Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[Br:10]Br>Br>[BrH:10].[Br:10][CH2:2][C:1]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1)=[O:3]
Reactant: BrBr
Reactant: CC(=O)c1ccncc1
Agent: Br
Product: O=C(CBr)c1ccncc1
Temperature: 70 °C
Reaction time: 2.5 h

Procedure:
4-Acetylpyridine (10 g) was combined with 48% hydrogen bromide solution (18 ml) and heated to 70° C. Bromine (4.7 ml) dissolved in 48% hydrogen bromide solution (5 ml) was then added dropwise and heating then continued for 2.5 h. The precipitate which had formed was collected by filtration, washed with 1:1 methanol:hexane (20 ml) and dried to give a cream solid (19.5 g) as a 2:1 mixture of product:starting material by 1H nmr.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:12]([OH:14])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[NH2:48][C:49]1[CH:111]=[CH:110][C:52]([C:53]([NH:55][C:56]2[CH:57]=[C:58]3[C:63](=[CH:64][CH:65]=2)[N:62]=[C:61]([N:66]2[CH2:71][C@@H:70]([NH:72][C:73]([O:75][C:76]([CH3:79])([CH3:78])[CH3:77])=[O:74])[CH2:69][C@@H:68]([NH:80][C:81]([O:83][C:84]([CH3:87])([CH3:86])[CH3:85])=[O:82])[CH2:67]2)[C:60]([N:88]2[CH2:93][C@@H:92]([NH:94][C:95]([O:97][C:98]([CH3:101])([CH3:100])[CH3:99])=[O:96])[CH2:91][C@@H:90]([NH:102][C:103]([O:105][C:106]([CH3:109])([CH3:108])[CH3:107])=[O:104])[CH2:89]2)=[N:59]3)=[O:54])=[CH:51][CH:50]=1>CN(C=O)C.CCOC(C)=O>[C:76]([O:75][C:73]([NH:72][C@@H:70]1[CH2:69][C@H:68]([NH:80][C:81]([O:83][C:84]([CH3:85])([CH3:86])[CH3:87])=[O:82])[CH2:67][N:66]([C:61]2[C:60]([N:88]3[CH2:93][C@@H:92]([NH:94][C:95]([O:97][C:98]([CH3:101])([CH3:100])[CH3:99])=[O:96])[CH2:91][C@@H:90]([NH:102][C:103]([O:105][C:106]([CH3:108])([CH3:107])[CH3:109])=[O:104])[CH2:89]3)=[N:59][C:58]3[C:63](=[CH:64][CH:65]=[C:56]([NH:55][C:53]([C:52]4[CH:110]=[CH:111][C:49]([NH:48][C:12]([C:3]5[CH:4]=[CH:5][C:6]6[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=6)[C:2]=5[OH:1])=[O:14])=[CH:50][CH:51]=4)=[O:54])[CH:57]=3)[N:62]=2)[CH2:71]1)=[O:74])([CH3:77])([CH3:78])[CH3:79]
Reactant: O=C(O)c1ccc2ccccc2c1O
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CN(c2nc3ccc(NC(=O)c4ccc(N)cc4)cc3nc2N2C[C@H](NC(=O)OC(C)(C)C)C[C@H](NC(=O)OC(C)(C)C)C2)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CN(c2nc3ccc(NC(=O)c4ccc(NC(=O)c5ccc6ccccc6c5O)cc4)cc3nc2N2C[C@H](NC(=O)OC(C)(C)C)C[C@H](NC(=O)OC(C)(C)C)C2)C1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 12.5 %

Procedure:
1-Hydroxy-naphthalene-2-carboxylic acid (142) (0.016 g, 0.085 mmol) was dissolved in DMF (0.8 mL) and HBTU (0.032 g, 0.085 mmol) followed by iPr2EtN (0.022 mL, 0.128 mmol) were added. The mixture was shaken at room temperature for 25 minutes. 4-Amino-N-(2,3-bis-((3R,5S)-3,5-bis-(tert-Butoxycarbonylamino)-piperidin-1-yl)-quinoxalin-6-yl)-benzamide (252) (0.06 g, 0.068 mmol) was added and the mixture was shaken at room temperature for 16 h. The mixture was diluted with EtOAc, washed with sodium bicarbonate and brine via extraction, dried over MgSO4 and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of hexane and EtOAc gave the desired product (253) (0.009 g, 0.0085 mmol, 12.5% yield). LC-MS (ESI): (exact mass: 1060.54, mol. wt: 1061.23) m/e=1062.0 [M+1]+.
Reaction SMILES: [CH2:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])[CH2:2][CH2:3][CH3:4].[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][OH:28])=[CH:23][CH:22]=1>CN(C=O)C>[CH2:1]([N:5]1[C:9](=[O:10])[C:8]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([CH2:27][OH:28])=[CH:23][CH:22]=2)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])[CH2:2][CH2:3][CH3:4]
Reactant: Nc1ccc(CO)cc1
Reactant: CCCCN1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Solvent: CN(C)C=O
Product: CCCCN1C(=O)C(Nc2ccc(CO)cc2)=C(c2ccccc2)S1(=O)=O
Temperature: 140 °C
Yield: 4.7 %

Procedure:
2-Butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide (110 mg, 0.331 mmol) was dissolved in dry DMF (0.5 mL) under nitrogen atmosphere. (4-Aminophenyl)methanol (122 mg, 0.991 mmol) was added and the reaction mixture was heated in a microwave reactor for 25 mins at 140° C. The crude product was purified by preparative HPLC affording the title compound (6 mg, 4.7%). 1H NMR (500 MHz, CD3CN): δ 1.00 (t, 3H), 1.43-1.52 (m, 2H), 1.78-1.85 (m, 2H), 3.03 (t, 1H), 3.75 (t, 2H), 4.40 (d, 2H), 6.77 (d, 2H), 6.97 (d, 2H), 7.13-7.19 (m, 4H), 7.24-7.28 (m, 1H), 7.76 (bs, 1H).
Reaction SMILES: [CH:1]1[C:18]2=[C:19]3[C:8]([C:9]4[C:20]5[C:13](=[CH:14][CH:15]=[CH:16][C:17]2=5)[CH:12]=[CH:11][CH:10]=4)=[CH:7][CH:6]=[CH:5][C:4]3=[CH:3][CH:2]=1.[Br:21]N1C(=O)CCC1=O>ClCCl>[Br-:21].[CH:16]1[C:17]2=[C:20]3[C:9]([C:8]4[C:19]5[C:4](=[CH:3][CH:2]=[CH:1][C:18]2=5)[CH:5]=[CH:6][CH:7]=4)=[CH:10][CH:11]=[CH:12][C:13]3=[CH:14][CH:15]=1
Reactant: O=C1CCC(=O)N1Br
Agent: c1cc2cccc3c4cccc5cccc(c(c1)c23)c54
Solvent: ClCCl
Product: [Br-]
Reaction time: 0.08 h

Procedure:
After 3.0 g (11 mmol) of perylene was dissolved in 700 mL of dichloromethane, the solution was stirred for 5 minutes. To the solution, 2.11 g (12 mmol, 1.1 eq) of N-bromosuccinimide was dropwise added slowly at room temperature, followed by stirring overnight. The reaction solution was purified by silica gel column chromatography using a developing solvent adjusted to dichloromethane:hexane=1:1 to remove N-bromosuccinimide. After the solvent was concentrated, yellow crystals (yield 90%) were obtained. The compound was identified by 1H-NMR and ESI-MS.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[N+:11]([O-])([OH:13])=[O:12].S(=O)(=O)(O)O.O>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: O=C(O)c1ccc(Cl)cc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: O
Product: O=C(O)c1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 42 °C

Procedure:
78.25 g (0.5mol) of 4-chlorobenzoic acid were suspended in 200 ml of methylene chloride, followed by the addition with stirring at room temperature of 33.5 g (0.55 mol) of 98% nitric acid. The mixture was heated with stirring to boiling temperature, followed by the dropwise addition over a period of 1 hour at that temperature of 63.5 g of 100% sulphuric acid. After cooling to 42° C., the mixture was stirred for 2 hours at that temperature. The reaction mixture was then poured onto 300 ml of water, and the methylene chloride subsequently distilled off. The residual suspension was filtered, the residue washed with water and dried at 90° C., giving 98.4 g (97.3% of the theoretical yield) of 4-chloro-3-nitrobenzoic acid melting at 182.9° to 184.0° C. with a purity of 99.5%. The content of unreacted 4-chlorobenzoic acid amounted to only about 0.1%.
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH2:5][CH:4]([C:7]2[C:15]([F:16])=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[C:9]([F:17])[CH:8]=2)[CH2:3]1.[C:18](OC(=O)C)(=[O:20])[CH3:19]>C(O)(=O)C>[C:18]([NH:1][CH:2]1[CH2:6][CH2:5][CH:4]([C:7]2[C:15]([F:16])=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[C:9]([F:17])[CH:8]=2)[CH2:3]1)(=[O:20])[CH3:19]
Reactant: NC1CCC(c2cc(F)c(C(=O)O)cc2F)C1
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)NC1CCC(c2cc(F)c(C(=O)O)cc2F)C1

Procedure:
A solution of 24.1 g (0.1 mol) of 4-[3(amino)cyclopentyl]-2,5-difluorobenzoic acid in a mixture of 50 ml of acetic anhydride and 100 ml of acetic acid was heated at reflux for 6 hours. The solvent was removed in vacuo and the residue triturated with water. The solid was removed by filtration, washed with water, and dried in vacuo to give 25.3 g of the title compound.
Reaction SMILES: C([O:3][C:4](=[O:25])[CH2:5][O:6][C:7]1[C:22]([Cl:23])=[C:21]([Cl:24])[C:10]2[S:11][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:13]([CH3:14])[C:9]=2[CH:8]=1)C>C(O)C.[OH-].[Na+]>[Cl:23][C:22]1[C:7]([O:6][CH2:5][C:4]([OH:25])=[O:3])=[CH:8][C:9]2[C:13]([CH3:14])=[C:12]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[S:11][C:10]=2[C:21]=1[Cl:24]
Reactant: CCOC(=O)COc1cc2c(C)c(-c3ccccc3)sc2c(Cl)c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1c(-c2ccccc2)sc2c(Cl)c(Cl)c(OCC(=O)O)cc12
Yield: 89 %

Procedure:
A mixture of 1.5 g of ethyl[ (6,7-dichloro-3-methyl-2-phenylbenzo[b]-thien-5-yl)oxy]acetate in 50 ml of 95% ethanol and 50 ml of 15% aqueous sodium hydroxide is stirred under reflux for 1 hour. The mixture is concentrated under vacuum to dryness. The residue is triturated with water, cooled to 0° and acidified with conc hydrochloric acid. The solid product is extracted exhaustively with a mixture of ethyl ether-ethyl acetate (1:1) and the ether extracts are washed and dried over anhydrous magnesium sulfate. Removal of the solvents under reduced pressure leaves a tan-colored residue which is recrystallized from acetone to give 1.24 g of [(6,7-dichloro-3-methyl-2-phenylbenzo[b]thien-5-yl)oxy]acetic acid as shiny platelets, mp 232°-233° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:18]3[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][C:19]=3[CH:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)O)[CH:8]=2)[N:3]=1.C(OCC)(=O)C>C(O)C.[OH-].[Pd+2].[OH-].[Pd]>[CH2:25]([C:19]1[CH:20]=[CH:21][CH:22]=[C:23]([CH3:24])[C:18]=1[C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH2:1])[C:11]([N:12]1[CH2:13][CH2:14][O:15][CH2:16][CH2:17]1)=[CH:10]2)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: Cc1cccc(C(O)c2ccccc2)c1-c1ccc2nc(N)c(N3CCOCC3)cc2c1
Agent: [Pd+2]
Agent: [Pd]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1cccc(Cc2ccccc2)c1-c1ccc2nc(N)c(N3CCOCC3)cc2c1
Reaction time: 72 h

Procedure:
A mixture of (2-(2-amino-3-morpholinoquinolin-6-yl)-3-methylphenyl)(phenyl)methanol (0.245 g, 0.576 mmol) and palladium hydroxide, 20 wt % Pd (dry basis) on carbon, wet (0.380 g, 2.71 mmol) in ethanol (15 mL) and ethyl acetate (5.0 mL) was stirred under H2 balloon overnight. 400 mg more Pd(OH)2 was added and stirred for 72 h. The product mixture was filtered through a pad of celite. The filtrate was concentrated and purified on HPLC (10-100% MeCN/H2O with 0.1% TFA) to afford 6-(2-benzyl-6-methylphenyl)-3-morpholinoquinolin-2-amine as white solid. MS (ESI, pos. ion) m/z: 410 (M+1).
Reaction SMILES: C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.[Br:19][C:20]1[CH:21]=[C:22]([CH:26]=[C:27]([N+:29]([O-:31])=[O:30])[CH:28]=1)[C:23]([OH:25])=O.[CH3:32][O:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41][NH2:42].CCN(CC)CC>CCOC(C)=O>[Br:19][C:20]1[CH:21]=[C:22]([CH:26]=[C:27]([N+:29]([O-:31])=[O:30])[CH:28]=1)[C:23]([NH:42][CH2:41][CH2:40][O:39][CH2:38][CH2:37][O:36][CH2:35][CH2:34][O:33][CH3:32])=[O:25]
Reactant: O=C(O)c1cc(Br)cc([N+](=O)[O-])c1
Reactant: COCCOCCOCCN
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COCCOCCOCCNC(=O)c1cc(Br)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.8 %

Procedure:
T3P, 50 wt % in EtOAc (25 mL, 42.0 mmol) was slowly added to a solution of 3-bromo-5-nitrobenzoic acid (7.05 g, 28.7 mmol), 2-(2-(2-methoxyethoxy)ethoxy)ethanamine (4 g, 24.25 mmol) and Et3N (12 mL, 86 mmol) in EtOAc (50 mL) whilst immersed in an ice-bath. Once the addition was complete, the ice bath was removed and the reaction allowed to stir at rt for 2 h. The mixture was partitioned between sat. aq. NaHCO3 solution (100 mL) and EtOAc (100 mL). The organic layer was washed with aq K2CO3 solution (10 g in 100 mL) and brine (100 mL), before being dried (MgSO4), filtered and concentrated in vacuo to afford the sub-title compound (8.23 g) as a brown oil.
Reaction SMILES: [CH2:1]([N:3]([CH2:29][CH3:30])[CH2:4][CH2:5][NH:6][C:7](=[O:28])[C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:25])[CH2:16][O:17]CC2C=CC=CC=2)=[CH:10][C:9]=1[O:26][CH3:27])[CH3:2]>CO.[Pd]>[CH2:29]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][NH:6][C:7](=[O:28])[C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:25])[CH2:16][OH:17])=[CH:10][C:9]=1[O:26][CH3:27])[CH3:30]
Reactant: CCN(CC)CCNC(=O)c1ccc(NC(=O)COCc2ccccc2)cc1OC
Agent: [Pd]
Solvent: CO
Product: CCN(CC)CCNC(=O)c1ccc(NC(=O)CO)cc1OC
Reaction time: 1.5 h
Yield: 22.6 %

Procedure:
340 mg (0.82 mmol) of N-(2-diethylamino-ethyl)-4-(2-benzyloxy-acetylamino)-2-methoxy-benzamide is mixed in 40 ml of methanol with 200 mg of palladium on carbon (10%), and it is hydrogenated for 1.5 hours at normal pressure and at room temperature. After the catalyst is drawn off on diatomaceous earth, the filtrate is concentrated by evaporation, and the residue is chromatographed on 10 g of Isolute NH2 (50 μm) with a gradient from methylene chloride. The correspondingly combined fractions are concentrated by evaporation and again on 20 g of Isolute NH2 (50 μm) with a gradient from cyclohexane to cyclohexane:methylene chloride=50:50, and 60 mg (22.6% of theory) of N-(2-diethylamino-ethyl)-4-(2-hydroxy-acetylamino)-2-methoxy-benzamide is obtained as an oil.
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[C:14]([CH3:15])=[CH:13][C:12]([C:16]2[N:20]=[C:19]([C:21]3[CH:26]=[C:25]([O:27][CH3:28])[N:24]=[C:23]([CH:29]4[CH2:33][CH2:32][CH2:31][CH2:30]4)[CH:22]=3)[O:18][N:17]=2)=[CH:11][C:10]=1[CH2:34][CH3:35])(=O)=O.[CH3:36][C:37]1([CH3:44])[O:41][CH:40]([CH2:42][NH2:43])[CH2:39][O:38]1>C(#N)C>[CH:29]1([C:23]2[CH:22]=[C:21]([C:19]3[O:18][N:17]=[C:16]([C:12]4[CH:13]=[C:14]([CH3:15])[C:9]([O:8][CH2:7][CH2:6][NH:43][CH2:42][CH:40]5[CH2:39][O:38][C:37]([CH3:44])([CH3:36])[O:41]5)=[C:10]([CH2:34][CH3:35])[CH:11]=4)[N:20]=3)[CH:26]=[C:25]([O:27][CH3:28])[N:24]=2)[CH2:30][CH2:31][CH2:32][CH2:33]1
Reactant: CC1(C)OCC(CN)O1
Reactant: CCc1cc(-c2noc(-c3cc(OC)nc(C4CCCC4)c3)n2)cc(C)c1OCCOS(C)(=O)=O
Solvent: CC#N
Product: CCc1cc(-c2noc(-c3cc(OC)nc(C4CCCC4)c3)n2)cc(C)c1OCCNCC1COC(C)(C)O1
Temperature: 65 °C
Reaction time: 16 h
Yield: 86.2 %

Procedure:
A mixture of 2-(4-(5-(2-cyclopentyl-6-methoxypyridin-4-yl)-1,2,4-oxadiazol-3-yl)-2-ethyl-6-methylphenoxy)ethyl methanesulfonate (195 mg, 0.389 mmol) and rac-2,2-dimethyl-1,3-dioxolane-4-methanamine (51 mg, 0.389 mmol) in acetonitrile (6 mL) is stirred at 65° C. for 16 h. The mixture is separated by prep. HPLC to give rac-2-(4-(5-(2-cyclopentyl-6-methoxypyridin-4-yl)-1,2,4-oxadiazol-3-yl)-2-ethyl-6-methylphenoxy)-N-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)ethanamine (180 mg) as a white solid. This material is dissolved in 2 N aq. HCl (1 mL) and dioxane (5 mL) and stirred at 60° C. for 1 h. The solvent is evaporated and the crude product is purified by prep. TLC eluting with DCM containing 15% of methanol followed by prep. HPLC to give the title compound (16 mg) as a white solid; LC-MS: tR=0.91 min, [M+H]+=497.11; 1H NMR (CD3OD): δ 7.82 (s, 1H), 7.80 (s, 1H), 7.48 (s, 1H), 7.22 (s, 1H), 4.00 (t, J=5.0 Hz, 2H), 3.98 (s, 3H), 3.82-3.89 (m, 1H), 3.53-3.63 (m, 2H), 3.20-3.30 (m, 1H), 3.08 (t, J=5.0 Hz, 2H), 2.88 (dd, J1=12.1 Hz, J2=3.7 Hz, 1H), 2.70-2.81 (m, 3H), 2.38 (s, 3H), 2.05-2.15 (m, 2H), 1.84-1.95 (m, 4H), 1.69-1.81 (m, 2H), 1.30 (t, J=7.5 Hz, 3H).
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[CH:23]=[CH:22][C:7]([C:8]([O:10][C:11]2[C:16]([F:17])=[C:15]([F:18])[C:14]([F:19])=[C:13]([F:20])[C:12]=2[F:21])=[O:9])=[CH:6][CH:5]=1.[C:24](Cl)([Cl:26])=[S:25]>O.C(Cl)(Cl)Cl>[Cl:26][C:24]([O:3][C:4]1[CH:23]=[CH:22][C:7]([C:8]([O:10][C:11]2[C:12]([F:21])=[C:13]([F:20])[C:14]([F:19])=[C:15]([F:18])[C:16]=2[F:17])=[O:9])=[CH:6][CH:5]=1)=[S:25]
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)c1ccc(O)cc1
Reactant: S=C(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=C(Oc1c(F)c(F)c(F)c(F)c1F)c1ccc(OC(=S)Cl)cc1
Temperature: 5 °C

Procedure:
A solution of 1.34 g of sodium hydroxide in water was added dropwise over 15 minutes with vigorous stirring to a solution of 8.45 g of pentafluorophenyl 4-hydroxybenzoate and 3.2 ml of thiophosgene in 100 ml of chloroform at -20° C. The mixture was stirred at 5° C. until the reaction was complete and the organic layer separated, dried over calcium chloride and the solvent evaporated. Chromatography of the residue on silica gel eluting with hexane/ethyl acetate mixtures afforded 5.9 g of the title compound.
Reaction SMILES: [CH:1]([F:9])([F:8])[C:2]([F:7])([F:6])[C:3](Cl)=[O:4].N1C=CC=CC=1.[CH:16]([O:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH2:17].O>ClCCl>[CH2:19]([O:18][CH:16]=[CH:17][C:3](=[O:4])[C:2]([F:7])([F:6])[CH:1]([F:9])[F:8])[CH2:20][CH2:21][CH3:22]
Reactant: C=COCCCC
Reactant: O=C(Cl)C(F)(F)C(F)F
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCOC=CC(=O)C(F)(F)C(F)F
Temperature: 0 °C
Reaction time: 15 h

Procedure:
With stirring and at 0° C., 25.0 g (152 mmol) of 3H-tetrafluoropropionyl chloride—dissolved in 20 ml dichloromethane—were added to a mixture of 14.4 g (182 mmol) of pyridine and 15.2 g (152 mmol) of butyl vinyl ether in 250 ml of dichloromethane. After the addition, stirring was continued at room temperature for another 15 h. 250 ml of water were then added to the mixture, and the organic phase was separated off, dried and concentrated. This gave 12.5 g (36% of theory) of a yellowish oil.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[S:12][N:11]=[C:10]([CH3:13])[N:9]=2)=[CH:6][CH:7]=1.FC(F)(F)C(O)=O.[NH:21]1[CH2:26][CH2:25][C:24]2([C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:28]=[CH:27]2)[CH2:23][CH2:22]1.C(=O)([O-])[O-].[K+].[K+]>>[CH3:13][C:10]1[N:9]=[C:8]([C:5]2[N:4]=[N:3][C:2]([N:21]3[CH2:26][CH2:25][C:24]4([C:34]5[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=5)[CH:28]=[CH:27]4)[CH2:23][CH2:22]3)=[CH:7][CH:6]=2)[S:12][N:11]=1
Reactant: Cc1nsc(-c2ccc(Cl)nn2)n1
Reactant: C1=CC2(CCNCC2)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Product: Cc1nsc(-c2ccc(N3CCC4(C=Cc5ccccc54)CC3)nn2)n1

Procedure:
The object product (22 mg, 25%) was obtained in the same manner as in Example 1 and using 3-chloro-6-(3-methyl-1,2,4-thiadiazol-5-yl)pyridazine (51 mg), spiro[indene-1,4′-piperidine] trifluoroacetate (105 mg) and potassium carbonate (70 mg).
Reaction SMILES: [C:1]([C:4]1[CH:14]=[CH:13][C:7]2[O:8][CH2:9][C:10](=[O:12])[NH:11][C:6]=2[CH:5]=1)(=O)[CH3:2].[SiH](CC)(CC)CC>C(O)(C(F)(F)F)=O>[CH2:1]([C:4]1[CH:14]=[CH:13][C:7]2[O:8][CH2:9][C:10](=[O:12])[NH:11][C:6]=2[CH:5]=1)[CH3:2]
Reactant: CC(=O)c1ccc2c(c1)NC(=O)CO2
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCc1ccc2c(c1)NC(=O)CO2
Temperature: 80 °C

Procedure:
To a solution of 6-Acetyl-2H-benzo[b][1,4]oxazin-3(4H)-one (14) (0.5 mmol) in TFA (4 mL) was added Et3SiH (1.0 mmol). The reaction was heated at 80° C. for 2 h and then concentrated in vacuo. The residue was treated with sat aqueous NaHCO3 and the resulting solid was isolated by filtration, washed with water and dried in vacuo to give a white solid: 1H NMR (DMSO-d6, 400 MHz): δ=10.63 (s, 1H), 6.81-6.87 (m, 1H), 6.71 (s, 1H), 6.74 (d, J=8.1 Hz, 1H), 4.51 (s, 2H), 2.46-2.54 (m, 2H), 1.12 ppm (t, J=7.6 Hz, 3H). ESI-MS: m/z 178.0 (M+H)+.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:13][CH2:12]1.CN(C)C=O.[H-].[Na+].[Si:29]([O:36][CH2:37][CH2:38]I)([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30]>CO.ClCCl.ClCCl.O1CCCC1>[Si:29]([O:36][CH2:37][CH2:38][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:13][CH2:12]1)([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30]
Reactant: CCOC(=O)N1CCC(Nc2nc3ccccc3[nH]2)CC1
Reactant: CC(C)(C)[Si](C)(C)OCCI
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCC(Nc2nc3ccccc3n2CCO[Si](C)(C)C(C)(C)C)CC1
Reaction time: 24 h

Procedure:
Combine (1H-benzimidazol-2-yl)(1-(ethoxycarbonyl)piperidin-4-yl)amine (4.00 g, 13.87 mmol) and dimethylformamide (12 mL) and tetrahydrofuran (60 mL). Cool in an ice-bath. Add sodium hydride (24 mg, 15.3 mmol). After 24 hours, add 2-(t-butyldimethylsilyloxy) ethyl iodide (3.97 g, 13.87 mmol). After 60 hours, add ice to quench the reaction. Evaporate the quenched reaction mixture in vacuo to remove most of the tetrahydrofuran. Partition the evaporated reaction mixture between water and ethyl acetate. Separate the layers and extract the organic layer three times with water. Dry the organic layer over MgSO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting sequentially with dichloromethane and then 5% methanol/dichloromethane to give (1-(2-(t-butyldimethylsilyloxy)ethyl)-1H-benzimidazol-2-yl)(1-(ethoxycarbonyl)piperidin-4-yl)amine: Rf=0.14 (silica gel, 40% ethyl acetate/dichloromethane).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][CH:12]([CH3:14])[CH3:13])=[C:3]1[C:15]([NH:17][C@H:18]([C:23]([NH:25][CH:26]([C:35](=[O:48])[CH2:36][O:37][C:38](=[O:47])[C:39]1[C:44]([Cl:45])=[CH:43][CH:42]=[CH:41][C:40]=1[Cl:46])[CH2:27][C:28]([O:30]C(C)(C)C)=[O:29])=[O:24])[CH2:19][CH:20]([CH3:22])[CH3:21])=[O:16].C(O)(C(F)(F)F)=O>>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][CH:12]([CH3:14])[CH3:13])=[C:3]1[C:15]([NH:17][C@H:18]([C:23]([NH:25][CH:26]([C:35](=[O:48])[CH2:36][O:37][C:38](=[O:47])[C:39]1[C:44]([Cl:45])=[CH:43][CH:42]=[CH:41][C:40]=1[Cl:46])[CH2:27][C:28]([OH:30])=[O:29])=[O:24])[CH2:19][CH:20]([CH3:21])[CH3:22])=[O:16]
Reactant: CC(C)Cc1c(C(=O)N[C@@H](CC(C)C)C(=O)NC(CC(=O)OC(C)(C)C)C(=O)COC(=O)c2c(Cl)cccc2Cl)n(C)c2ccccc12
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Cc1c(C(=O)N[C@@H](CC(C)C)C(=O)NC(CC(=O)O)C(=O)COC(=O)c2c(Cl)cccc2Cl)n(C)c2ccccc12
Yield: 60 %

Procedure:
Treatment of N-[(1-methyl-3-isobutyl-indole-2-carbonyl)leucinyl]-3-amino-5-(2,6-dichlorobenzoyl)oxy-4-oxo pentanoic acid, tert-butyl ester (63 mg, 0.089 mmol) with TFA as described in Example 80 gave the titled product (34.5 mg, 60%) as a white powder. MS C32H37Cl2N3O7, [M+H]+ =646, [M−H]−=644. TLC (CH2Cl2/MeOH, 90/10): Rf=0.23.
Reaction SMILES: [Cl:1][C:2]1[NH:7][C:6](=[O:8])[N:5]([CH3:9])[C:4](=[O:10])[CH:3]=1.[CH3:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Cl)=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[N:7]([CH2:17][C:16]2[CH:19]=[CH:20][C:13]([O:12][CH3:11])=[CH:14][CH:15]=2)[C:6](=[O:8])[N:5]([CH3:9])[C:4](=[O:10])[CH:3]=1
Reactant: Cn1c(=O)cc(Cl)[nH]c1=O
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(Cn2c(Cl)cc(=O)n(C)c2=O)cc1
Temperature: 60 °C

Procedure:
A mixture of 6-chloro-3-methylpyrimidine-2,4(1H,3H)-dione (16.2 g, 101 mmol), p-methoxybenzyl chloride (16.5 mL, 122 mmol) and potassium carbonate (7.0 g, 50.7 mmol) in anhydrous DMF (200 mL) is heated at 60° C. for 3 hours. Additional potassium carbonate (3.0 g, 21.7 mmol) is added, and the reaction mixture heated at 60° C. for another 3 hours. After hot filtration, the filtrate is evaporated to dryness under reduced pressure. The obtained oil is directly used for the synthesis in the next step. A small amount of product is further purified by silica-gel flash chromatography to give pure product as crystals. 1H NMR (400 MHz, MeOH-d4) δ 3.37 (s, 3H), 3.83 (s, 3H), 5.24 (s, 2H), 5.96 (s, 1H), 6.91 and 7.32 (AB, 4H, J=6.8 Hz). MS (FAB) m/z 281.23 [M+H]+.