Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([C:4]1[C:17]2[O:16][C:15]([CH3:19])([CH3:18])[S:14][C:13]=2[C:12]([C:20]([C:41]2[C:49]3[S:50][C:51]([CH3:54])([CH3:53])[O:52][C:48]=3[C:47]([C:55](Cl)=[O:56])=[C:46]3[C:42]=2[S:43][C:44]([CH3:59])([CH3:58])[O:45]3)([C:22]2[C:30]3[S:31][C:32]([CH3:35])([CH3:34])[O:33][C:29]=3[C:28]([C:36](Cl)=[O:37])=[C:27]3[C:23]=2[S:24][C:25]([CH3:40])([CH3:39])[O:26]3)[OH:21])=[C:6]2[S:7][C:8]([CH3:11])([CH3:10])[O:9][C:5]=12)=[O:3].[OH:60][CH2:61][CH2:62][NH:63][CH2:64][CH2:65][OH:66]>C1C=CC=CC=1.O>[OH:60][CH2:61][CH2:62][N:63]([CH2:64][CH2:65][OH:66])[C:2]([C:4]1[C:17]2[O:16][C:15]([CH3:19])([CH3:18])[S:14][C:13]=2[C:12]([C:20]([C:41]2[C:49]3[S:50][C:51]([CH3:54])([CH3:53])[O:52][C:48]=3[C:47]([C:55]([N:63]([CH2:64][CH2:65][OH:66])[CH2:62][CH2:61][OH:60])=[O:56])=[C:46]3[C:42]=2[S:43][C:44]([CH3:59])([CH3:58])[O:45]3)([C:22]2[C:30]3[S:31][C:32]([CH3:35])([CH3:34])[O:33][C:29]=3[C:28]([C:36]([N:63]([CH2:64][CH2:65][OH:66])[CH2:62][CH2:61][OH:60])=[O:37])=[C:27]3[C:23]=2[S:24][C:25]([CH3:40])([CH3:39])[O:26]3)[OH:21])=[C:6]2[S:7][C:8]([CH3:11])([CH3:10])[O:9][C:5]=12)=[O:3]
Reactant: OCCNCCO
Reactant: CC1(C)Oc2c(c(C(O)(c3c4c(c(C(=O)Cl)c5c3SC(C)(C)O5)OC(C)(C)S4)c3c4c(c(C(=O)Cl)c5c3SC(C)(C)O5)OC(C)(C)S4)c3c(c2C(=O)Cl)OC(C)(C)S3)S1
Solvent: c1ccccc1
Solvent: O
Product: CC1(C)Oc2c(c(C(O)(c3c4c(c(C(=O)N(CCO)CCO)c5c3SC(C)(C)O5)OC(C)(C)S4)c3c4c(c(C(=O)N(CCO)CCO)c5c3SC(C)(C)O5)OC(C)(C)S4)c3c(c2C(=O)N(CCO)CCO)OC(C)(C)S3)S1
Reaction time: 8 h
Yield: 63.4 %

Procedure:
Tris-(8-chlorocarbonyl-2,2,6,6-tetramethyl-benzo[1,2-d:5,4-d']-bis(1,3)oxathiol-4-yl)methanol (0.80 g, 0.80 mmol) was dissolved in benzene (200 mL). A solution of of bis(2-hydroxyethyl)amine (8.0 g, 48 mmol) in water (200 mL) was added and after vigorous stirring overnight, the mixture was transferred to a separatory funnel. The aqueous layer was removed and the remaining solid plus the benzene layer was evaporated, dissolved in methanol and passed through a short column (neutral alumina). After elution of unwanted materials with acetonitrile, the amide was eluted with methanol. After evaporation, the product was stirred with water (50 mL) at 40° C. for 2 h and then isolated by filtration. After drying, 0.60 g (60%) of the pure amide was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:3]=1[C:4]#[N:5].[N:11]1[CH:16]=[CH:15][C:14]([C:17]2([CH2:22][C:23](O)=[O:24])[NH:21][CH:20]=[CH:19][S:18]2)=[CH:13][CH:12]=1>>[C:4]([C:3]1[CH:6]=[C:7]([Cl:10])[CH:8]=[CH:9][C:2]=1[NH:1][C:23](=[O:24])[CH2:22][C:17]1([C:14]2[CH:15]=[CH:16][N:11]=[CH:12][CH:13]=2)[NH:21][CH:20]=[CH:19][S:18]1)#[N:5]
Reactant: O=C(O)CC1(c2ccncc2)NC=CS1
Reactant: N#Cc1cc(Cl)ccc1N
Product: N#Cc1cc(Cl)ccc1NC(=O)CC1(c2ccncc2)NC=CS1

Procedure:
This compound was prepared according to the method described in Example 1c by employing 2-amino-5-chlorobenzonitrile (Aldrich) and 2-(4-pyridyl)-thiazole acetic acid (Example 1, Step b). Mp: 164-166° C. MS m/z: 355.0 (M+1). Calc'd for C17H11ClN4OS: 354.03.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[CH2:12][OH:13])=[CH:6][CH:5]=1)([O-:3])=[O:2].C([O:18]O)(C)(C)C>C(Cl)Cl.C(OCC)(=O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C@@H:10]2[O:18][C@H:11]2[CH2:12][OH:13])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CC(C)(C)OO
Reactant: O=[N+]([O-])c1ccc(/C=C/CO)cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc([C@@H]2O[C@H]2CO)cc1
Temperature: -5 °C
Reaction time: 0.17 h
Yield: 97 %

Procedure:
A flame-dried 50 ml three-necked flask was fitted with a thermometer and a dropping funnel, flushed with nitrogen, and charged with a mixture of powdered, activated 3 Å molecular sieves (0.45 g) and dry CH2Cl2 (15 ml). After cooling to −5° C., L-(+)-diethyl tartrate (92.8 mg, 0.45 mmol) and Ti(O-i-Pr)4 (88.5 ul, 0.30 mmol) were added sequentially. The mixture was cooled to −20° C. in a CCl4 dry ice bath, (E)-3-(4-nitrophenyl)-2-propenol 4 (1.074 g, 6 mmol) (dissolved in dry methylene chloride (15 ml) and dried with 3Å molecular sieves for 10-15 min prior to addition) was added and the mixture was stirred for 10 minutes. A 7.0 M solution of t-butylhydroperoxide (TBHP) in CH2Cl2 (1.72 ml, 12 mmol) was added, taking care to maintain the temperature around −20° C. After stirring, at −20° C. for 2 hrs, the cold (−20° C.) reaction mixture was quenched with a 10% aqueous solution of sodium hydroxide saturated with sodium chloride (0.48 ml). Ether in the amount of 10% of the total volume of the reaction mixture was added, the cold bath removed and the stirred mixture allowed to warm to 10° C. Stirring was maintained for an additional 10 minutes at 10° C., whereupon anhydrous MgSO4 (0.48 g,) and Celite® (0.06 g) were added. After a final 15 min. of stirring, the mixture was allowed to settle and the clear solution was filtered through a pad of Celite® and washed with ethyl ether. Concentration of the ether solution gave the crude product containing TBHP, which was dissolved in a minimum amount of ethyl acetate, filtered through a small pad of silica gel, and recrystallized from CH2Cl2-hexanes to yield compound 5, (2S, 3S)-3-(4-nitrophenyl) oxiranemethanol (1.13 g, 97%) as light yellow needles: mp 100-101° C. (literature value: 98-99° C.); Rf=0.62 (5% CH3OH—CH2Cl2); 1H NMR (300 MHz, CDCl3) δ: 8.22 (d, aromatic, 2H, J=8.7 Hz), 7.45 (d, aromatic, 2H, J=8.7 Hz), 4.10 (m, 2H) 3.89 (m, 1H), 3.20 (m, 1H), 1.74 (m, 1H); 13C NMR (CDCl3): d 147.88(C), 144.35(C), 126.41(CH), 123.82(CH), 62.94(CH), 60.62(CH2), 54.30(CH). Anal. Calcd for C9H9NO4: C, 55.38; H, 4.65; N, 7.18. Found: C, 55-65; H, 4.54; N, 7.17.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([OH:15])=O.[C:16]1([CH:22]2[CH2:26][CH2:25][NH:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[C:13]([N:24]1[CH2:25][CH2:26][CH:22]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:23]1)=[O:15]
Reactant: c1ccc(C2CCNC2)cc1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1onc(-c2ccccc2)c1C(=O)N1CCC(c2ccccc2)C1
Temperature: 25 °C

Procedure:
5-Methyl-3-phenylisooxazole-4-carboxylic acid (40 mg, 0.197 mmol), 3-phenyl-pyrrolidine (31.6 mg, 0.215 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (86.2 mg, 0.268 mmol) and diisopropylethylamine (25.4 mg, 0.197 mmol) were mixed in dimethylformamide (1.5 mL) and stirred at room temperature. Solvent was evaporated in vacuo, and the residue was taken up in methanol (1 mL), filtered and purified by preparative chromatography. The combined fractions were partitioned between NaHCO3 (sat) and ethylacetate. The organic layer was washed with water and concentrated in vacuo to afford the title compound. HRMS (ESI, pos. ion) m/z calcd for C21H20N2O2: 332.1525, found 332.1539.
Reaction SMILES: CS[C:3]1[S:4][C:5](=[CH:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][C:14]([C:20]#[N:21])=[C:13]3[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:6](=[O:8])[N:7]=1.[NH3:28]>CO>[NH2:28][C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][C:14]([C:20]#[N:21])=[C:13]3[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)/[C:6](=[O:8])[N:7]=1
Reactant: CSC1=NC(=O)C(=Cc2ccc3ncc(C#N)c(-c4ccccc4)c3c2)S1
Reactant: N
Solvent: CO
Product: N#Cc1cnc2ccc(/C=C3\SC(N)=NC3=O)cc2c1-c1ccccc1

Procedure:
Similar procedure as described in example 41c was used, starting from 6-(2-methylsulfanyl-4-oxo-4H-thiazol-5-ylidenemethyl)-4-phenyl-quinoline-3-carbonitrile (example 62e), and ammonia in methanol to give 6-[2-amino-4-oxo-4H-thiazol-(5Z)-ylidenemethyl]-4-phenyl-quinoline-3-carbonitrile. LC-MS m/e 357 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C(N(CC)CC)C.[CH3:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=1[S:49](Cl)(=[O:51])=[O:50]>C(#N)C>[CH3:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=1[S:49]([O:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34])(=[O:51])=[O:50]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Reactant: Cc1ccccc1S(=O)(=O)Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1ccccc1S(=O)(=O)Oc1ccc(-c2cc3cc(CN4CCCCC4)ccc3n2C(=O)OC(C)(C)C)c2c1CNC2=O
Yield: 69 %

Procedure:
In a similar manner to Step 1 of Example 233, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0304 g, 0.0659 mmol) was dissolved in acetonitrile (0.650 mL), and the solution was treated with triethylamine (0.0550 mL, 0.395 mmol) and 2-methylbenzenesulfonyl chloride (0.0280 mL, 0.198 mmol) to obtain 4-(2-methylbenzenesulfonyloxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0280 g, yield 69%).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[OH:11])[CH2:8]2.[Cl:12][C:13]1[C:14](F)=[CH:15][C:16]([F:26])=[C:17]([CH:25]=1)[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O.O>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[O:11][C:14]1[C:13]([Cl:12])=[CH:25][C:17]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])=[C:16]([F:26])[CH:15]=1)[CH2:8]2
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(F)cc1F
Reactant: OC1C2CC3CC(C2)CC1C3
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)c1cc(Cl)c(OC2C3CC4CC(C3)CC2C4)cc1F
Temperature: 70 °C
Yield: 21.1 %

Procedure:
To a solution of 2-adamantanol (3.09 g, 20.26 mmol) in anhydrous dimethylsulfoxide (40 mL) was added tert-butyl 5-chloro-2,4-difluorobenzoate (6.56 g, 26.38 mmol) and cesium carbonate (13.20 g, 40.51 mmol), and the reaction mixture was heated at 70° C. for 16 hours. The solution was then cooled to ambient temperature and charged with an additional portion of 2-adamantanol (0.51 g, 3.34 mmol) and the reaction mixture was heated at 70° C. for an additional 24 hours. This process was repeated twice by addition of 2-adamantanol (0.49 g, 3.21 mmol) and (0.51 g, 3.31 mmol) respectively over an additional 48 hours. The mixture was cooled to ambient temperature and diluted with water (300 mL) and extracted with ethyl acetate (4×100 mL). The combined organic layers were washed with water (100 mL) and brine (100 mL); dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was recrystallized from hexanes and then triturated with methanol to give the title compound (1.63 g, 16%): 1H NMR (300 MHz, CDCl3) δ 7.88 (d, J=7.8 Hz, 1H), 6.62 (d, J=12.5 Hz, 1H), 4.49 (br s, 1H), 2.20-2.10 (m, 4H), 1.99-1.68 (m, 10H), 1.57 (s, 9H).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:5]([NH:7][NH2:8])=[O:6].[CH3:13]OC(C1C=C(C2C=CC(NC(=O)C3C(F)=CC=CC=3F)=CC=2)C(C)=CC=1)=O>>[I:1][C:2]1[CH:3]=[C:4]([C:5]2[O:6][CH:13]=[N:8][N:7]=2)[CH:9]=[CH:10][C:11]=1[CH3:12]
Reactant: Cc1ccc(C(=O)NN)cc1I
Reactant: COC(=O)c1ccc(C)c(-c2ccc(NC(=O)c3c(F)cccc3F)cc2)c1
Product: Cc1ccc(-c2nnco2)cc1I

Procedure:
3-Iodo-4-methyl benzoic acid methyl ester was treated with hydrazine to form 3-Iodo-4-methyl benzoic acid hydrazide. 2-(3-Iodo-4-methyl-phenyl)-[1,3,4]oxadiazole was prepared from 3-iodo-4-methyl benzoic acid hydrazide according to a method analogous to that described in J. of Medicinal Chemistry (2001), 44(8): 1268-85, the entire teachings of which are incorporated herein by reference. Compounds 46, 68, 69, 70, and 71 were prepared via an amide coupling reaction analogous to that described in step A of the synthesis of Compound 1, followed by a Suzuki coupling reaction analogous to that described in step B of the synthesis of Compound 1. The amide coupling reaction and Suzuki coupling reaction are shown for Compound 69 in Scheme XX below:
Reaction SMILES: [CH:1]1([CH2:7][C@@H:8]([NH:24][CH3:25])[CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][CH3:23])[CH2:12][CH2:11]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:33][C:34]1([C:40](Cl)=[O:41])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>ClCCl>[CH:1]1([CH2:7][C@@H:8]([N:24]([CH3:25])[C:40]([C:34]2([CH3:33])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]2)=[O:41])[CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][CH3:23])[CH2:12][CH2:11]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC1(C(=O)Cl)CCCCC1
Reactant: CN[C@H](CC1CCCCC1)CN1CCN(c2ccccc2OC)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccccc1N1CCN(C[C@@H](CC2CCCCC2)N(C)C(=O)C2(C)CCCCC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.3 %

Procedure:
To a solution of 0.30 g (0.87 mmol) of {(1R)-1-cyclohexylmethyl-2-[4-(2-methoxyphenyl)-piperazin-1-yl]-ethyl}-methyl-amine and 0.25 mL (1.74 mmol) of triethylamine in 10 mL of dichloromethane at 0° C. was added dropwise 0.21 g (1.31 mmol) of 1-methyl-cyclohexanecarboxylic acid chloride in 4 mL of dichloromethane. The reaction mixture was allowed to stir under nitrogen overnight at ambient temperature, and was then concentrated on a rotary evaporator, diluted with ethyl acetate and washed with aqueous NaHCO3 and brine. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated on a rotary evaporator to yield the crude product, which was purified by flash chromatography on silica gel (dichloromethane/methanol) and then converted to the dihydrochloride salt of the title compound with ethanolic HCl to yield 0.41 g (86%) of white solid; mp=208-210° C.; MS (+) ESI m/z=470 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([C:12]2[CH:38]=[CH:37]C3C4C(CCOC=3C=2)=CN(C2N(C3C=CC(F)=CC=3F)N=CN=2)N=4)C1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:40]1[CH:61]=[CH:60][C:43]2[C:44]3[N:48]([CH2:49][CH2:50][O:51][C:42]=2[CH:41]=1)[CH:47]=[C:46]([C:52]1[N:53]([CH:57]([CH3:59])[CH3:58])[N:54]=[CH:55][N:56]=1)[N:45]=3>>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH2:10][CH:12]([C:40]2[CH:61]=[CH:60][C:43]3[C:44]4[N:48]([CH2:49][CH2:50][O:51][C:42]=3[CH:41]=2)[CH:47]=[C:46]([C:52]2[N:53]([CH:57]([CH3:59])[CH3:58])[N:54]=[CH:55][N:56]=2)[N:45]=4)[CH2:38][CH2:37]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(Br)cc1OCC2
Reactant: CC(C)(C)OC(=O)N1CC(c2ccc3c(c2)OCCc2cn(-c4ncnn4-c4ccc(F)cc4F)nc2-3)C1
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc1OCC2
Yield: 31 %

Procedure:
4-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-piperidine-1-carboxylic acid tert-butyl ester was prepared similarly to 3-{2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulen-8-yl}-azetidine-1-carboxylic acid tert-butyl ester from 8-bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene (3.0 g, 8.0 mmol) and 4-piperidine-1-carboxylic acid tert-butyl ester zinc iodide (12 mmol) (prepared similarly to 3-azetidine-1-carboxylic acid tert-butyl ester zinc iodide) to give 4-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-piperidine-1-carboxylic acid tert-butyl ester (1.2 g, 31%). LCMS: RT=5.06 min, M+H+=479
Reaction SMILES: [Br:1][C:2]1[N:6]2[CH2:7][CH2:8][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:10][C:5]2=[C:4]([C:18]([OH:20])=O)[N:3]=1.[CH3:21][NH:22][C:23](=[O:30])[C@H:24]([CH2:26][CH:27]([CH3:29])[CH3:28])[NH2:25].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[Br:1][C:2]1[N:6]2[CH2:7][CH2:8][N:9]([C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12])[CH2:10][C:5]2=[C:4]([C:18](=[O:20])[NH:25][C@@H:24]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:23]([NH:22][CH3:21])=[O:30])[N:3]=1
Reactant: CNC(=O)[C@@H](N)CC(C)C
Reactant: CC(C)(C)OC(=O)N1CCn2c(Br)nc(C(=O)O)c2C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)[C@H](CC(C)C)NC(=O)c1nc(Br)n2c1CN(C(=O)OC(C)(C)C)CC2
Reaction time: 2 h
Yield: 48 %

Procedure:
To a solution of 3-bromo-7-(tert-butoxycarbonyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxylic acid (11) (0.53 g, 1.53 mmol), L-leucine-N-methylamide (0.26 g, 1.80 mmol) and DIEA (0.5 mL, 2.9 mmol) in DMF (20 mL) was added TBTU (0.69 g, 2.15 mmol) in two batches over 10 minutes at 0° C. After stirring from 0° C. to room temperature for 2 hours, the reaction was quenched with water and evaporated under vacuum. The residue was extracted between saturated aqueous NaHCO3 and EtOAc. The organic layer was dried over anhydrous Na2SO4 and evaporated to dryness. The crude mixture was purified by column chromatography with 70% to 100% EtOAc/Hexanes to give the desired product 20C as an oil (48% yield). LCMS (+ESI) m/z 474.1, 475.1 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][C:21]=1[N+:22]([O-])=O)[NH:7][C:8]([C:10]1[NH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])([O-])=O.[CH:25](=O)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[C:26]1([C:25]2[NH:22][C:21]3[CH:20]=[CH:19][C:6]([NH:7][C:8]([C:10]4[NH:11][C:12]5[C:17]([CH:18]=4)=[CH:16][CH:15]=[CH:14][CH:13]=5)=[O:9])=[CH:5][C:4]=3[N:1]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(Nc1ccc([N+](=O)[O-])c([N+](=O)[O-])c1)c1cc2ccccc2[nH]1
Reactant: O=Cc1ccccc1
Product: O=C(Nc1ccc2[nH]c(-c3ccccc3)nc2c1)c1cc2ccccc2[nH]1

Procedure:
Compound 203 was prepared according to the procedure similar to that described in Scheme III from 3,4-dinitro-N-(indol-2-oyl)aniline and benzaldehyde. 1H NMR (500 MHz, CD3OD) δ 8.20 (d, J=1.5 Hz, 1H), 8.09 (dd, J=1.5, 8 Hz, 2H). 7.66 (d, J=8 Hz, 1H), 7.61 (d, J=8.5 Hz, 1H), 7.57-7.52 (m, 4H), 7.48 (dd, J=0.5, 8 Hz, 1H), 7.34 (s, 1H), 7.25 (dt, J=1, 7 Hz, 1H), 7.09 (dt, J=0.5, 8 Hz, 1H).
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[OH:12][C:13]1([CH3:40])[C@@H:18]([CH3:19])[CH2:17][N:16]([C:20]2[C:25]([N+:26]([O-:28])=[O:27])=[CH:24][N:23]=[C:22]3[CH2:29][CH2:30][CH2:31][C:21]=23)[CH2:15][C@H:14]1[NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36]>C(Cl)Cl>[OH:12][C:13]1([CH3:40])[C@@H:18]([CH3:19])[CH2:17][N:16]([C:20]2[C:25]([N+:26]([O-:28])=[O:27])=[CH:24][N+:23]([O-:9])=[C:22]3[CH2:29][CH2:30][CH2:31][C:21]=23)[CH2:15][C@H:14]1[NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C[C@H]1CN(c2c([N+](=O)[O-])cnc3c2CCC3)C[C@@H](NC(=O)OC(C)(C)C)C1(C)O
Solvent: ClCCl
Product: C[C@H]1CN(c2c([N+](=O)[O-])c[n+]([O-])c3c2CCC3)C[C@@H](NC(=O)OC(C)(C)C)C1(C)O
Reaction time: 2 h

Procedure:
mCPBA (260 mg, 1.5 mmol) was added to a mixture of tert-butyl [(3R,5S)-4-hydroxy-4,5-dimethyl-1-(3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)piperidin-3-yl]carbamate (312 mg, 0.768 mmol) in DCM (3.2 mL). After 2 h, LCMS showed only 30% conversion of starting material. mCPBA was added several more times (to a total amount of about 10 eq.) until LCMS showed complete consumption of starting material (after approximately 7 h). A saturated solution of NaHCO3 was then added to the mixture and the resulting mixture was extracted with DCM. The combined organic extracts were dried and then concentrated to dryness under reduced pressure. The crude sub-title compound was used in the next step without further purification. LCMS calc. for C20H31N4O6 (M+H)+ m/z=423.2. found 423.2.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[N:3]=1.[CH3:19][NH2:20].CO>>[Cl:8][C:6]1[CH:7]=[C:2]([NH:20][CH3:19])[N:3]=[C:4]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[N:5]=1
Reactant: COc1ccc(CSc2nc(Cl)cc(Cl)n2)cc1
Reactant: CN
Solvent: CO
Product: CNc1cc(Cl)nc(SCc2ccc(OC)cc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56 %

Procedure:
4,6-dichloro-2-(4-methoxybenzylsulfanyl)pyrimidine (3.0 g, 10 mmol) was dissolved in a 40% methylamine-methanol solution (20 ml) and stirred overnight at room temperature. The solvent was distilled away under reduced pressure, water was added and extracted twice with ethyl acetate. After combining the organic layers and washing with a saturated saline solution, it was dried with MgSO4 and the solvent was distilled away under reduced pressure. Separation and purification were performed by silica gel column chromatography (hexane:ethyl acetate=1:2) to obtain 1.64 g (56% yield) of 4-chloro-2-(4-methoxybenzylsulfanyl)-6-methylaminopyrimidine.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.Br[CH:16]([CH3:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18].C(=O)([O-])[O-].[Cs+].[Cs+].C([O-])([O-])=O.[Na+].[Na+]>C(#N)C>[CH3:1][C:2]1([CH3:14])[C:6]([CH3:7])([CH3:8])[O:5][B:4]([C:9]2[CH:13]=[N:12][N:11]([CH:16]([CH3:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:10]=2)[O:3]1
Reactant: CCOC(=O)C(C)Br
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)C(C)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Temperature: 90 °C
Reaction time: 4 h
Yield: 68 %

Procedure:
A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.40 g, 2.1 mmol, Aldrich, Cat. 525057), ethyl 2-bromopropanoate (290 μL, 2.3 mmol), and cesium carbonate (1.5 g, 4.6 mmol) in acetonitrile (8 mL) was stirred at 90° C. for 4 h. After cooling, the reaction mixture was worked up with aqueous Na2CO3, extracted with ethyl acetate (3×20 mL), and washed with brine. The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexanes (0-50%) to afford the desired product (0.42 g, 61%). LCMS (M+H)+: m/z=295.1.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[N:20]=[C:19]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[N:18]=[C:17]([O:27][CH2:28][CH2:29][C:30]([OH:32])=O)[C:16]=2[O:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[O:40][CH3:41])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:42][C:43]1[CH:49]=[CH:48][CH:47]=[C:46]([CH3:50])[C:44]=1[NH2:45]>>[CH3:42][C:43]1[CH:49]=[CH:48][CH:47]=[C:46]([CH3:50])[C:44]=1[NH:45][C:30](=[O:32])[CH2:29][CH2:28][O:27][C:17]1[C:16]([O:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[O:40][CH3:41])=[C:15]([NH:14][S:11]([C:8]2[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:10][CH:9]=2)(=[O:13])=[O:12])[N:20]=[C:19]([N:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)[N:18]=1
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(N2CCOCC2)nc1OCCC(=O)O
Reactant: Cc1cccc(C)c1N
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(N2CCOCC2)nc1OCCC(=O)Nc1c(C)cccc1C

Procedure:
The procedure described in Example 3 was repeated by use of 3-[6-(4-t-butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-morpholino-4-pyrimidinyloxy]propionic acid and 2,6-dimethylaniline, to thereby obtain the title compound as a colorless oil.