4' and C6'), 8.21 (Cc and Cd), 19.90 (C1), 40.72 (Ca and Cb), 45.87 (Cm), and 48.50 (Ck); EIMS (m/z) 296 (M+).
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:16]N1C(=O)CCC1=O>[N+]([O-])(O)=O.C(O)(=O)C>[Br:16][C:8]1[C:9]([C:12]([O:14][CH3:15])=[O:13])=[N:10][O:11][C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1cc(-c2ccccc2)on1
Reactant: O=C1CCC(=O)N1Br
Solvent: O=[N+]([O-])O
Solvent: CC(=O)O
Product: COC(=O)c1noc(-c2ccccc2)c1Br
Yield: 77.8 %

Procedure:
A solution of methyl 5-phenylisoxazole-3-carboxylate (100 mg, 0.492 mmol) and N-bromosuccinimide (119 mg, 0.669 mmol) in 5% fuming nitric acid in acetic acid (2 mL) was heated to 150° C. for 10 minutes via microwave. The reaction mixture was concentrated and purified by silica gel chromatography with hexanes/ethyl acetate (10/1) to afford methyl 4-bromo-5-phenylisoxazole-3-carboxylate (108 mg). The compound had an HPLC ret. time=3.21 min.−Column: YMC S5 COMBISCREEN® 4.6×50 mm; Gradient time: 4 min; Flow rate=4 ml/min; Solvent A=10% MeOH−90% Water−0.2% H3PO4; Solvent B=90% MeOH−10% water−0.2% H3PO4; Start % B=0; Final % B=100. LC-MS: M+1=284+.
Reaction SMILES: [CH3:1][CH:2]([CH2:18][CH3:19])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[CH:13][C:14]([OH:17])=[N:15][CH:16]=2)=[CH:7][CH:6]=1.[F:20][C:21]1[CH:29]=[C:28]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH:27]=[CH:26][C:22]=1[C:23](Cl)=[O:24]>N1C=CC=CC=1>[F:20][C:21]1[CH:29]=[C:28]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH:27]=[CH:26][C:22]=1[C:23]([O:17][C:14]1[CH:13]=[N:12][C:11]([C:8]2[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH:2]([CH3:1])[CH2:18][CH3:19])=[CH:6][CH:7]=2)=[CH:16][N:15]=1)=[O:24]
Reactant: CCCCCCCCc1ccc(C(=O)Cl)c(F)c1
Reactant: CCC(C)COc1ccc(-c2cnc(O)cn2)cc1
Solvent: c1ccncc1
Product: CCCCCCCCc1ccc(C(=O)Oc2cnc(-c3ccc(OCC(C)CC)cc3)cn2)c(F)c1
Reaction time: 8 h

Procedure:
8.0 mmol of 5-[4-(2-methylbutoxy)-phenyl]-2-pyrazinol (known from Japanese Preliminary Published Application 92,276/'85) are added with stirring to a mixture of 7.0 mmol of 2-fluoro-4-octylbenzoyl chloride and 5 ml of pyridine and left to stand overnight. This gives optically active (S) 2-(2-fluoro-4-octylbenzoyloxy)-5-[4-(2-methylbutoxy)-phenyl]-pyrazine after extraction with toluene (30 ml) and water (20 ml), working up of the toluene phase and subsequent distillation.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]#[N:13])=[CH:8][CH:7]=1)=[O:4].[CH2:14]([CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(OCC)C>[CH2:14]([CH:21]1[CH2:26][CH2:25][N:24]([CH2:2][C:3]([NH:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]#[N:13])=[CH:8][CH:7]=2)=[O:4])[CH2:23][CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: c1ccc(CC2CCNCC2)cc1
Reactant: N#Cc1ccc(NC(=O)CCl)cc1
Solvent: CCOCC
Product: N#Cc1ccc(NC(=O)CN2CCC(Cc3ccccc3)CC2)cc1

Procedure:
The title compound is prepared from 2-chloro-N-(4-cyano-phenyl)-acetamide [J. Org. Chem., 23, 141. (1958)] and 4-benzyl-piperidine according to the method described in Example 142b. Melting Point: 120-124° C. (diethylether)
Reaction SMILES: [Br:1][C:2]1[C:3]([F:10])=[CH:4][C:5]([F:9])=[C:6]([CH:8]=1)[NH2:7].C(N(CC)CC)C.[C:18](Cl)(=[O:22])[CH:19]([CH3:21])[CH3:20]>C1COCC1>[Br:1][C:2]1[C:3]([F:10])=[CH:4][C:5]([F:9])=[C:6]([NH:7][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:8]=1
Reactant: CC(C)C(=O)Cl
Reactant: Nc1cc(Br)c(F)cc1F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)C(=O)Nc1cc(Br)c(F)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.7 %

Procedure:
Into a solution of 2.6 g (12.6 mmol) of 5-bromo-2,4-difluoroaniline and 2.1 mL (15.1 mmol) of triethylamine in 50 mL THF at 0° C. was slowly added 1.6 mL (15.1 mmol) of isobutyryl chloride. The reaction mixture was stirred at room temperature for 2 hours and concentrated in vacuo. The residue was dissolved in EtOAc and washed with H2O, saturated aqueous Na2CO3 and brine. The organic layer was dried over MgSO4 and concentrated in vacuo to give 3.3 g (11.8 mmol, 94%) of N-(5-bromo-2,4-difluorophenyl)-2-methylpropanamide: ESMS m/e: 278.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][N:3]=1.[Cl:14][C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:1][C:2]1[N:7]=[C:6]([C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:14])[C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][N:3]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: CCOC(=O)c1cnc(Cl)nc1Cl
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CCOC(=O)c1cnc(Cl)nc1-c1ccccc1Cl
Temperature: 160 °C

Procedure:
In a microwave tube was added 1 eq. of ethyl 2,4-dichloropyrimidine-5-carboxylate (200 mg, 0.91 mmol), 0.5 eq. of 3-chlorophenyl boronic acid (67 mg), 0.1 eq. of Pd2(dba)3 (83 mg), 3 eq. of K3PO4 in 4 mL of Dioxane. To this solution was added 1 eq. of tri-(t-butyl)phospine. The reaction was heated in the microwave to 160° C./300 W/for 1200 sec. The crude product was purified by prep HPLC. ES+=296.8.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:7][CH2:6][NH:5][C:4]1=[O:8].[C:9]([C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Br)=[CH:15][CH:14]=1)([CH3:12])([CH3:11])[CH3:10].Cl>O.CN(C=O)C>[C:9]([C:13]1[CH:14]=[CH:15][C:16]([CH2:17][N:3]2[CH2:7][CH2:6][NH:5][C:4]2=[O:8])=[CH:19][CH:20]=1)([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)c1ccc(CBr)cc1
Reactant: O=C1NCCN1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)c1ccc(CN2CCNC2=O)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Sodium hydride (approximately 60% strength suspension in oil, 1.2 g, approximately 30 mmol) was added portionwise to a solution of imidazolidin-2-one (2.58 g, 30 mmol) in abs. DMF (40 mL) under a blanket of argon within 10 min. The reaction mixture was stirred for 90 min at RT and a solution of 4-tert-butylbenzyl bromide (3.7 mL, 20.1 mmol) in abs. DMF (3 mL) was then added. The reaction mixture was stirred at RT over a period of 3 h and then added to a mixture of H2O (100 mL) and 2N hydrochloric acid solution in H2O (10 mL). The resulting mixture was stirred for 30 min, and the resulting crystals were separated with the aid of a frit and washed with H2O (3×30 mL). The isolated solid matter was recrystallized from a mixture of H2O (100 mL) and EtOH (120 mL). The substance formed (1.4 g, mp: 122-127° C.) is compound D.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[NH:11][C:12]1[S:13][C:14](=[CH:18][C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][CH:28]=2)[N:25]=[CH:24][CH:23]=[CH:22]3)[C:15](=[O:17])[N:16]=1.O.O.O.O.O.O.O.O.O.[S-2].[Na+].[Na+]>CCO>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([NH:11][C:12]2[S:13][C:14](=[CH:18][C:19]3[CH:20]=[C:21]4[C:26](=[CH:27][CH:28]=3)[N:25]=[CH:24][CH:23]=[CH:22]4)[C:15](=[O:17])[N:16]=2)[CH:4]=1
Reactant: O=C1N=C(Nc2cc([N+](=O)[O-])ccc2Cl)SC1=Cc1ccc2ncccc2c1
Agent: [Na+]
Agent: [S-2]
Solvent: CCO
Solvent: O
Product: Nc1ccc(Cl)c(NC2=NC(=O)C(=Cc3ccc4ncccc4c3)S2)c1
Temperature: 25 °C
Yield: 20.5 %

Procedure:
A mixture of 2-(2-chloro-5-nitro-phenylamino)-5-quinolin-6-ylmethylene-thiazol4-one (100 mg, 0.42 mmol) and sodium sulfide nonahydrate (350 mg, 1-66 mmol) in 4 ml of EtOH was heated by microwave (SmithSynthesizer-Personal Chemistry) at 130 for 2 hours. The reaction mixture was cooled to room temperature and concentrated by vacuum distillation, then water was added and neutralized with aqueous ammonium chloride. Generated solid was collected by filtration and washed with water, followed by desiccation in vacuo to afford the title product (33 mg, 0.086 mmol). 1H NMR(DMSO-d6) δ 12.63 (s, 1H) 8.94 (m, 1H) 8.47 (d, 1H) 4.16 (s, 1H) 8.10 (d, 1H) 7.87 (dd, 1H) 7.84 (s, 1H) 7.56 (dd, 1H) 7.12 (d, 1H) 6.40 (d, 1H) 6.38 (s, 1H) 5.37 (s, 2H).:LC/MS: m/z 381 (M+1)
Reaction SMILES: [NH2:1][C:2]1[N:3]([N:15]=CC2C=CC=CC=2)[CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=2)[N:6]=1.O.NN.O>C(O)COCCO>[NH2:15][N:3]1[CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=2)[N:6]=[C:2]1[NH2:1]
Reactant: COc1cccc(-c2cn(N=Cc3ccccc3)c(N)n2)c1
Agent: NN
Solvent: OCCOCCO
Solvent: O
Product: COc1cccc(-c2cn(N)c(N)n2)c1

Procedure:
A solution of 8.1 g of 2-amino-1-benzylideneamino-4-(3-methoxyphenyl)-imidazole and 5.5 ml of hydrazine hydrate in 28 ml of diethylene glycol is stirred at 170° C. for 7 hours. After cooling, 150 ml of water are added to the reaction mixture. The product that has separated out is filtered off with suction, washed with water and recrystallized from 100 ml of ethanol. In that manner there is obtained the title compound, m.p. 181°-182° C., 1H-NMR (DMSO): δ=7.17 (m, 3H); 7.06 (s, 1H); 6.64 (m, 1H); 5.52 (s, 2H); 5.35 (s, 2H); 3.74 (s, 3H).