Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([C@@H:7]([NH2:11])[C:8]([OH:10])=O)=[CH:5][CH:6]=1.[CH3:12][NH-:13].[CH:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OCC)(=O)C>CO>[CH3:12][N:13]1[C:8](=[O:10])[C@@H:7]([C:4]2[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=2)[NH:11][C@H:14]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: N[C@@H](C(=O)O)c1ccccc1
Reactant: O=Cc1ccccc1
Reactant: C[NH-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: CN1C(=O)[C@@H](c2ccccc2)N[C@H]1c1ccccc1
Yield: 31 %

Procedure:
A solution of (R)-phenylglycine methyl amide (2.0 g, 12.2 mmol), benzaldehyde (990 μL, 9.7 mmol), and p-toluenesulfonic acid monohydrate (232 mg, 1.2 mmol) dissolved in 20 mL of methanol was heated to reflux for 16 hours. Concentration of the reaction mixture followed by silica gel chromatography (30-40% ethyl acetate in hexanes, linear gradient) afforded the title compound in 31% yield (750 mg, 3.0 mmol) and the more quickly eluting (2S, 5R) isomer in 58% yield (1.43 g, 5.7 mmol). IR (film) 3478, 3324, 3086, 3063, 3031, 2958, 2917, 2863, 1959, 1890, 1814, 1698, 1603, 1477, 1456, 1428, 1400, 1343, 1281, 1204, 1107, 1069, 1027, 985.9, 935.2, 916.7, 868.6, 834.7, 732.9, 698.1 cm−1; 1H NMR (300 MHz, CDCl3) δ 7.41 (m, 10H, ArH), 5.33 (s, 1H, NCHN), 4.66 (s, 1H, CHCO), 2.65 (s, 3H, CH3), 2.46 (s, 1H, NH); 13C NMR (75 MHz, CDCl 3) δ 173.4, 139.0, 138.6, 129.8, 129.3, 128.9, 128.3, 128.0, 127.7, 77.3, 63.7, 28.0; HRMS (CI) exact mass calc'd for (C16H16N2O) requires m/z 252.1263, found m/z 252.1265. [α]D=−8.6 (c=1.0, CHCl3). The relative stereochemistry of catalyst 3 was confirmed by NOE studies.
Reaction SMILES: [NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@H:2]([C:10]([OH:12])=O)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:23][C@@H:24]([C:32]([O:34][CH3:35])=[O:33])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.ClC(OCC(C)C)=O>>[NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@H:2]([C:10]([NH:23][C@@H:24]([C:32]([O:34][CH3:35])=[O:33])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:12])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Reactant: COC(=O)[C@H](N)Cc1ccccc1
Agent: CC(C)COC(=O)Cl
Product: COC(=O)[C@@H](Cc1ccccc1)NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Yield: 66 %

Procedure:
Condensation of ZPheOH (7.5 g.) and HDPheOMe (5.4 g.) by the mixed anhydride method using isobutyl chloroformate gave ZPhe-DPheOMe in 66% yield. Debenzyloxycarbonylation of ZPhe-DPheOMe (6.9 g.) by hydrogenation with palladium catalyst gave HPhe-DPheOMe in 100% yield. Condensation of BocProOH (3.23 g.) and HPhe-DPheOMe (4.9 g.) by the mixed anhydride method using isobutyl chloroformate gave BocPro-Phe-DPheOMe in 70% yield. Hydrazinolysis of BocPro-Phe-DPheOMe (5.0 g.) gave BocPro-Phe-DPheNHNH2 in 84% yield.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[N:8]=[C:9]([CH:11]3[CH2:16][CH:15]([CH:17]=[O:18])[CH2:14][CH2:13][NH:12]3)[S:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.C(C(O)=O)(F)(F)F.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][CH2:35]Br)=[CH:30][CH:29]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[C:7]2[N:8]=[C:9]([CH:11]3[CH2:16][CH:15]([CH:17]=[O:18])[CH2:14][CH2:13][N:12]3[CH2:35][CH2:34][C:31]3[CH:32]=[CH:33][C:28]([O:27][CH3:26])=[CH:29][CH:30]=3)[S:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=CC1CCNC(c2nc3c(Cl)cccc3s2)C1
Reactant: COc1ccc(CCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(CCN2CCC(C=O)CC2c2nc3c(Cl)cccc3s2)cc1
Temperature: 25 °C

Procedure:
Mix [2-(4-chlorobenzothiazolyl)](4-piperidinyl)methanone.CF3CO2H (9.19 mmol), 2-(4-methoxyphenyl)ethyl bromide (2.07 g, 9.64 mmol), potassium carbonate (3.33 g, 24.1 mmol) and dimethylformamide (35 mL) and heat at 90° C. overnight. Cool to room temperature and partition between a 2:1 mixture of ethyl acetate/toluene and water. Separate the aqueous phase and wash the organic phase with water and brine. Dry (MgSO4) and evaporate the solvent in vacuo. Purify by chromatography to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][N:8]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[C:5]2=[N:6][CH:7]=1.[I:21]N1C(=O)CCC1=O>ClCCl>[I:21][C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([CH3:1])[CH:3]=2)[N:8]([Si:11]([CH:15]([CH3:17])[CH3:16])([CH:12]([CH3:14])[CH3:13])[CH:18]([CH3:20])[CH3:19])[CH:9]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Cc1cnc2c(ccn2[Si](C(C)C)(C(C)C)C(C)C)c1
Solvent: ClCCl
Product: Cc1cnc2c(c1)c(I)cn2[Si](C(C)C)(C(C)C)C(C)C
Reaction time: 0.17 h
Yield: 76.2 %

Procedure:
5-Methyl-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (6, 1.1 g, 3.8 mmol) and 10 mL of dichloromethane are combined in a round bottom flask and stirred for 10 minutes. A slurry of N-iodosuccinimide (1.0 g, 4.6 mmol) in 5 mL of dichloromethane is added and stirred at room temperature overnight. The reaction is quenched with sodium thiosulfate (20 mL, 1M in water) and the aqueous layer is extracted with ethyl acetate. The combined organic layer is washed with water and brine, dried with sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material is purified by silica gel column chromatography, eluting with ethyl acetate and hexanes. Appropriate fractions are combined and concentrated under vacuum to provide the desired compound as a light yellow oil (8, 1.2 g, 75%). MS (ESI) [M+H+]+=415.08.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[C:15]([OH:17])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=1)(=O)=O.[F:20][C:21]([F:33])([F:32])[O:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1>C(Cl)Cl.C(O)(C(F)(F)F)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:20][C:21]([F:32])([F:33])[O:22][C:23]1[CH:28]=[CH:27][C:26]([C:7]2[CH:16]=[C:15]([OH:17])[C:14]3[C:9]([CH:8]=2)=[CH:10][CH:11]=[CH:12][CH:13]=3)=[CH:25][CH:24]=1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: O=S(=O)(Oc1cc(O)c2ccccc2c1)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Oc1cc(-c2ccc(OC(F)(F)F)cc2)cc2ccccc12

Procedure:
4-Hydroxy-2-naphthyl trifluoromethanesulfonate (100 mg, 0.34 mmol), 4-(trifluoromethoxy)phenyl boronic acid (0.14 g, 0.68 mmol) and Pd(PPh3)4 (20 mg, 0.017 mmol) in DME/2M K2CO3 (1/1) were heated at reflux under an argon atmosphere. After approximately 2 hours the solution was cooled and partitioned between aqueous 1N hydrochloric acid and ethyl acetate. The organic phase was dried over MgSO4, filtered and concentrated. The residue was purified by silica gel chromatography using a hexanes/ethyl acetate gradient to give the title compound. LCMS1 3.94 min. (M+H)=305
Reaction SMILES: C([NH:9][C:10]1[CH:15]=[CH:14][N:13]([CH:16]2[CH:20]([O:21]C(=O)C3C=CC=CC=3)[CH2:19][CH:18]([CH:30]=[CH:31][P:32]([O:37]CC)([O:34]CC)=[O:33])[O:17]2)[C:12](=[O:40])[CH:11]=1)(=O)C1C=CC=CC=1.NC1NC(=O)C2N=NN(C3OC(C=CP(=O)(O)O)CC3O)C=2N=1>>[NH2:9][C:10]1[CH:15]=[CH:14][N:13]([CH:16]2[O:17][CH:18]([CH:30]=[CH:31][P:32](=[O:33])([OH:34])[OH:37])[CH2:19][CH:20]2[OH:21])[C:12](=[O:40])[CH:11]=1
Reactant: CCOP(=O)(C=CC1CC(OC(=O)c2ccccc2)C(n2ccc(NC(=O)c3ccccc3)cc2=O)O1)OCC
Agent: Nc1nc2c(nnn2C2OC(C=CP(=O)(O)O)CC2O)c(=O)[nH]1
Product: Nc1ccn(C2OC(C=CP(=O)(O)O)CC2O)c(=O)c1
Yield: 84.6 %

Procedure:
Compound 11.2 (97 mg, 86.5% yield) was synthesized from compound 11.1 (215 mg) using the procedure for the preparation of compound 10.2. 1H NMR (D2O) δ 1.8 (m, 1H), 2.05 (m, 1H), 4.3 (d, 1H, J=4.8), 4.8 (m, 1H), 5.69 (s, 1H), 6.0 (m, 1H), 6.2 (m, 1H), 7.52 (d, 1H, J=7.8). 31P NMR (D2O) d 9.8. LRMS (ESI) MH+ C10H14N3O6P requires 304.2. Found 304.0.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]([O:15]C2CCCCO2)[CH3:14])(=O)=O)=CC=1.CC1C=CC(S(OC[C@@H](OC2CCCCO2)C)(=O)=O)=CC=1.[F:43][C:44]1([F:88])[CH2:49][CH2:48][CH:47]([C:50]2[C:59]3[CH:58]([OH:60])[CH2:57][C:56]([CH3:62])([CH3:61])[CH2:55][C:54]=3[N:53]=[C:52]([CH:63]3[CH2:68][CH2:67][N:66]([C:69]4[N:74]=[CH:73][C:72]([OH:75])=[CH:71][N:70]=4)[CH2:65][CH2:64]3)[C:51]=2[CH:76]([F:87])[C:77]2[CH:82]=[CH:81][C:80]([C:83]([F:86])([F:85])[F:84])=[CH:79][CH:78]=2)[CH2:46][CH2:45]1>>[F:88][C:44]1([F:43])[CH2:45][CH2:46][CH:47]([C:50]2[C:59]3[CH:58]([OH:60])[CH2:57][C:56]([CH3:61])([CH3:62])[CH2:55][C:54]=3[N:53]=[C:52]([CH:63]3[CH2:64][CH2:65][N:66]([C:69]4[N:74]=[CH:73][C:72]([O:75][CH2:12][C@H:13]([OH:15])[CH3:14])=[CH:71][N:70]=4)[CH2:67][CH2:68]3)[C:51]=2[CH:76]([F:87])[C:77]2[CH:78]=[CH:79][C:80]([C:83]([F:85])([F:84])[F:86])=[CH:81][CH:82]=2)[CH2:48][CH2:49]1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H](C)OC2CCCCO2)cc1
Reactant: CC1(C)Cc2nc(C3CCN(c4ncc(O)cn4)CC3)c(C(F)c3ccc(C(F)(F)F)cc3)c(C3CCC(F)(F)CC3)c2C(O)C1
Agent: Cc1ccc(S(=O)(=O)OC[C@H](C)OC2CCCCO2)cc1
Product: C[C@@H](O)COc1cnc(N2CCC(c3nc4c(c(C5CCC(F)(F)CC5)c3C(F)c3ccc(C(F)(F)F)cc3)C(O)CC(C)(C)C4)CC2)nc1

Procedure:
Reactions similar to those of Example 37 were performed except for using (2R)-2-(tetrahydro-2H-pyran-2-yloxy)propyl 4-methylbenzenesulfonate, which was synthesized by the method described in B. A. Jones et al., Journal of Heterocyclic Chemistry, 1982, Vol. 19, pp. 551-556, instead of (2S)-2-(tetrahydro-2H-pyran-2-yloxy)propyl 4-methylbenzenesulfonate, and from 50 mg (77 μmol) of 4-(4,4-Difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-2-[1-(5-hydroxy pyrimidin-2-yl)piperidin-4-yl]-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-5-ol, which was prepared by a method similar to that of Example 4, 39 mg of the title compound was obtained as a white solid (yield: 71%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:31])[CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:19][CH:18]=3)=[O:15])=[CH:7][C:6]=2[CH:32]=1.B([O-])([O-])O[C:35]1[CH:40]=[CH:39][C:38]([N:41]([CH3:48])[CH2:42][CH2:43][O:44][CH2:45][CH2:46][CH3:47])=[CH:37][CH:36]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:48][N:41]([C:38]1[CH:37]=[CH:36][C:35]([C:2]2[CH:3]=[CH:4][C:5]3[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([CH2:23][N:24]([CH3:31])[CH:25]5[CH2:30][CH2:29][O:28][CH2:27][CH2:26]5)=[CH:21][CH:22]=4)=[O:15])=[CH:7][C:6]=3[CH:32]=2)=[CH:40][CH:39]=1)[CH2:42][CH2:43][O:44][CH2:45][CH2:46][CH3:47]
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(Br)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
Reactant: CCCOCCN(C)c1ccc(OB([O-])[O-])cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCCOCCN(C)c1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCS3(=O)=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.6 %

Procedure:
Under argon atmosphere, a mixture of 7-bromo-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (300 mg), 4-[N-methyl-N-(2-propoxyethyl)amino]phenyl borate (205 mg) and potassium carbonate (176 mg) in toluene/ethanol/water (10/1/1 ml) was stirred at room temperature for 1 hour. To the mixture was added tetrakistriphenylphosphinepalladium (40 mg), and the mixture was refluxed for 8 hours, cooled, extracted with ethyl acetate, washed with saturated brine, dried with magnesium sulfate and was concentrated under reduced pressure. The residue was purified with silica gel column chromatography (ethanol/ethyl acetate=1:4) to give crystals, which were recrystallized from ethanol to give pale yellow crystals of 7-[4-[N-methyl-N-(2-propoxyethyl)amino]phenyl]-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 72) (210 mg).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[CH3:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[CH:31]=[CH:30][C:29](C(O)=O)=[CH:28][CH:27]=1.[NH2:35][CH2:36][C@@H:37]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[OH:38]>>[OH:38][C@H:37]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH2:36][NH:35][C:16]([C@@H:9]1[CH2:10][C:11](=[N:13][O:14][CH3:15])[CH2:12][N:8]1[C:6]([C:29]1[CH:28]=[CH:27][C:26]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[CH3:19])=[CH:31][CH:30]=1)=[O:7])=[O:18]
Reactant: NC[C@H](O)c1ccccc1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: Cc1ccccc1-c1ccc(C(=O)O)cc1
Product: CON=C1C[C@@H](C(=O)NC[C@H](O)c2ccccc2)N(C(=O)c2ccc(-c3ccccc3C)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, 2′-methyl[1,1′-biphenyl]-4-carboxylic acid, and (1R)-2-amino-1-phenylethanol, the title compound was obtained in 84% purity by HPLC. MS(ESI+): m/z=472.
Reaction SMILES: [C:1](NC(N)=N)#[N:2].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]=[C:15]=[N:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:23]([F:26])([F:25])[F:24])=[C:10]([O:27][Si](C(C)(C)C)(C)C)[C:9]=1[S:35]([N:38]([CH3:40])[CH3:39])(=[O:37])=[O:36].[N:41]#CN.C(N(CC)C(C)C)(C)C.[F-].[Cs+]>>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]([C:1]#[N:2])[C:15]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:23]([F:24])([F:26])[F:25])=[NH:41])=[C:10]([OH:27])[C:9]=1[S:35]([N:38]([CH3:39])[CH3:40])(=[O:36])=[O:37]
Reactant: N#CNC(=N)N
Reactant: CN(C)S(=O)(=O)c1c(Cl)ccc(N=C=Nc2ccccc2C(F)(F)F)c1O[Si](C)(C)C(C)(C)C
Reactant: N#CN
Agent: [Cs+]
Agent: [F-]
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)S(=O)(=O)c1c(Cl)ccc(N(C#N)C(=N)Nc2ccccc2C(F)(F)F)c1O
Yield: 37 %

Procedure:
Following the general procedure for cyanoguanidine formation outlined in example 12, N-[4-chloro-2-tert-butyldimethylsilyloxy-3-(N″,N″-dimethylaminosulfonyl)phenyl]-N′-(2-trifluoromethylphenyl)carbodiimide (250 mg, 0.47 mmol), cyanamide (79 mg, 1.88 mmol) and N,N-diisopropylethylamine (73 mg, 0.56 mmol) were reacted, followed by desilylation with Cesium fluoride (86 mg, 0.56 mmol) to form the desired product (80 mg, 37%). EI-MS m/z 462.0 (M+). 1H NMR (DMSO-d6) δ 2.86 (s, 6H), 7.14 (d, 1H), 7.53 (m, 2H), 7.59 (d, 1H), 7.75 (t, 1H), 7.77 (d, 1H), 8.91 (s, 1H), 9.28 (s, 1H), 10.53 (s, 1H).
Reaction SMILES: O1CCCC1.[CH2:6]([O:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18](Cl)=[N:19][OH:20])=[CH:13][CH:12]=1)[CH2:7][CH2:8][CH3:9].[C:22]([C:24]1[C:25]([NH2:30])=[N:26][CH:27]=[CH:28][CH:29]=1)#[CH:23].C(N(CC)CC)C>O>[CH2:6]([O:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]2[CH:23]=[C:22]([C:24]3[C:25]([NH2:30])=[N:26][CH:27]=[CH:28][CH:29]=3)[O:20][N:19]=2)=[CH:13][CH:12]=1)[CH2:7][CH2:8][CH3:9]
Reactant: CCCCOc1ccc(CC(Cl)=NO)cc1
Reactant: C#Cc1cccnc1N
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CCCCOc1ccc(Cc2cc(-c3cccnc3N)on2)cc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 21.1 %

Procedure:
To a tetrahydrofuran (3 mL) solution of (4-butoxy-phenyl)-acetohydroximoyl chloride (150 mg, 0.619 mmol) described in Manufacturing Example 67-1-4 and 3-ethynyl-pyridin-2-ylamine (47 mg, 0.395 mmol) described in Manufacturing Example 1-2-3 was added triethylamine (216 μL, 1.55 mmol) at room temperature, which was stirred for 2 hours at 50° C. Water was added to the reaction solution at room temperature, which was then extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate. The solvent was devaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=4:1-2:1) to obtain the title compound (27 mg, 14%).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4](S(O)(=O)=O)=[CH:3][CH:2]=1.C(OC([N:22]1[CH2:26][CH2:25][C@H:24]([NH2:27])[C@@H:23]1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=O)C1C=CC=CC=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[BrH:48].C(Cl)[Cl:50]>C(O)(=O)C>[BrH:48].[BrH:48].[Cl:50][C:3]1[CH:2]=[C:1]([CH:6]=[CH:5][CH:4]=1)[CH2:11][NH:27][C@H:24]1[CH2:25][CH2:26][NH:22][C@H:23]1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: N[C@H]1CCN(C(=O)OCc2ccccc2)[C@H]1c1ccccc1
Reactant: ClCCl
Agent: Br
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: Clc1cccc(CN[C@H]2CCN[C@H]2c2ccccc2)c1
Reaction time: 16 h
Yield: 79 %

Procedure:
A mixture of cis-3-amino-2-phenyl-pyrrolidine-1-carboxylic acid benzyl ester p-toluenesulfonate (0.15 g, 0.32 mmol), obtained from preparatory example 6,3-chlorobenzaldehyde (0.34 mmol), and sodium triacetoxyborohydride (0.082 g, 0.38 mmol) was stirred in 3 mL of methylene chloride at rt for 16 h. The reaction was washed 1× with 1M NaOH, dried through cotton, and concentrated to give an oil. The oil was dissolved in acetic acid (1 mL) and a solution of 30% hydrogen bromide in acetic acid (0.302 g, 1.12 mmol) was added. The solution was stirred for 16 h and the resultant solids were collected, washed with ether, and concentrated under vacuum to give 0.114 g (79%) of the title compound. 1H NMR (2HBr, CD3OD) δ 7.72-7.68 (m, 2H), 7.64-7.57 (m, 3H), 7.45-7.31 (m, 4H), 5.31-5.29 (d, J=7.46 Hz, 1H), 4.45-4.41 (q, J=7.88 Hz, 1H), 4.31-4.28 (d, J=12.85 Hz, 1H), 4.04-4.01 (d, J=12.85 Hz, 1H), 3.97-3.91 (ddd, J=12.13, 9.33, 2.90 Hz, 1H), 3.62-3.54 (m, 1H), 2.89-2.81 (m, 1H), 2.66-2.56 (m, 1H). MS APCI: [M+H]+=287.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([CH2:9][C:10]#N)[C:6]([N+:12]([O-])=O)=[CH:5][CH:4]=1.[H-].[Na+].[I:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21].CN([CH:30]=[O:31])C>>[I:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]([N:12]1[C:6]2[C:7](=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:9]([CH:30]=[O:31])=[CH:10]1)=[O:21]
Reactant: CN(C)C=O
Reactant: O=C(Cl)c1ccccc1I
Reactant: COc1ccc([N+](=O)[O-])c(CC#N)n1
Agent: [H-]
Agent: [Na+]
Product: COc1ccc2c(n1)c(C=O)cn2C(=O)c1ccccc1I
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Under an argon atmosphere, 0.56 mmol of the compound obtained in Step A are dissolved in 5 ml of DMF, and then 0.68 mmol of NaH are added at 0° C., over a period of 30 minutes. After 30 minutes' stirring at 0° C., 0.68 mmol of 2-iodobenzoyl chloride dissolved in 5 ml of DMF is added dropwise to the mixture. After 3 hours' stirring, the solvents are removed by evaporation and the residue is taken up in water and extracted with dichloromethane. After drying over magnesium sulphate and removal of the solvents by evaporation, the residue is purified by flash chromatography over silica gel (eluant:petroleum ether/ethyl acetate) to yield the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])O[C:6]2=[O:13].Cl.[N:15]1[CH:20]=[CH:19][C:18]([NH:21][NH2:22])=[CH:17][CH:16]=1.C(O)(=O)C>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:22]([NH:21][C:18]1[CH:19]=[CH:20][N:15]=[CH:16][CH:17]=1)[C:6]2=[O:13]
Reactant: NNc1ccncc1
Reactant: COc1ccc2c(c1)C(=O)OC2=O
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc2c(c1)C(=O)N(Nc1ccncc1)C2=O
Yield: 33.9 %

Procedure:
A mixture of 5-methoxyisobenzofuran-1,3-dione (33.0 g), 4-pyridinylhydrazine hydrochloride (25.7 g) and glacial acetic acid (100 ml) was heated overnight, under reflux, under nitrogen, with stirring. Water (100 ml) was added, and the mixture was evaporated and dried in vacuo. The residue was triturated with acetone, the acetone decanted, and the residue was triturated with methanol to give 16.1 g of 5-methoxy-2-(4-pyridinylamino)isoindol-1,3-dione. To a mixture of lithium aluminum hydride (6.00 g) and dry tetrahydrofuran (150 ml) at ambient temperature, under nitrogen, 5-methoxy-2-(4-pyridinylamino)isoindol-1,3-dione hydrochloride (16.1 g) was added in portions, with stirring. The reaction mixture was stirred at room temperature, under nitrogen, 4 hrs, and sodium sulfate decahydrate was added in portions. The mixture was filtered through a bed of celite, the filter cake was washed thoroughly with ethyl acetate, and the filtrate was concentrated in vacuo. The residue was chromatographed over silica gel, eluting with 7% methanol-dichloromethane followed by 185:14:1 dichloromethane:methanol:ammomium hydroxide. The appropriate fractions were collected and concentrated. The residue was crystallized from ethanol to give 5.8 (46%) of product, mp 166-167° C.
Reaction SMILES: CC(C)([O-])C.[K+].[Cl:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].[CH:14](OCC)=O.[NH2:19][C:20]([NH2:22])=[S:21]>C1COCC1>[ClH:7].[NH2:19][C:20]1[S:21][C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:14][N:22]=1
Reactant: CCOC(=O)CCl
Reactant: NC(N)=S
Reactant: CCOC=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cnc(N)s1
Product: Cl
Temperature: -1 °C
Reaction time: 2 h

Procedure:
To a -10° C. solution of potassium tert-butoxide (110 g, 0.98 mol) in THF (1.9 L) was added a solution of ethyl chloroacetate (100 mL, 0.934 mol) and ethyl formate (75 mL, 0.928 mol)in THF (400 mL) dropwise over 2 hours, with good mechanical stirring. The thick solution was stirred another 2 hours at ca. -1° C. then the reaction was quenched by addition of a solution of NaCl (150 g) in 1N HCL (750 mL). The mixture was allowed to warm to 20° C. and the lower aqueous layer (containing some precipitated salt) was separated. The organic layer was stripped under vacuum on a rotary evaporator. The oil was redissolved in 500 mL ethyl acetate, dried with 75 g Na2SO4 for 1 hour, filtered and concentrated under vacuum (40°-50° C. bath temperature) to an oil. The resulting crude chloroaldehyde (161 g) and thiourea (70 g, 0.92 mol) were dissolved in THF (2 L) and warmed to gentle reflux (60° C.). The thiourea dissolved during warming, and within 20 minutes, product precipitated from solution. After 100 minutes the suspension was allowed to cool to room temperature, then was cooled in an ice-bath for 1 hour. The product was collected on a fritted Buchner funnel and washed with 2×100 mL cold THF, then dried overnight in a vacuum oven at 50° C. Yield: 122 g of title compound as a tan-colored solid, m.p. 182°-185° C. (dec.). 1H NMR (DMSO-d6H) δ7.86 (s, 1H), 4.19 (q, 2H), 1.21 (t, 3H). 13C NMR (DMSO-d6) δ171.9, 160.4, 140.4, 114.4, 61.1, 14.2.