Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[C:27](=[O:28])[N:7]2[CH:8]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([OH:26])[CH:21]=3)[C:9]3[NH:10][C:11]4[C:16]([C:17]=3[CH2:18][C:6]2([CH3:29])[C:5]1=[O:30])=[CH:15][C:14]([Cl:19])=[CH:13][CH:12]=4.[NH3:31]>CO>[NH2:31][CH2:2][CH2:3][N:4]1[C:27](=[O:28])[N:7]2[CH:8]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([OH:26])[CH:21]=3)[C:9]3[NH:10][C:11]4[C:16]([C:17]=3[CH2:18][C:6]2([CH3:29])[C:5]1=[O:30])=[CH:15][C:14]([Cl:19])=[CH:13][CH:12]=4
Reactant: CC12Cc3c([nH]c4ccc(Cl)cc34)C(c3cccc(O)c3)N1C(=O)N(CCBr)C2=O
Reactant: N
Solvent: CO
Product: CC12Cc3c([nH]c4ccc(Cl)cc34)C(c3cccc(O)c3)N1C(=O)N(CCN)C2=O
Temperature: 140 °C

Procedure:
To a solution of 200 mg (3aSR,10RS)-2-(2-Bromo-ethyl)-6-chloro-10-(3-hydroxy-phenyl)-3a-methyl-3a,4,9,10-tetrahydro-2,9,10a-triaza-cyclopenta[b]fluorene-1,3-dione (example 26) in 3 ml methanol are added 1.2 ml of a 7 M solution of ammonia in methanol. The mixture is heated in a sealed tube to 140° C. for 1 h using a microwave reactor. The solvent is removed under reduced pressure. Water is added and the mixture is extracted with ethyl acetate. The organic layer is dried with magnesium sulfate. The solvent is removed under reduced pressure. The crude product is purified by preparative HPLC. 24 mg of the title compound are obtained. MS: m/z (MH+)=425.1
Reaction SMILES: C([N:3]1[C:9]2[N:10]=[CH:11][C:12]([CH2:14][CH2:15][O:16][C:17]3[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][C:18]=3[CH3:26])=[CH:13][C:8]=2[C:7](=[O:27])[N:6]([CH3:28])[C:5]2[CH:29]=[CH:30][CH:31]=[N:32][C:4]1=2)C.[NH2:33][C:34]1[CH:43]=[CH:42][C:37]([C:38]([O:40][CH3:41])=[O:39])=[CH:36][CH:35]=1.[CH3:44][CH2:45]N(CC)CC>C(Cl)Cl.CCOC(C)=O>[CH2:44]([N:32]1[C:4]2[NH:3][C:9]3[N:10]=[CH:11][C:12]([CH2:14][CH2:15][O:16][C:17]4[CH:25]=[CH:24][C:20]([C:21]([NH:33][C:34]5[CH:35]=[CH:36][C:37]([C:38]([O:40][CH3:41])=[O:39])=[CH:42][CH:43]=5)=[O:22])=[CH:19][C:18]=4[CH3:26])=[CH:13][C:8]=3[C:7](=[O:27])[N:6]([CH3:28])[C:5]=2[CH:29]=[CH:30][CH2:31]1)[CH3:45]
Reactant: CCN1c2ncc(CCOc3ccc(C(=O)Cl)cc3C)cc2C(=O)N(C)c2cccnc21
Reactant: COC(=O)c1ccc(N)cc1
Reactant: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCN1CC=CC2=C1Nc1ncc(CCOc3ccc(C(=O)Nc4ccc(C(=O)OC)cc4)cc3C)cc1C(=O)N2C
Yield: 72.1 %

Procedure:
A solution of 4-[2-(11-ethyl-6,11-dihydro-5-methyl-6-oxo-5H-dipyrido[3,2-b:2′,3′-e][1,4]diazepin-8-yl)ethoxy]-3-methylbenzoyl chloride (47.0 mg, 0.11 mmol), methyl 4-aminobenzoate (15.8 mg, 0.11 mmol) and Et3N (15.3 μL, 0.11 mmol) in CH2Cl2 (4 mL) was stirred at 25° C. for 5 h. The reaction mixture was diluted with EtOAc and the resulting solution was successively washed with aqueous saturated NaHCO3 solution and brine, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (Hexane:EtOAc, 1:1) to give the title compound (45 mg, 76% yield) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[N:9]=[C:8]([C:11]3[O:15][C:14]([P:16]([O:21][CH2:22][CH3:23])([O:18][CH2:19][CH3:20])=[O:17])=[CH:13][CH:12]=3)[N:7]([CH2:24][CH:25]([CH3:27])[CH3:26])[C:6]=2[C:5]([CH2:28][CH2:29][CH2:30][CH2:31]O)=[CH:4][C:3]=1[F:33].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Br)(Br)(Br)[Br:54]>C(Cl)Cl>[NH2:1][C:2]1[C:10]2[N:9]=[C:8]([C:11]3[O:15][C:14]([P:16]([O:21][CH2:22][CH3:23])([O:18][CH2:19][CH3:20])=[O:17])=[CH:13][CH:12]=3)[N:7]([CH2:24][CH:25]([CH3:27])[CH3:26])[C:6]=2[C:5]([CH2:28][CH2:29][CH2:30][CH2:31][Br:54])=[CH:4][C:3]=1[F:33]
Reactant: CCOP(=O)(OCC)c1ccc(-c2nc3c(N)c(F)cc(CCCCO)c3n2CC(C)C)o1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOP(=O)(OCC)c1ccc(-c2nc3c(N)c(F)cc(CCCCBr)c3n2CC(C)C)o1

Procedure:
To a cold (0° C.) solution of 1.0 mmol of 4-amino-7-(4-hydroxybutyl)-5-fluoro-1-isobutyl-2-(2-diethylphosphono-5-furanyl)benzimidazole in 20 mL of CH2Cl2 was added 3.0 mmol of PPh3 and 3.0 mmol of CBr4. After 40 min. at room temperature solvent was removed and the residue was subjected to chromatography to give 4-amino-7-(4-bromobutyl)-5-fluoro-1-isobutyl-2-(2-diethylphosphono-5-furanyl)benzimidazole. CCl4 gave the corrosponding chloro compound.
Reaction SMILES: [C:1]([CH2:3][C:4]1([N:17]2[CH:21]=[C:20]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]4[NH:28][CH:29]=[CH:30][C:23]=34)[CH:19]=[N:18]2)[CH2:7][N:6]([C:8]2[N:9]=[CH:10][C:11]([C:14](O)=[O:15])=[N:12][CH:13]=2)[CH2:5]1)#[N:2].Cl.[CH:32]1([C@H:35]([NH2:40])[C:36]([F:39])([F:38])[F:37])[CH2:34][CH2:33]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O.CO>[C:1]([CH2:3][C:4]1([N:17]2[CH:21]=[C:20]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]4[NH:28][CH:29]=[CH:30][C:23]=34)[CH:19]=[N:18]2)[CH2:5][N:6]([C:8]2[N:9]=[CH:10][C:11]([C:14]([NH:40][C@@H:35]([CH:32]3[CH2:34][CH2:33]3)[C:36]([F:39])([F:38])[F:37])=[O:15])=[N:12][CH:13]=2)[CH2:7]1)#[N:2]
Reactant: N[C@@H](C1CC1)C(F)(F)F
Reactant: N#CCC1(n2cc(-c3ccnc4[nH]ccc34)cn2)CN(c2cnc(C(=O)O)cn2)C1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CO
Solvent: CCN(CC)CC
Product: N#CCC1(n2cc(-c3ccnc4[nH]ccc34)cn2)CN(c2cnc(C(=O)N[C@@H](C3CC3)C(F)(F)F)cn2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 27.8 %

Procedure:
A mixture of 5-{3-(cyanomethyl)-3-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}pyrazine-2-carboxylic acid (10 mg, 0.02 mmol), (1S)-1-cyclopropyl-2,2,2-trifluoroethanamine HCl salt (6.6 mg, 0.037 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (12 mg, 0.027 mmol) and triethylamine (16 μL, 0.11 mmol) in N,N-dimethylformamide (0.3 mL) was stirred at room temperature for 3 h. It was diluted with methanol, purified by RP-HPLC (pH=2) to afford the desired product (2.9 mg) as TFA salt. LCMS (M+H)+: m/z=522.4. 1H NMR (500 MHz, DMSO-d6): δ 12.01 (s, 1H), 8.92 (s, 1H), 8.90 (d, J=9.4 Hz, 1H), 8.69 (d, J=1.1 Hz, 1H), 8.41 (s, 1H), 8.27 (d, J=5.3 Hz, 1H), 8.04 (d, J=1.0 Hz, 1H), 7.65-7.57 (m, 1H), 7.46 (d, J=5.3 Hz, 1H), 7.01 (s, 1H), 4.84 (d, J=9.8 Hz, 2H), 4.58 (d, J=9.8 Hz, 2H), 4.10-3.97 (m, 1H), 3.78 (s, 2H), 1.46-1.33 (m, 1H), 0.73-0.61 (m, 1H), 0.61-0.53 (m, 1H), 0.53-0.44 (m, 1H), 0.27-0.17 (m, 1H).
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C@H:9]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:10][OH:11].Cl[C:20](=[O:26])[C:21]([O:23]CC)=[O:22].[OH-].[Na+].Cl>ClCCl.O>[OH:11][CH2:10][C@H:9]([NH:8][C:20](=[O:26])[C:21]([OH:23])=[O:22])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: N[C@@H](CO)Cc1ccccc1
Reactant: CCOC(=O)C(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(O)C(=O)N[C@@H](CO)Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
Triethylamine (0.703 mL; 5.01 mmol) was added to the mixture of (R)-2-amino-3-phenylpropan-1-ol (0.515 g; 3.34 mmol) and ethyl 2-chloro-2-oxoacetate (0.400 mL; 3.50 mmol) in dichloromethane (15 mL) at 0° C. After addition, the mixture was stirred at room temperature for 30 minutes, diluted with 40 mL of dichloromethane and washed successively with an aqueous solution of sodium carbonate and water. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. Water (5 mL) and a 2M solution of sodium hydroxide (5 mL; 10 mmol) were added to the resulting residue and the mixture was stirred at room temperature for 10 minutes. Water (10 mL) was added and the pH of the solution was adjusted to 1 by addition of a 6N hydrochloric acid. The formed precipitate was filtered off, and the filtrate was extracted with ethyl acetate (5×20 mL). The combined organic layers were dried over magnesium sulfate and evaporated to dryness to give 0.671 g (91%) of (R)-2-(1-hydroxy-3-phenylpropan-2-ylamino)-2-oxoacetic acid as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[C:10]([Cl:15])[C:9]=2[Cl:16])=[N:6][CH:5]=[C:4]([NH:17][C:18](=[O:20])[CH3:19])[N:3]=1.[CH:21]1([C:24](Cl)=[O:25])[CH2:23][CH2:22]1>>[CH:21]1([C:24]([NH:1][C:2]2[C:7]([C:8]3[CH:13]=[C:12]([Cl:14])[CH:11]=[C:10]([Cl:15])[C:9]=3[Cl:16])=[N:6][CH:5]=[C:4]([NH:17][C:18](=[O:20])[CH3:19])[N:3]=2)=[O:25])[CH2:23][CH2:22]1
Reactant: O=C(Cl)C1CC1
Reactant: CC(=O)Nc1cnc(-c2cc(Cl)cc(Cl)c2Cl)c(N)n1
Product: CC(=O)Nc1cnc(-c2cc(Cl)cc(Cl)c2Cl)c(NC(=O)C2CC2)n1

Procedure:
This compound was prepared in an analogous manner to Example 9 from 2-amino-6-acetamido-3-(2,3,5-trichlorophenyl)pyrazine (Example 1) and cyclopropylcarbonyl chloride (Aldrich). Yield 0.387 g (61%) N.m.r. (D6DMSO) δ: 0.53 (2H, m), 0.7 (2H, m), 1.75 (1H, m), 2.18 (3H, s), 7.43 (1H, d), 7.87 (1H, d), 9.22 (1H, s), 10.36 (1H, b), 10.83 (1H, b).
Reaction SMILES: II.FC(F)(F)C(OC1C(OC(=O)C(F)(F)F)=C([I:14])C=CC=1)=O.O=C([C@H](CC1C=C(O)C(O)=CC=1)N)O.[CH2:38]([O:40][C:41](=[O:74])[C@H:42]([CH2:51][C:52]1[CH:57]=[CH:56][C:55]([O:58][C:59]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:60])=[C:54]([O:66][C:67]([O:69][C:70]([CH3:73])([CH3:72])[CH3:71])=[O:68])[CH:53]=1)[NH:43][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH3:39]>ClCCl>[CH2:38]([O:40][C:41](=[O:74])[C@H:42]([CH2:51][C:52]1[C:57]([I:14])=[CH:56][C:55]([O:58][C:59]([O:61][C:62]([CH3:63])([CH3:64])[CH3:65])=[O:60])=[C:54]([O:66][C:67]([O:69][C:70]([CH3:73])([CH3:72])[CH3:71])=[O:68])[CH:53]=1)[NH:43][C:44]([O:46][C:47]([CH3:48])([CH3:49])[CH3:50])=[O:45])[CH3:39]
Reactant: CCOC(=O)[C@H](Cc1ccc(OC(=O)OC(C)(C)C)c(OC(=O)OC(C)(C)C)c1)NC(=O)OC(C)(C)C
Reactant: O=C(Oc1cccc(I)c1OC(=O)C(F)(F)F)C(F)(F)F
Agent: II
Agent: N[C@@H](Cc1ccc(O)c(O)c1)C(=O)O
Solvent: ClCCl
Product: CCOC(=O)[C@H](Cc1cc(OC(=O)OC(C)(C)C)c(OC(=O)OC(C)(C)C)cc1I)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 77 %

Procedure:
Iodine (7.4 mmol) and bis(trifluoroacetoxy)iodobenzene (8.16 mmol) were added to a solution of the tri-boc protected dopa analog 14 (5.7 mmol) in anhydrous dichloromethane (60 mL) under argon. (t-Boc, or Boc, stands for (t)ert-(B)ut(O)xy(c)arbonyl.) The reaction mixture was stirred at room temperature for 40 min and then quenched with a saturated solution of sodium thiosulfate. The organic layer was washed with water (3×10 mL), dried with anhydrous sodium sulfate, filtered and evaporated in rotary evaporator. The product was purified by silica gel column chromatography using 15-20% ethyl acetate in hexane as the mobile phase to give the iodo analog, N-(tert-butoxycarbonyl)-3,4-di(tert-butoxycarbonyloxy)-6-iodo-L-phenylalanine ethyl ester 15, as white foam in 77% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13](C(O)=O)=[CH:12][C:11]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N:10]2)=[CH:5][CH:4]=1.C(N(CC)CC)C>S(Cl)(Cl)=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH:13]=[CH:12][C:11]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N:10]2)=[CH:7][CH:8]=1
Reactant: CCOC(=O)c1cc(C(=O)O)n(-c2ccc(OC)cc2)n1
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1ccn(-c2ccc(OC)cc2)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 91.5 %

Procedure:
A solution of 1-[(4-methoxy)phenyl]-3-(ethoxycarbonyl)pyrazole-5-carboxylic acid (3.2 g, 11.1 mmol) in 20 mL of thionyl chloride was stirred at 80° C. for 1 h. The volatiles were then removed and the residue was azeotroped with 20 mL of toluene and dried in vacuo. The residue was dissolved in 50 mL of methylene chloride and then there was added triethylamine (4.6 mL, 33.3 mmol) and 4-(N-pyrrolidinocarbonyl)aniline (3.2 mL, 54.3 mmol). The reaction mixture was allowed to stir at ambient temperature for 4 h. The volatiles were removed and the residue was dissolved in ethyl acetate, washed sequentially with 10% aq HCl and brine, dried (MgSO4), filtered through a short pad of silica gel and concentrated to afford 2.5 g (50%) of the title compound. A small portion was further purified by prep HPLC (C18 reverse phase column, elution with a H2O/CH3CN gradient with 0.5% TFA) and lyophilized to afford the title compound as a white powder. LRMS (ES+): 463.1 (M+H)+.
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][S:6][C:7]1[CH:12]=[C:11]([F:13])[C:10]([CH3:14])=[C:9]([F:15])[CH:8]=1)C.C(OC(OCC)CSC1C=CC(C)=C(F)C=1)C>>[F:13][C:11]1[C:12]2[CH:4]=[CH:5][S:6][C:7]=2[CH:8]=[C:9]([F:15])[C:10]=1[CH3:14]
Reactant: CCOC(CSc1cc(F)c(C)c(F)c1)OCC
Agent: CCOC(CSc1ccc(C)c(F)c1)OCC
Product: Cc1c(F)cc2sccc2c1F

Procedure:
The same procedure as in Reference Example 1 (3) is repeated, except that 1,1-diethoxy-2-(3,5-difluoro-4-methylphenylthio)ethane is substituted for the 1,1-diethoxy-2-(3-fluoro-4-methylphenylthio)ethane, to obtain 4,6-difluoro-5-methylbenzo[b]thiophene.
Reaction SMILES: N1N=C(C2C=CC=CC=2C([N:14]2[CH2:18][CH:17]3[CH2:19][N:20]([C:22](OC(C)(C)C)=O)[CH2:21][CH:16]3[CH2:15]2)=O)NC=1.C(OC(N1CC2C(CNC2)C1)=O)(C)(C)C.[F:44][C:45]1[CH:53]=[CH:52][CH:51]=[C:50]([N:54]2[N:58]=[CH:57][CH:56]=[N:55]2)[C:46]=1[C:47]([OH:49])=O.[N:59]1[N:60]=[C:61]([C:64]2C=CC=CC=2C(O)=O)[NH:62][CH:63]=1>>[F:44][C:45]1[CH:53]=[CH:52][CH:51]=[C:50]([N:54]2[N:58]=[CH:57][CH:56]=[N:55]2)[C:46]=1[C:47]([N:14]1[CH2:15][CH:16]2[CH:17]([CH2:19][N:20]([C:22]3[N:60]=[C:61]([CH3:64])[N:62]=[CH:63][N:59]=3)[CH2:21]2)[CH2:18]1)=[O:49]
Reactant: O=C(O)c1c(F)cccc1-n1nccn1
Reactant: O=C(O)c1ccccc1-c1nnc[nH]1
Reactant: CC(C)(C)OC(=O)N1CC2CN(C(=O)c3ccccc3-c3nnc[nH]3)CC2C1
Agent: CC(C)(C)OC(=O)N1CC2CNCC2C1
Product: Cc1ncnc(N2CC3CN(C(=O)c4c(F)cccc4-n4nccn4)CC3C2)n1

Procedure:
Example 303 was prepared in a manner analogous to Intermediate 59 substituting the product of Step C for Intermediate 15 and Intermediate 12 for 2-(4H-[1,2,4]triazol-3-yl)-benzoic acid. MS (ESI) mass calculated for C19H19FN8O, 394.41; m/z found, 395.0. 1H NMR (500 MHz, CDCl3): 8.51-8.42 (m, 1H), 7.89-7.81 (m, 2H), 7.75 (d, J=3.5 Hz, 1H), 7.54-7.45 (m, 1H), 7.20-7.11 (m, 1H), 4.02-3.51 (m, 8H), 3.32-3.23 (m, 1H), 3.17-3.00 (m, 2H), 2.50-2.40 (m, 3H).
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:32]=[CH:31][C:13]([NH:14][C:15]3[N:20]=[C:19]([C:21]4[N:25]([CH:26]([CH3:28])[CH3:27])[C:24]([CH3:29])=[N:23][CH:22]=4)[C:18]([F:30])=[CH:17][N:16]=3)=[CH:12][C:11]=2[CH3:33])[CH2:6][CH2:5]1)(=O)C.O.Cl>C(O)(C)C>[N:7]1([C:10]2[CH:32]=[CH:31][C:13]([NH:14][C:15]3[N:20]=[C:19]([C:21]4[N:25]([CH:26]([CH3:28])[CH3:27])[C:24]([CH3:29])=[N:23][CH:22]=4)[C:18]([F:30])=[CH:17][N:16]=3)=[CH:12][C:11]=2[CH3:33])[CH2:8][CH2:9][NH:4][CH2:5][CH2:6]1
Reactant: CC(=O)N1CCN(c2ccc(Nc3ncc(F)c(-c4cnc(C)n4C(C)C)n3)cc2C)CC1
Agent: Cl
Solvent: CC(C)O
Solvent: O
Product: Cc1cc(Nc2ncc(F)c(-c3cnc(C)n3C(C)C)n2)ccc1N1CCNCC1

Procedure:
2-{4-[4-(Acetyl)piperazin-1-yl]3-methylanilino}-4-(1-isopropyl-2-methyl-1H-imidazol-5-yl)-5-fluoropyrimidine (Example 116; 1.89 g, 4.19 mmol) was stirred and heated in isopropanol (20 ml), H2O (5 ml) and 33% hydrochloric acid (4 ml) at 90° C. for 10 hours. The solvent was evaporated under reduced pressure to give a residue which was partitioned between water and DCM, basified with sat. sodium hydrogen carbonate and the aqueous layer was extracted with DCM twice. The organics were combined, washed with brine, dried and evaporation of solvent to give the title compound as a crisp foam which was dried in vac oven overnight at 50° C. (1.53 g, 89%) NMR (400 MHz) 1.39 (d, 6H), 2.23 (s, 3H), 2.51 (s, 3H, under DMSO signal), 2.72 (m, 4H), 2.85 (m, 4H), 3.29 (s, 1H under H2O signal), 5.42 (septet, 1H), 6.95 (d, 1H), 7.30 (d, 1H), 7.35 (d, 1H), 7.40 (dd, 1H), 8.48 (d, 1H), 9.24 (s, 1H); 19F NMR (400 MHz) −149.59 (t, 1F); m/z 410.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][N:11]([CH:21]([C:24]1[N:25]([CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:26](=[O:34])[C:27]2[C:32]([CH3:33])=[N:31][S:30][C:28]=2[N:29]=1)[CH2:22][CH3:23])[C:12](=[O:20])[C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)(C)(C)C.[ClH:43]>CCOCC>[Cl-:43].[NH2:7][CH2:8][CH2:9][CH2:10][N:11]([CH:21]([C:24]1[N:25]([CH2:35][C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:26](=[O:34])[C:27]2[C:32]([CH3:33])=[N:31][S:30][C:28]=2[N:29]=1)[CH2:22][CH3:23])[C:12](=[O:20])[C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1
Reactant: CCC(c1nc2snc(C)c2c(=O)n1Cc1ccccc1)N(CCCNC(=O)OC(C)(C)C)C(=O)c1ccc(C)cc1
Reactant: Cl
Solvent: CCOCC
Product: CCC(c1nc2snc(C)c2c(=O)n1Cc1ccccc1)N(CCCN)C(=O)c1ccc(C)cc1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 20 h
Yield: 87 %

Procedure:
(+) {3-[[1-(5-Benzyl-3-methyl-4-oxo-4,5-dihydro-isothiazolo[5,4-d]pyrimidin-6-propyl]-(4-methyl-benzoyl)-amino]-propyl}-carbamic acid tert-butyl ester (method 12) (0.117 g, 0.19 mmol) was dissolved in 2M HCl in ether and the mixture was stirred at r.t. for 20 h. The precipitated product was filtered off and washed with ether and dried in vacuo to yield the pure (+) N-(3-amino-propyl)-N-[1-(5-benzyl-3-methyl-4-oxo-4,5-dihydro-isothiazolo[5,4-d]pyrimidin-6-yl)-propyl]-4-methyl-benzamide chloride salt (91 mg, 87%). White powder, mp. 127.8-129.2° C. m/z 490 (MH+), 1H NMR (DMSO-d6, 500 MHz, 96° C.) δ: 0.63 (t, 3H), 1.40-1.74 (m, 2H), 1.75-1.96 (m, 1H), 2.05-2.20 (m, 1H), 2.39 (s, 3H), 2.46 (t, 2H), 2.72 (s, 3H), 3.36 (t, 2H), 4.83 (d, 1H), 5.50 (bs, 1H), 5.77 (d, 1H), 6.95-7.37 (m, 9H), 7.79 (bs, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N+:10]([O-:12])=[O:11])=[CH:4][CH:3]=1.C[O:14][CH:15](OC)[CH2:16][CH2:17][CH2:18][CH:19]=O>CCOC(C)=O.CCCCCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8]/[C:9](/[N+:10]([O-:12])=[O:11])=[CH:19]\[CH2:18][CH2:17][CH2:16][CH:15]=[O:14])=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])CCc1ccc(Cl)cc1
Reactant: COC(CCCC=O)OC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=CCCC/C=C(\Cc1ccc(Cl)cc1)[N+](=O)[O-]
Yield: 45.1 %

Procedure:
Prepared according to the general procedure B from 1-chloro-4-(2-nitroethyl)benzene 112g (24 mmol) and 5,5-dimethoxypentanal 131 (16 mmol) to provide the title compound as yellow oil (1.93 g, 45% yield) after silica gel chromatography (EtOAc/Hexane).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][C:9](=O)[CH2:10]2)(=[O:3])[CH3:2].Cl.[C:17]1([C@H:23]([NH2:25])[CH3:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C([BH3-])#N.[Na+]>CO>[C:1]([NH:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][CH:9]([NH:25][CH:23]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:24])[CH2:10]2)(=[O:3])[CH3:2]
Reactant: C[C@@H](N)c1ccccc1
Reactant: CC(=O)Nc1cccc2c1CCC(=O)C2
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CC(=O)Nc1cccc2c1CCC(NC(C)c1ccccc1)C2

Procedure:
Starting from 16.24 g (0.08 mol) of 5-acetylamino-2-tetralone, 240 ml of methanol, 19.0 g (0.12 mol) of (R)-1-phenylethylamine-hydrochloride and 6.0 g (0.096 mol) of sodium cyanoborohydride, the title compound is obtained analogously to Example 4.1.11 and is crystallised from 75 ml of toluene. Yield 18.5 g (74.9% of theory), melting point 158° C. It consists of approximately equal parts of the (R/R)- and (S/R)-diastereoisomers.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:24])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[CH:17]=[CH:16][N:15]=[C:14]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O.CO>[C:18]1([C:14]2[N:13]([CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:5]([OH:24])=[O:4])[CH:17]=[CH:16][N:15]=2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: COC(=O)CCCCCCCn1ccnc1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)CCCCCCCn1ccnc1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.9 %

Procedure:
Add sodium hydroxide (6.0 g, 150 mmol) in water (50 mL) to a suspension of 8-(2-phenylimidazol-1-yl)octanoic acid methyl ester (7.60 g, 25 mmol) in methanol (100 mL) at 0° C. under nitrogen. Warm the mixture to room temperature and stir for a total of 8 hours. Remove the solvent under reduced pressure, dilute the residue with water (300 mL), cool to 0° C., and acidify to pH 1 with 1 N HCl. Collect the precipitate and triturate with hexanes to afford 8-(2-phenylimidazol-1-yl)octanoic acid (4.22 g, 52%). APCI mass spectrum m/z 285 [C17H22N2O2—H]−.
Reaction SMILES: C1(C(N2C3C(=CC(S(N)(=O)=O)=CC=3)CC2)=O)CCCCC1.[NH:22]1[C:30]2[C:25](=[CH:26][C:27]([S:31]([NH2:34])(=[O:33])=[O:32])=[CH:28][CH:29]=2)[CH2:24][CH2:23]1.[F:35][C:36]1[CH:37]=[C:38]([CH:42]=[CH:43][C:44]=1[F:45])[C:39](Cl)=[O:40]>>[F:35][C:36]1[CH:37]=[C:38]([CH:42]=[CH:43][C:44]=1[F:45])[C:39]([N:22]1[C:30]2[C:25](=[CH:26][C:27]([S:31]([NH2:34])(=[O:32])=[O:33])=[CH:28][CH:29]=2)[CH2:24][CH2:23]1)=[O:40]
Reactant: O=C(Cl)c1ccc(F)c(F)c1
Reactant: NS(=O)(=O)c1ccc2c(c1)CCN2
Agent: NS(=O)(=O)c1ccc2c(c1)CCN2C(=O)C1CCCCC1
Product: NS(=O)(=O)c1ccc2c(c1)CCN2C(=O)c1ccc(F)c(F)c1
Yield: 78.8 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 55, indoline-5-sulfonamide (Intermediate 54A, 90 mg, 0.45 mmol) and 3,4-difluorobenzoyl chloride (69 μL, 0.54 mmol) were converted to the title compound (120 mg, 78%). 1H NMR (DMSO-d6) δ 7.60-7.21 (m, 6H), 7.01 (s, 2H), 3.85 (t, J=8.6 Hz, 2H), 2.92 (t, J=8.6 Hz, 2H); MS(ESI+) m/z 338.9 (M+H)+.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].C(=O)([O-])[O-].[K+].[K+].[C:16]1([SH:32])[C:29]2[C:30]3=[C:31]4[C:26](=[CH:27][CH:28]=2)[CH:25]=[CH:24][CH:23]=[C:22]4[CH:21]=[CH:20][C:19]3=[CH:18][CH:17]=1>CN(C=O)C>[CH:18]1[C:19]2[C:30]3=[C:31]4[C:22](=[CH:21][CH:20]=2)[CH:23]=[CH:24][CH:25]=[C:26]4[CH:27]=[CH:28][C:29]3=[C:16]([S:32][C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[CH:4]=[O:5])[CH:17]=1
Reactant: Sc1ccc2ccc3cccc4ccc1c2c34
Reactant: O=Cc1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccccc1Sc1ccc2ccc3cccc4ccc1c2c34
Temperature: 130 °C
Yield: 46.2 %

Procedure:
2-fluoro-benzaldehyde (477 mg, 3.8 mmol), potassium carbonate (700 mg, 5.0 mmol) and pyrene-1-thiol (300 mg, 1.28 mmol) were dissolved in 15 mL of dry DMF under dry nitrogen, topped with a reflux condenser. The reaction mixture was heated to 130° C. for 24 h. After cooling the mixture was added to 50 mL of saturated potassium carbonate solution, and the mixture was extracted with 3 portions of ether. The extracts were dried with magnesium sulfate and evaporated. The residue of the crude product was further purified by chromatography on silica gel using 10:1 petroleum ether (60-80) and EtOAc as eluent to afford a yellow solid (200 mg, 46%). 1H-NMR (500 MHz, CDCl3): δ 6.56 (dd, J=0.8, 7.9 Hz, 1H), 7.07-7.22 (m, 2H), 7.89 (dd, J=1.7, 7.2 Hz, 1H), 8.02-8.28 (m, 8H), 8.58 (d, J=9.2 Hz, 1H), 10.45 (s, 1H). 13C-NMR (125 MHz, CDCl3): δ 124.7, 124.9, 125.3, 125.5, 125.9, 126.0, 126.4, 127.1, 128.0, 128.7, 129.0, 130.8, 131.0, 132.5, 133.3, 133.4, 133.8, 133.9, 137.0, 143.2, 191.6. EI-MS: m/z M+Calculated 338.1, found 338.1.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:9])=[CH:4][C:3]=1[F:18].[Li]CCCC.CN([CH:27]=[O:28])C.CCOC(C)=O.CCCCCCC>C1COCC1>[F:18][C:3]1[CH:4]=[C:5]([C@@H:8]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:9])[CH:6]=[CH:7][C:2]=1[CH:27]=[O:28]
Reactant: CN(C)C=O
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1ccc(Br)c(F)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: C[C@H](NC(=O)OC(C)(C)C)c1ccc(C=O)c(F)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 26.2 %

Procedure:
A solution of (S)-tert-butyl 1-(4-bromo-3-fluorophenyl)ethylcarbamate (318 mg, 1 mmol) in dry THF (5 mL) was cooled to −78° C. BuLi (2.5 M, 840 μL, 2.1 mmol) was added dropwise and the resulting solution was stirred at −78° C. for 1 h. Then DMF (232 μL, 3.00 mmol) was added in one portion. The reaction was stirred for another 30 min at −78° C. then quenched with sat. NH4Cl solution. The reaction was stirred at room temperature for another 30 min then diluted with EtOAc, washed with water and brine. The separated organic was dried over Na2SO4, filtered and concentrated. Silica gel column chromatography (EtOAc/heptane 0 to 80%) provided (S)-tert-butyl 1-(3-fluoro-4-formylphenyl)ethylcarbamate as a white solid (70 mg, 26.2% yield).