Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([CH3:7])=[N:4][C:3]=1C(Cl)Cl.[C:11](=[O:14])(O)[O-:12].[Na+]>C(O)C.CCOC(C)=O>[Br:1][C:2]1[S:6][C:5]([CH3:7])=[N:4][C:3]=1[C:11]([OH:12])=[O:14]
Reactant: Cc1nc(C(Cl)Cl)c(Br)s1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1nc(C(=O)O)c(Br)s1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a solution of 5-bromo-4-(dichloromethyl)-2-methyl-1,3-thiazole (7.58 g, 29.0 mmol) in ethanol (180.0 mL) was added saturated aqueous sodium bicarbonate (60.0 mL) and the system was stirred at 80° C. overnight. The mixture was then cooled to room temperature, diluted with EtOAc, extracted with water, dried over sodium sulfate and concentrated. The crude reaction mixture was purified using normal phase conditions (0%→÷30% EtOAc: hexanes) to afford a mixture of the desired compound and an acetal byproduct. This mixture was then treated with 1N HCl (12.25 mL, 12.25 mmol) for 0.5 h at room temperature followed by neutralization with 2N NaOH to a pH of 7.0. Extraction with EtOAc and water afforded the product as a pale yellow crystalline solid. To this solid (5.0 g, 24.26 mmol) in THF/t-BuOH/Water (40 mL/80 mL/20 mL) was added sodium phosphate (17.22 g, 121.0 mmol), 2-methyl-2-butene (64.0 mL, 607 mmol) and sodium chlorite (5.49 g, 60.7 mmol) and was stirred at room temperature for 1 h. The system was then acidified with 1N HCl to a pH of 3.0, extracted with EtOAc, washed with water, dried over sodium sulfate and concentrated. Removal of solvent in vacuo afforded the title compound (2-5) as a powder. 1H NMR (500 MHz, CDCl3) δ 2.72 (s, 3H). ESI+ MS: 222.8 [M+H]+.
Reaction SMILES: [CH:1]([O:14][C:15]([C:17]1[N:18]2[C@H:21]([S@:22](=[O:27])[CH2:23][C:24]=1[CH2:25]Cl)[C@H:20]([NH:28][C:29](=[O:68])/[C:30](=[N:45]\[O:46][C@@H:47]([CH2:60][C:61]([O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[O:62])[C:48]([O:50][CH2:51][C:52]1[CH:57]=[CH:56][C:55]([O:58][CH3:59])=[CH:54][CH:53]=1)=[O:49])/[C:31]1[N:32]=[C:33]([NH:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[S:34][C:35]=1[Cl:36])[C:19]2=[O:69])=[O:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-:70].[Na+]>C(#N)C>[CH:1]([O:14][C:15]([C:17]1[N:18]2[C@H:21]([S@:22](=[O:27])[CH2:23][C:24]=1[CH2:25][I:70])[C@H:20]([NH:28][C:29](=[O:68])/[C:30](=[N:45]\[O:46][C@@H:47]([CH2:60][C:61]([O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[O:62])[C:48]([O:50][CH2:51][C:52]1[CH:57]=[CH:56][C:55]([O:58][CH3:59])=[CH:54][CH:53]=1)=[O:49])/[C:31]1[N:32]=[C:33]([NH:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[S:34][C:35]=1[Cl:36])[C:19]2=[O:69])=[O:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(COC(=O)[C@H](CC(=O)OC(C)(C)C)O/N=C(\C(=O)N[C@@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(CCl)C[S@@](=O)[C@H]23)c2nc(NC(=O)OC(C)(C)C)sc2Cl)cc1
Reactant: [I-]
Agent: [Na+]
Solvent: CC#N
Product: COc1ccc(COC(=O)[C@H](CC(=O)OC(C)(C)C)O/N=C(\C(=O)N[C@@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(CI)C[S@@](=O)[C@H]23)c2nc(NC(=O)OC(C)(C)C)sc2Cl)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 59.9 %

Procedure:
To a solution of (S)-4-tert-butyl 1-(4-methoxybenzyl) 2-(((Z)-(2-(((5R,6R,7R)-2-((benzhydryloxy)carbonyl)-3-(chloromethyl)-5-oxido-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-7-yl)amino)-1-(2-((tert-butoxycarbonyl)amino)-5-chlorothiazol-4-yl)-2-oxoethylidene)amino)oxy)succinate (27 g, 24.98 mmol) in Acetonitrile (300 mL) was added sodium iodide (5.62 g, 37.5 mmol). The mixture was stirred at room temperature over 1.5 h. LCMS indicated completion of the reaction. The solid was filtered off, the filtrate was concentrated under vacuum, and the residue was purified by CombiFlash Rf automated silica gel chromatography (330 g column), eluting with EtOAc/Hexanes (0-50%) to afford (S)-4-tert-butyl 1-(4-methoxybenzyl) 2-(((Z)-(2-(((5R,6R,7R)-2-((benzhydryloxy)carbonyl)-3-(iodomethyl)-5-oxido-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-7-yl)amino)-1-(2-((tert-butoxycarbonyl)amino)-5-chlorothiazol-4-yl)-2-oxoethylidene)amino)oxy)succinate (18 g, 14.97 mmol, 59.9% yield) as a red-brown solid. LCMS: (M+H)+: 1118.1
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:19]#[C:20][C:21]4[CH:31]=[CH:30][C:24]([C:25]([O:27]CC)=[O:26])=[CH:23][N:22]=4)[CH:17]=3)[S:12][C:11]([CH3:33])([CH3:32])[CH:10]=2)=[CH:5][CH:4]=1)[CH3:2].[OH-].[Na+].Cl>C1COCC1.CCO>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH2:19][CH2:20][C:21]4[CH:31]=[CH:30][C:24]([C:25]([OH:27])=[O:26])=[CH:23][N:22]=4)[CH:17]=3)[S:12][C:11]([CH3:32])([CH3:33])[CH:10]=2)=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccc(CC)cc2)=CC(C)(C)S3)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCc1ccc(C2=CC(C)(C)Sc3ccc(CCc4ccc(C(=O)O)cn4)cc32)cc1
Temperature: 40 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
To a solution of ethyl 6-[[4-(4-ethylphenyl)-2,2-dimethyl-(2H)-thiochromen-6-yl]-ethynyl]-nicotinate (Compound 241, 110.0 mg, 0.24 mmol) in 3.0 mL THF and 3.0 mL EtOH was added NaOH (120.0 mg, 3.0 mmol, 3.0 mL of a 1M aqueous solution). This mixture was heated to 40° C. for 1 hour, cooled to room temperature, and the resulting solution was stirred overnight. The reaction mixture was acidified with 10% aqueous HCl and extracted with EtOAc. The combined organic layers were washed with H2O, saturated aqueous NaCl, and dried (Na2SO4) before removing the solvent under reduced pressure to give 100 mg (96%) of the title compound as a colorless solid. 1H NMR (300 MHz, d6 -acetone) δ: 9.08 (1H, d, J=2.0 Hz), 8.30 (1H, dd, J=2.2, 8.2 Hz), 7.66 (1H, d, J=8.2 Hz), 7.46 (2H, s), 7.31-7.21 (5H, m), 5.95 (1H, s), 2.69 (2H, q, J=7.6 Hz), 1.48 (6H, s), 1.25 (3H, t, J=7.6 Hz).
Reaction SMILES: N#N.CCN(CC)CC.[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH2:22][C:23]([OH:25])=O)[CH:15]=[C:16]([O:20][CH3:21])[C:17]=1[O:18][CH3:19].[CH3:26][O:27][C:28]([C:30]1[CH:34]=[C:33]([C:35]2[CH:40]=[CH:39][C:38]([NH2:41])=[CH:37][C:36]=2[N+:42]([O-:44])=[O:43])[O:32][C:31]=1[CH3:45])=[O:29]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:26][O:27][C:28]([C:30]1[CH:34]=[C:33]([C:35]2[CH:40]=[CH:39][C:38]([NH:41][C:23](=[O:25])[CH2:22][C:14]3[CH:15]=[C:16]([O:20][CH3:21])[C:17]([O:18][CH3:19])=[C:12]([O:11][CH3:10])[CH:13]=3)=[CH:37][C:36]=2[N+:42]([O-:44])=[O:43])[O:32][C:31]=1[CH3:45])=[O:29]
Reactant: COC(=O)c1cc(-c2ccc(N)cc2[N+](=O)[O-])oc1C
Reactant: COc1cc(CC(=O)O)cc(OC)c1OC
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(-c2ccc(NC(=O)Cc3cc(OC)c(OC)c(OC)c3)cc2[N+](=O)[O-])oc1C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 55 %

Procedure:
(The following reaction is done in an anhydrous N2 atmosphere.) Suspend EDCHCl (138 mg, 0.72 mmol) and Et3N (101 μL, 0.72) in anhydrous DCM (4.5 mL) and stir the resulting solution for 5 min at rt. Add 2-(3,4,5-Trimethoxy-phenyl)-acetic acid (163 mg, 0.72 mmol) and DMAP (8 mg, 0.07 mmol) and stir the resulting solution for 10 min. Add 5-(4-Amino-2-nitro-phenyl)-2-methyl-furan-3-carboxylic acid methyl ester (58) (100 mg, 0.36 mmol) and stir the reaction solution for 22 h at rt. Quench reaction solution with sat. aqu. NH4Cl and water, separate layers and extract aqu. layer with DCM (3 times). Wash the combined organic layer with water and brine and dry with Na2SO4. Purify the crude product by preparative radial chromatography (silica gel, EtOAc/CyH 1+1) to obtain 2-Methyl-5-{2-nitro-4-[2-(3,4,5-trimethoxy-phenyl)-acetylamino]-phenyl}-furan-3-carboxylic acid methyl ester (59) (96 mg, 55%) as an yellow solid. 1H NMR (400 MHz, CDCl3): 2.55 (s, 3H); 3.65 (s, 2H); 3.79 (s, 3H); 3.81 (s, 6H); 3.82 (s, 3H); 6.50 (s, 2H); 6.77 (s, 1H); 7.53 (d, 1H, J=8.6 Hz); 7.66 (dd, 1H, J1=8.6 Hz, J2=2.0 Hz); 7.93 (br.s, 1 H); 7.96 (d, 1H, J=2.0 Hz).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.[CH2:9]([O:11][C:12]1[CH:17]=[CH:16][C:15]([S:18](N2CCC(O)CC2C)(=[O:20])=[O:19])=[CH:14][C:13]=1[C:29]1[NH:34][C:33](=[O:35])[C:32]2=[C:36]([CH3:40])[N:37]=[C:38]([CH3:39])[N:31]2[N:30]=1)[CH3:10]>>[CH2:9]([O:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([N:6]2[CH2:7][CH2:8][CH:3]([CH2:2][OH:1])[CH2:4][CH2:5]2)(=[O:19])=[O:20])=[CH:14][C:13]=1[C:29]1[NH:34][C:33](=[O:35])[C:32]2=[C:36]([CH3:40])[N:37]=[C:38]([CH3:39])[N:31]2[N:30]=1)[CH3:10]
Reactant: CCOc1ccc(S(=O)(=O)N2CCC(O)CC2C)cc1-c1nn2c(C)nc(C)c2c(=O)[nH]1
Reactant: OCC1CCNCC1
Product: CCOc1ccc(S(=O)(=O)N2CCC(CO)CC2)cc1-c1nn2c(C)nc(C)c2c(=O)[nH]1

Procedure:
By the same method, starting with 100 mg (0.261 mmol) of 4-ethoxy-3-(5,7-dimethyl-4-oxo-3,4-dihydroimidazo[5,1-][1,2,4]triazin-2-yl)-benzenesulphonyl chloride and 90 mg (0.784 mmol) of 4-hydroxymethylpiperidine, 22 mg (18% of theory) of 2-[2-ethoxy-5-(4-hydroxy-methylpiperidine-1-sulphonyl)-phenyl]-5,7-dimethyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one are obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[N:20]=[C:19]([C:24]([O:26]CC)=[O:25])[CH:18]=[N:17]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CCO.C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[N:20]=[C:19]([C:24]([OH:26])=[O:25])[CH:18]=[N:17]3)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cnc2cc(N3CCN(C(=O)OC(C)(C)C)CC3)ccc2n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc3nc(C(=O)O)cnc3c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.8 %

Procedure:
To a solution of ethyl 6-(4-(tert-butoxycarbonyl)piperazin-1-yl)quinoxaline-2-carboxylate (500 mg, 1.3 mmol) in EtOH/THF (5 mL) was added NaOH (5 ml, 2 mmol) followed by stirring for 2 hrs at r.t. After extraction by EA, the combined organic layers were concentrated in vacuo to yield 6-(4-(tert-butoxycarbonyl)piperazin-1-yl)quinoxaline-2-carboxylic acid as a red solid (260 mg, yield: 56%).
Reaction SMILES: [CH2:1]([C:5]([CH2:10][CH2:11][CH2:12][CH3:13])([CH2:8][OH:9])[CH2:6][OH:7])[CH2:2][CH2:3][CH3:4].[CH3:14]I>>[CH2:1]([C:5]([CH2:10][CH2:11][CH2:12][CH3:13])([CH2:6][O:7][CH3:14])[CH2:8][OH:9])[CH2:2][CH2:3][CH3:4]
Reactant: CI
Reactant: CCCCC(CO)(CO)CCCC
Product: CCCCC(CO)(CCCC)COC

Procedure:
2,2-Di-n-butyl-3-methoxy-1-propanol was prepared from 2,2-di-n-butyl-1,3-propandiol and methyl iodide through the same procedure as described above.
Reaction SMILES: [C:1]1([C:7]2[N:22]=[C:10]3[CH:11]=[C:12]([C:16]4[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=4)[CH:13]=[C:14]([NH2:15])[N:9]3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30][C:31](Cl)=[O:32]>>[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30][C:31]([NH:15][C:14]1[N:9]2[N:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:22]=[C:10]2[CH:11]=[C:12]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[CH:13]=1)=[O:32]
Reactant: O=C(Cl)Cc1ccccc1Cl
Reactant: Nc1cc(-c2ccncc2)cc2nc(-c3ccccc3)nn12
Product: O=C(Cc1ccccc1Cl)Nc1cc(-c2ccncc2)cc2nc(-c3ccccc3)nn12

Procedure:
The title compound, MS m/e (%): 440 (M+H+, 100), was prepared in accordance with the general method of example 31 from 2-phenyl-7-pyridin-4-yl-[1,2,4]triazolo[1,5-a]pyridin-5-ylamine and 2-chlorophenylacetyl chloride.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.Cl[CH:8]([CH2:12][CH:13]=O)[C:9](=[O:11])[CH3:10]>C(O)C>[CH3:13][C:12]1[N:1]=[C:2]2[N:6]([C:8]=1[C:9](=[O:11])[CH3:10])[CH:5]=[CH:4][S:3]2
Reactant: CC(=O)C(Cl)CC=O
Reactant: Nc1nccs1
Solvent: CCO
Product: CC(=O)c1c(C)nc2sccn12
Yield: 11.7 %

Procedure:
2-Aminothiazole was recrystallized from anhydrous ethanol, filtered and dried before use. A solution of 2-aminothiazole (16) (20.9 g, 202.4 mmoL) and 3-Chloro-2,5-pentanedione (2) (33.7 g, 97%, 242.9 mmol, 1.2 eq) in 180 mL of anhydrous ethanol was refluxed for 72 h in an oil bath. The black reaction mixture was cooled and concentrated under reduced pressure. The residue was treated with saturated sodium bicarbonate solution in portions, and then extracted with dichloromethane. The organic phase was dried and concentrated. The residue was purified by flash chromatography on a silica gel column using dichloromethane-methanol (80:1). The product fractions were collected (TLC, Rf 0.60 neutral form; Rf=0.5 salt form, dichloromethane-methanol 40:1) and concentrated providing white solid product 17 in 11.7% yield, 1.6 g neutral form and 3.2 g salt form. 1H NMR (CDCl3) δ 2.55 (s, 3H, 5-COCH3), 2.70 (s, 3H, 6-CH3), 6.78 (d, 1H, J=4.8 Hz), 8.39 (d, 1H, J=4.8 Hz).
Reaction SMILES: C([O-])(=O)C.[NH4+].[OH:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=1[OH:15])[CH:10]=O.[N+:16]([CH3:19])([O-:18])=[O:17]>>[N+:16]([CH:19]=[CH:10][C:9]1[CH:8]=[C:7]([OH:6])[C:14]([OH:15])=[CH:13][CH:12]=1)([O-:18])=[O:17]
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1ccc(O)c(O)c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: O=[N+]([O-])C=Cc1ccc(O)c(O)c1
Yield: 61 %

Procedure:
Ammonium acetate (5.6 g, 72.73 mmol, 1.00 equiv) was added to a solution of 3,4-dihydroxybenzaldehyde (10 g, 72.41 mmol, 1.00 equiv) and nitromethane (50 mL). The resulting mixture was heated at reflux for about 16 hours, and then concentrated in vacuo. The resulting residue was then purified by silica gel column chromotagraphy (ethyl acetate/petroleum ether (1:5)) to give the title compound as a yellow oil (8 g, yield=61%).
Reaction SMILES: [CH3:1][C:2]1[S:13][C:5]2[CH2:6][N:7]([CH3:12])[CH2:8][CH2:9][CH:10]([OH:11])[C:4]=2[CH:3]=1.[C:14]([C:17]1[CH:22]=[CH:21][C:20](F)=[C:19]([Cl:24])[CH:18]=1)(=[O:16])[NH2:15]>>[C:14]([C:17]1[CH:22]=[CH:21][C:20]([O:11][CH:10]2[CH2:9][CH2:8][N:7]([CH3:12])[CH2:6][C:5]3[S:13][C:2]([CH3:1])=[CH:3][C:4]2=3)=[C:19]([Cl:24])[CH:18]=1)(=[O:16])[NH2:15]
Reactant: Cc1cc2c(s1)CN(C)CCC2O
Reactant: NC(=O)c1ccc(F)c(Cl)c1
Product: Cc1cc2c(s1)CN(C)CCC2Oc1ccc(C(N)=O)cc1Cl

Procedure:
The same method as in Example 1 was conducted using 2,7-dimethyl-5,6,7,8-tetrahydro-4H-thieno[2,3-c]azepin-4-ol (Reference Example 23) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 4-carbamoyl-2-chloro-1-fluorobenzene instead of 1-fluoronaphthalene to give the objective compound.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][N:8]1[C:12](=[O:13])[C:11]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:10]2[C:9]1=[O:18].C1OCCOCCOCCOCCOCCOC1.[CH:37]1(Br)[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1>CS(C)=O.O>[CH:37]1([O:7][N:8]2[C:9](=[O:18])[C:10]3[C:11](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:13])[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: BrC1CCCCC1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1OC1CCCCC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 92.5 %

Procedure:
Solid potassium carbonate (6.91 g, 50.0 mmol) was added to a solution of N-hydroxyphthalimide (4.08 g, 25.0 mmol) and 18-crown-6 (661 mg, 2.5 mmol) in dimethyl sulfoxide (62 mL), and the mixture was stirred at 25° C. for 5 min. To the mixture cyclohexyl bromide (12.3 mL, 100.0 mmol) was added, and the mixture stirred at 80° C. for 3 h. After ice-cooling, the mixture was poured into cold water and the resulting precipitate was collected by filtration in vacuo, washed with water (25 mL) and hexanes (15 mL) and dried in vacuo to afford 2-cyclohexyloxy-isoindole-1,3-dione (5.67 g, 93%) as a white solid which was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])/[C:3](/[CH3:8])=[CH:4]\[C:5]([OH:7])=[O:6].[NH3:11]>[OH-].[NH4+]>[NH2:11][C:3]([C:2]([F:10])([F:9])[F:1])([CH3:8])[CH2:4][C:5]([OH:7])=[O:6]
Reactant: C/C(=C/C(=O)O)C(F)(F)F
Reactant: N
Agent: [NH4+]
Agent: [OH-]
Product: CC(N)(CC(=O)O)C(F)(F)F

Procedure:
A solution of 3-trifluoromethylcrotonic acid (10 g) and liquid ammonia (23 ml) in ammonium hydroxide (27 ml sd=0.88) was heated in a closed steel vessel at 148°-152° C. for 16 hours evaporation of the cooled solution gave 3-amino-3-trifluoromethylbutyric acid (10.2 g), as a viscous colourless oil. ##STR6##
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]1[C:6]([F:15])=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][CH:9]=[CH:8]2.N1C=CC=CC=1.[Br:23]Br>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]1[C:6]([F:15])=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][C:9]([Br:23])=[CH:8]2
Reactant: BrBr
Reactant: COC(=O)Cc1ccc2ncccc2c1F
Solvent: c1ccncc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)Cc1ccc2ncc(Br)cc2c1F

Procedure:
To a solution of (5-fluoro-quinolin-6-yl)-acetic acid methyl ester (2.0 g, 9 mmol) in CCl4 (20 ml) and pyridine (1.48 ml, 18 mmol) was added bromine (0.9 ml, 18 mmol) dropwise at 5° C. The solution was heated to reflux for 20 minutes. After cooling, the reaction was quenched by sat. aq. NaHCO3 and the mixture extracted with dichloromethane and concentrated. The residue was purified by flash column chromatography to return the title compound (1.8 g, 66%). 1H-NMR (CDCl3, 300 MHz): 8.9 (d, 1H), 8.5 (d, 1H), 7.8 (d, 1H), 7.6 (m, 1H), 3.9 (d, 2H), 3.7 (s, 3H).
Reaction SMILES: [C:1]([O:14][C@H:15]([CH2:41][O:42][C:43](=[O:55])[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])[CH2:16][S:17][CH2:18][C@@H:19]([C:38](O)=[O:39])[NH:20][C:21](=[O:37])[O:22][CH2:23][CH:24]1[C:36]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:30]2[C:25]1=[CH:26][CH:27]=[CH:28][CH:29]=2)(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.[NH2:90][C:91]1([CH2:94][OH:95])[CH2:93][CH2:92]1>C(Cl)Cl>[C:43]([O:42][CH2:41][C@@H:15]([O:14][C:1](=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:16][S:17][CH2:18][C@H:19]([NH:20][C:21]([O:22][CH2:23][CH:24]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:30]=2[C:31]2[C:36]1=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:37])[C:38]([NH:90][C:91]1([CH2:94][OH:95])[CH2:93][CH2:92]1)=[O:39])(=[O:55])[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54]
Reactant: CCCCCCCCCCCC(=O)OC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)OC(=O)CCCCCCCCCCC
Reactant: NC1(CO)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCCCCCCCCC(=O)OC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)NC1(CO)CC1)OC(=O)CCCCCCCCCCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (5R,9R)-9-(dodecanoyloxy)-1-(9H-fluoren-9-yl)-3,12-dioxo-2,11-dioxa-7-thia-4-azatricosane-5-carboxylic acid (6, 1 eq) and HBTU (1.2 eq) in DCM (0.06 M) was added DIEA (3.5 eq), followed by (1-aminocyclopropyl) methanol hydrochloride (1.2 eq). The reaction was stirred at room temperature for 2 hours. The crude mixture was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 30-50% EtOAc/Hex to give (R)-3-((R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(1-(hydroxymethyl)cyclopropylamino)-3-oxopropylthio)propane-1,2-diyl didodecanoate.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[C:6]([O:12][CH3:13])[CH:5]=1.C1C(=O)N([Br:22])C(=O)C1.[O-]S([O-])=O.[Na+].[Na+]>CC#N>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:5]=[C:6]([O:12][CH3:13])[CH:7]=[C:8]([O:10][CH3:11])[C:9]=1[Br:22]
Reactant: COC(=O)c1cc(OC)cc(OC)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: COC(=O)c1cc(OC)cc(OC)c1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.7 %

Procedure:
3,5-Dimethoxy-benzoic acid methyl ester (4.0 g) was dissolved in MeCN (28 mL), and NBS (4.4 g ) was added at 0° C. After stirring at room temperature for 3 hours, saturated Na2SO3 (15 mL) was added. The mixture was evaporated under vacuum and extracted with ether (1×, 500 mL). After the solvent was removed, the crude material was subjected to silica gel chromatography using effluent of 10-40% ethyl acetate and hexanes. The fractions containing product were combined and the solvent was removed under reduced pressure to provide 2-bromo-3,5-dimethoxy-benzoic acid methyl ester (5.2 g, 93%) as a clear oil.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][CH:11]([CH2:14][OH:15])[CH2:12][OH:13])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O.[CH2:17]1[CH2:21][O:20][CH2:19][CH2:18]1>>[CH2:3]([O:10][CH:11]1[CH2:12][O:13][CH2:17][CH2:21][O:20][CH2:19][CH2:18][O:15][CH2:14]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: OCC(CO)OCc1ccccc1
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: c1ccc(COC2COCCOCCOC2)cc1
Temperature: 23 °C
Yield: 19 %

Procedure:
To a refluxing suspension of sodium hydride (60% in mineral oil, pre-washed with hexane, 84 mg, 2.1 mmol) in dry THF (5 mL), a solution of 17 (182 mg, 1.0 mmol) and di(ethyleneglycol)dimethanesulfonate (260 mg, 1.0 mmol) in dry THF (5 mL) was added dropwise. The resulting mixture was heated under reflux for 20 h, afterward was cooled to 23° C. and H2O (2 mL) was added. The solvent was removed and the aqueous phase was extracted with CHCl3. The organic extracts were washed several times with water, dried (Na2SO4) and evaporated. The residue was purified by flash-chromatography (2:3 CH2Cl2/EtOAc) to afford 49 mg (19%) of 18 as a colourless oil: 1H NMR (CDCl3) δ 7.36-7.26 (m, 5H), 4.66 (s, 2H), 3.75-3.57 (m, 13H); MS (ESI) m/z 275 [M+Na]+.
Reaction SMILES: [NH:1]1[C:6](=[O:7])[C:5](=[O:8])[NH:4][C:3]2[S:9][CH:10]=[CH:11][C:2]1=2.[Br:12]Br>C(O)(=O)C>[Br:12][C:10]1[S:9][C:3]2[NH:4][C:5](=[O:8])[C:6](=[O:7])[NH:1][C:2]=2[CH:11]=1
Reactant: O=c1[nH]c2ccsc2[nH]c1=O
Reactant: BrBr
Solvent: CC(=O)O
Product: O=c1[nH]c2cc(Br)sc2[nH]c1=O
Yield: 90.6 %

Procedure:
Thieno[2,3-b]pyrazine-2,3(1H,4H)-dione (0.10 g, 0.59 mmol) was reacted with bromine (0.095 g, 0.59 mmol) in acetic acid following the procedure outlined in example 3 (Method E). Yield 0.132 g (91%) of the title compound. M.p. >300° C. 1H-NMR (DMSO-D6, δ): 6.87 (s, 1H), 12.05 (s, 2H).
Reaction SMILES: [OH:1][N:2]1[CH:6]=[CH:5][CH:4]=[N:3]1.[CH3:7][N:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:9](Cl)=[O:10]>CCOC(C)=O.CCCCCCC>[N:2]1([O:1][C:9](=[O:10])[N:8]([CH3:7])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[N:3]1
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: On1cccn1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CN(C(=O)On1cccn1)c1ccccc1

Procedure:
The title compound was prepared from 1-hydroxypyrazole and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to flash chromatography (Quad flash 25, EtOAc-heptane) (79%, oil which slowly crystallizes). HPLC-MS m/z=218.1 (M+1), Rt: 2.82 min. Mp 63-67° C.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[CH2:12][NH:11][CH2:10][CH2:9][C:7]=2[N:8]=1.Br[C:14]1[CH:15]=[C:16]([CH:27]=[CH:28][N:29]=1)[C:17]([NH:19][C:20]1[CH:21]=[C:22]([CH3:26])[CH:23]=[CH:24][CH:25]=1)=[O:18]>>[CH3:26][C:22]1[CH:21]=[C:20]([NH:19][C:17](=[O:18])[C:16]2[CH:15]=[CH:14][N:29]=[C:28]([N:11]3[CH2:10][CH2:9][C:7]4[N:8]=[C:3]([S:2][CH3:1])[N:4]=[CH:5][C:6]=4[CH2:12]3)[CH:27]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: Cc1cccc(NC(=O)c2ccnc(Br)c2)c1
Reactant: CSc1ncc2c(n1)CCNC2
Product: CSc1ncc2c(n1)CCN(c1cc(C(=O)Nc3cccc(C)c3)ccn1)C2

Procedure:
In a manner similar to that described for Example 138, 2-(methylsulfanyl)-5,6,7,8-tetrahydropyrido[4,3-d]-pyrimidine and 2-bromo-N-m-tolyl-isonicotinamide were converted to the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH:6]2[CH2:7][C:8]([CH2:10][CH:3]1[CH2:4][CH2:5]2)=O.[CH2:11]([N:13]([CH2:31][CH3:32])[C:14]([C:16]1[CH:17]=[CH:18][C:19]2[C:20](=O)[C:21]3[C:26]([O:27][C:28]=2[CH:29]=1)=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:15])[CH3:12]>>[CH2:31]([N:13]([CH2:11][CH3:12])[C:14]([C:16]1[CH:17]=[CH:18][C:19]2[C:20](=[C:8]3[CH2:10][CH:3]4[N:2]([CH3:1])[CH:6]([CH2:5][CH2:4]4)[CH2:7]3)[C:21]3[C:26]([O:27][C:28]=2[CH:29]=1)=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:15])[CH3:32]
Reactant: CN1C2CCC1CC(=O)C2
Reactant: CCN(CC)C(=O)c1ccc2c(=O)c3ccccc3oc2c1
Product: CCN(CC)C(=O)c1ccc2c(c1)Oc1ccccc1C2=C1CC2CCC(C1)N2C

Procedure:
Following Procedure 7 and substituting tropinone for N-carbethoxynortropinone, compound 6a was converted to the title compound. MS m/z=403.2 (M+1); 1H NMR 300 MHz (CDCl3) δ 1.2 (br s, 6H), 1.9 (m, 2H), 2.5 (s, 3H), 2.8 (m, 2H), 3.1 (m, 2H), 3.3 (m, 2H), 3.4 (br s, 2H), 3.6 (m, 4H), 7.0-7.3 (m, 7H).