Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][C:7]2([C:17](OCC)=[O:18])[CH2:12][CH2:11][CH:10]([C:13]([F:16])([F:15])[F:14])[CH2:9][CH2:8]2)=[C:4](I)[CH:3]=1.C([Mg]Cl)(C)C.[Cl-].[Li+]>C1COCC1>[Br:1][C:2]1[CH:23]=[C:22]2[C:5]([CH2:6][C:7]3([CH2:12][CH2:11][CH:10]([C:13]([F:15])([F:14])[F:16])[CH2:9][CH2:8]3)[C:17]2=[O:18])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1(Cc2ccc(Br)cc2I)CCC(C(F)(F)F)CC1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1c2cc(Br)ccc2CC12CCC(C(F)(F)F)CC2
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 52.7 %

Procedure:
Ethyl 1-(4-bromo-2-iodobenzyl)-4-(trifluoromethyl)cyclohexanecarboxylate (Intermediate 77, 2.41 g, 4.64 mmol) was dissolved in THF (40 mL). The atmosphere was exchanged to argon, and the solution was cooled to −78° C. Isopropylmagnesium chloride-lithium chloride (1.3 M in THF) (2.86 mL, 3.71 mmol) was added dropwise. The reaction mixture was stirred at −78° C. for 15 min. The reaction mixture left to warm up to r.t., while stirred for 30 min. The reaction is mixture was quenched with sat. NH4Cl. Brine was added, and the phases were separated. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by preparative chromatography (XBridge C18 (10 μm, 50×250 mm) column with a gradient of 50-100% MeCN) in (95% 0.05M NH4OAc in MilliQ water and 5% MeCN) over 15 min at a flow rate of 100 mL/min). The purification provided the title compound (0.849 g, 52% yield): 1H NMR (400 MHz, CDCl3) δ ppm 1.51-1.61 (m, 3 H) 1.75-1.84 (m, 2 H) 1.97 (m, 2 H) 2.18 (m, 2 H) 2.90 (s, 2 H) 7.29 (dd, 1 H) 7.69 (dd, 1 H) 7.84 (d, 1 H); MS (ES+) 346 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[S:5][C:6]([C:12]2[N:16]=[CH:15][N:14]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[N:13]=2)=[CH:7][C:8]=1[C:9]([NH2:11])=[O:10])([O-])=O.O.NN>CO>[NH2:1][C:4]1[S:5][C:6]([C:12]2[N:16]=[CH:15][N:14]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[N:13]=2)=[CH:7][C:8]=1[C:9]([NH2:11])=[O:10]
Reactant: C[Si](C)(C)CCOCn1cnc(-c2cc(C(N)=O)c([N+](=O)[O-])s2)n1
Agent: NN
Solvent: O
Solvent: CO
Product: C[Si](C)(C)CCOCn1cnc(-c2cc(C(N)=O)c(N)s2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 2-nitro-5-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,4-triazol-3-yl)thiophene-3-carboxamide (600 mg, 1.62 mmol) in MeOH (25 mL) was added FeCl3 (13 mg, 0.081 mmol). The solution was heated to reflux, and hydrazine hydrate (65%, 0.364 ml, 4.87 mmol) was added. After stirring for 30 minutes at reflux, the mixture was cooled to room temperature, combined with MeOH and silica gel, and evaporated to dryness. Flash chromatography (dry load, 0-10% MeOH/EtOAc) afforded the title compound as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][N:11]2[C:19]3[C:14](=[CH:15][C:16]([F:20])=[CH:17][CH:18]=3)[C@:13]3([CH2:22][C@:21]3([C:26]3[CH:31]=[CH:30][C:29](I)=[CH:28][CH:27]=3)[CH:23]([CH3:25])[CH3:24])[C:12]2=[O:33])[CH:5]=1.[C-:35]#[N:36].[Na+]>O1CCCC1.[Cu]I.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>[CH3:1][O:2][C:3](=[O:34])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][N:11]2[C:19]3[C:14](=[CH:15][C:16]([F:20])=[CH:17][CH:18]=3)[C@:13]3([CH2:22][C@:21]3([C:26]3[CH:31]=[CH:30][C:29]([C:35]#[N:36])=[CH:28][CH:27]=3)[CH:23]([CH3:25])[CH3:24])[C:12]2=[O:33])[CH:5]=1
Reactant: COC(=O)c1cccc(CN2C(=O)[C@@]3(C[C@]3(c3ccc(I)cc3)C(C)C)c3cc(F)ccc32)c1
Reactant: [C-]#N
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1cccc(CN2C(=O)[C@@]3(C[C@]3(c3ccc(C#N)cc3)C(C)C)c3cc(F)ccc32)c1
Temperature: 25 °C
Yield: 44.5 %

Procedure:
A solution of (1S,2S) and (1R,2R)-methyl-3-((-5′-fluoro-2-(4-iodophenyl)-2-isopropyl-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)methyl)benzoate (1.35 g, 2.4 mmol), NaCN (240 mg, 4.9 mmol), CuI (50 mg, 0.3 mmol) and Pd(PPh3)4 (140 mg, 0.12 mmol) in tetrahydrofuran (9.0 mL) was stirred at 65° C. for 2 hours. The mixture was cooled to room temperature and extracted with ethyl acetate and washed with brine, dried over anhydrous sodium sulfate, concentrated in vacuo. Purification by flash column chromatography eluting with Hexane/ethyl acetate (8:1 to 4:1) to afford light yellow oil (500 mg, yield 45.5%) LC/MS m/e calcd. for C29H25FN2O3: 469, observed (M+H)+: 469.2
Reaction SMILES: [F:1][C:2]1[C:3]([N:9]=[CH:10][N:11]([CH3:13])[CH3:12])=[N:4][C:5]([OH:8])=[N:6][CH:7]=1.[C:14]1([S:20](Cl)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>N1C=CC=CC=1>[CH3:12][N:11]([CH:10]=[N:9][C:3]1[C:2]([F:1])=[CH:7][N:6]=[C:5]([O:8][S:20]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:22])=[O:21])[N:4]=1)[CH3:13]
Reactant: CN(C)C=Nc1nc(O)ncc1F
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Product: CN(C)C=Nc1nc(OS(=O)(=O)c2ccccc2)ncc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 50.8 %

Procedure:
To a suspension of N′-(5-fluoro-2-hydroxypyrimidin-4-yl)-N,N-dimethylformamidine (0.10 g, 0.54 mmol) in pyridine (2 mL) was added benzene sulfonyl chloride (0.106 g, 0.60 mmol) and the mixture was agitated on an orbital shaker for 16 h at room temperature. The reaction mixture was partitioned between EtOAc and saturated aq NaHCO3, and the organic phase was dried over solid MgSO4, filtered, and concentrated under reduced pressure. Purification by reverse phase chromatography (H2O/MeCN gradient) afforded the title compound (0.089 g, 46% yield) as a white solid: mp 124-125° C.; 1H NMR (300 MHz, CDCl3) δ 8.54 (s, 1H), 8.12-8.07 (m, 3H), 7.73-7.66 (m, 1H), 7.62-7.56 (m, 2H), 3.21 (s, 6H); HPLC-MS (ESI) m/z 325 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][C:16]2[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][C:17]=2[NH:25][C:26]2[C:27]3[CH:35]=[CH:34][C:33]([CH:36]([CH3:38])[CH3:37])=[N:32][C:28]=3[N:29]=[CH:30][N:31]=2)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:39][C:40]1[CH:45]=[CH:44][C:43]([NH:46][C:47]([C@@H:49]2[CH2:53][CH2:52][CH2:51][N:50]2[C:54]([O:56][CH2:57][C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)=[O:55])=[O:48])=[CH:42][CH:41]=1>>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]([NH:39][C:40]3[CH:45]=[CH:44][C:43]([NH:46][C:47]([C@@H:49]4[CH2:53][CH2:52][CH2:51][N:50]4[C:54]([O:56][CH2:57][C:58]4[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=4)=[O:55])=[O:48])=[CH:42][CH:41]=3)=[O:21])=[CH:18][C:17]=2[NH:25][C:26]2[C:27]3[CH:35]=[CH:34][C:33]([CH:36]([CH3:37])[CH3:38])=[N:32][C:28]=3[N:29]=[CH:30][N:31]=2)=[CH:11][CH:10]=1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)O)ccc3Sc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1
Reactant: Nc1ccc(NC(=O)[C@@H]2CCCN2C(=O)OCc2ccccc2)cc1
Product: CC(C)c1ccc2c(Nc3cc(C(=O)Nc4ccc(NC(=O)[C@@H]5CCCN5C(=O)OCc5ccccc5)cc4)ccc3Sc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1
Yield: 64.9 %

Procedure:
The product from Example 1E (0.15 g, 0.28 mmol) and the Product from Example 3B (0.134 g, 0.395 mmol) were processed in the same manner as Example 1K to give a solid (0.155 g, 64%).
Reaction SMILES: [C:1]1([C@H:11]([NH:13][CH:14]2[CH2:17][N:16](C(OCC3C=CC=CC=3)=O)[CH2:15]2)[CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1>CO.[C].[Pd]>[C:1]1([C@H:11]([NH:13][CH:14]2[CH2:17][NH:16][CH2:15]2)[CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: C[C@@H](NC1CN(C(=O)OCc2ccccc2)C1)c1cccc2ccccc12
Agent: [Pd]
Solvent: CO
Product: C[C@@H](NC1CNC1)c1cccc2ccccc12
Reaction time: 4 h
Yield: 77.5 %

Procedure:
To a solution of 5.0 g of 1-benzohydrylazetidin-3-one dissolved in 75 ml of toluene was added 2.98 ml of benzyloxycarbonyl chloride, and the mixture was stirred at 80° C. for 4 hours. The reaction mixture was evaporated, and then, to the residue were added water and ethyl acetate, the mixture was stirred and the liquids were separated. The organic layer washed with water and a saturated brine, dried and concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=19:1→4:1), and then, hexane was added thereto, and after collecting the precipitate by filtration, it washed with hexane to obtain 2.73 g of benzyl 3-oxoazetidine-1-carboxylate. (3) To a solution of 8.51 g of benzyl 3-oxoazetidine-1-carboxylate and 7.10 g (R)-(+)-1-(1-naphthyl)ethylamine dissolved in 170 ml of methylene chloride, 7.49 g of magnesium sulfate was added to the solution. The mixture was stirred at room temperature for 3 hours, and then, 9.5 ml of acetic acid and 13.18 g of sodium triacetoxy borohydride were added thereto, and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added a saturated aqueous sodium bicarbonate solution to make the mixture basic, chloroform was added to the same and the mixture was stirred, and the liquids were separated. The organic layer was dried and concentrated, and the residue was purified by NH silica gel column chromatography (hexane:ethyl acetate=4:1→1:1) to obtain 7.90 g of benzyl 3-[(R)-1-(naphthalen-1-yl)ethylamino]-azetidine-1-carboxylate. (4) To a solution of 9.45 g of benzyl 3-[(R)-1-(naphthalen-1-yl)ethylamino]azetidine-1-carboxylate dissolved in 190 ml of methanol, 1 g of palladium carbon (10% wet) was added thereto, and the reaction was carried out under hydrogen atmosphere at room temperature for 4 hours. Palladium carbon was removed, the solvent was evaporated, and the residue was purified by NH silica gel column chromatography (chloroform:methanol=1:0→19:1) to obtain 4.60 g of 3-[(R)-1-(naphthalen-1-yl)ethylamino]azetidine. To a solution of 4.60 g of 3-[(R)-1-(naphthalen-1-yl)ethylamino]azetidine dissolved in 30 ml of ethyl acetate, under ice-cooling, 13 ml of a solution of 4M hydrochloric acid in ethyl acetate was added dropwise, and the mixture was stirred for a while.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([O:12][C:13]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:14]=1[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:6]=[CH:5]2.C1(C)C=CC=CC=1.C(OCC)(=O)C.[CH3:42][N:43](C)C=O>[C-]#N.[Zn+2].[C-]#N.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>[C:42]([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([O:12][C:13]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:14]=1[C:15]([O:17][C:18]([CH3:20])([CH3:21])[CH3:19])=[O:16])[CH:6]=[CH:5]2)#[N:43]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)c1ccc([N+](=O)[O-])cc1Oc1ccc2cc(Br)ccc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1ccc([N+](=O)[O-])cc1Oc1ccc2cc(C#N)ccc2c1
Temperature: 25 °C

Procedure:
The compound (t-butyl 2-(6-bromo-2-naphthyloxy)-4-nitrobenzoate) (1.78 g) obtained in a previous production example, zinc cyanide (0.33 g) and tetrakis(triphenylphosphine)palladium (0) (690 mg) were reacted for 12 hours at 100° C. in N,N-dimethylformamide. After cooling to room temperature, toluene and ethyl acetate were added, the organic layer was washed with 2 N ammonia water and saturated saline and dried over magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel chromatography (300 g, hexane:ethyl acetate=6:1) to obtain 1.14 g of t-butyl 2-(6-cyano-2-naphthyloxy)-4-nitrobenzoate.
Reaction SMILES: Br[CH2:2][C:3](=[O:5])[CH3:4].[NH2:6][C@@H:7]([CH3:10])[CH2:8][OH:9].O>C(Cl)Cl>[OH:9][CH2:8][C@@H:7]([NH:6][CH2:2][C:3](=[O:5])[CH3:4])[CH3:10]
Reactant: C[C@H](N)CO
Reactant: CC(=O)CBr
Solvent: ClCCl
Solvent: O
Product: CC(=O)CN[C@@H](C)CO
Temperature: 0 °C
Reaction time: 2 h
Yield: 145.7 %

Procedure:
A solution of 1-bromopropan-2-one (7.8 mL, 102 mmol) in DCM (15 mL) was added dropwise to a solution of (S)-2-aminopropan-1-ol (18.2 g, 0.243 mol) and anhydrous DCM (150 mL) at 0° C. The reaction stirred at 0° C. for 2 h. Water (150 mL) was added, and the organic phase was separated. The aqueous was extracted with DCM (3×40 mL), and the combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated to give the crude product 19.5 g, which was used directly in the following step. LCMS: 132 (M+H)+.
Reaction SMILES: [C:1]1([N:7]2[C:11]([NH2:12])=[CH:10][C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([N:27]=[C:28]=[S:29])(=O)C1C=CC=CC=1>>[C:1]1([N:7]2[C:11]([NH:12][C:28]([NH2:27])=[S:29])=[CH:10][C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1cc(-c2ccccc2)nn1-c1ccccc1
Reactant: O=C(N=C=S)c1ccccc1
Product: NC(=S)Nc1cc(-c2ccccc2)nn1-c1ccccc1

Procedure:
1,3-Diphenyl-5-amino pyrazole (117.5 g.) and benzoyl isothiocyanate (89.65 g.) were reacted as described in Example IV to give 119.8 g. of product, mp 198°-201° C.
Reaction SMILES: [CH2:1]([C:4]1[NH:8][C:7]2[CH:9]=[C:10]([N:14]3[C:18](=[O:19])[C:17]4=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]4[C:15]3=[O:24])[CH:11]=[C:12]([CH3:13])[C:6]=2[N:5]=1)[CH2:2][CH3:3].Br[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[C:34]([C:39]([O:41][CH3:42])=[O:40])=[CH:35][CH:36]=[CH:37][CH:38]=2)=[CH:29][CH:28]=1>>[CH2:1]([C:4]1[N:8]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]3[C:34]([C:39]([O:41][CH3:42])=[O:40])=[CH:35][CH:36]=[CH:37][CH:38]=3)=[CH:29][CH:28]=2)[C:7]2[CH:9]=[C:10]([N:14]3[C:15](=[O:24])[C:16]4=[CH:23][CH:22]=[CH:21][CH:20]=[C:17]4[C:18]3=[O:19])[CH:11]=[C:12]([CH3:13])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2c(C)cc(N3C(=O)c4ccccc4C3=O)cc2[nH]1
Reactant: COC(=O)c1ccccc1-c1ccc(CBr)cc1
Product: CCCc1nc2c(C)cc(N3C(=O)c4ccccc4C3=O)cc2n1Cc1ccc(-c2ccccc2C(=O)OC)cc1

Procedure:
Prepared analogously to Example 1a from 2-n-propyl-4-methyl-6-phthalimido-1H-benzimidazole and methyl 4'-bromomethyl-biphenyl-2-carboxylate.
Reaction SMILES: [NH2:1][CH:2]([CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([O:16][CH3:17])=[O:15])[CH:9]=1)[C:3]#[N:4].[CH3:18][C:19]1[CH:20]=[C:21]([CH:43]=[CH:44][CH:45]=1)[CH2:22][C@@H:23]([C:40](O)=[O:41])[NH:24][C:25](=[O:39])[CH:26]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1>C(Cl)Cl>[CH3:17][O:16][C:14]([C:10]1[CH:9]=[C:8]([CH:13]=[CH:12][CH:11]=1)[O:7][CH2:6][CH2:5][CH:2]([NH:1][C:40](=[O:41])[C@H:23]([CH2:22][C:21]1[CH:43]=[CH:44][CH:45]=[C:19]([CH3:18])[CH:20]=1)[NH:24][C:25](=[O:39])[CH:26]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[C:3]#[N:4])=[O:15]
Reactant: COC(=O)c1cccc(OCCC(N)C#N)c1
Reactant: Cc1cccc(C[C@H](NC(=O)C(c2ccccc2)c2ccccc2)C(=O)O)c1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cccc(OCCC(C#N)NC(=O)[C@H](Cc2cccc(C)c2)NC(=O)C(c2ccccc2)c2ccccc2)c1
Reaction time: 1.5 h

Procedure:
To a solution of 2-amino-4-[3-(methoxycarbonyl)-phenoxy]-butyronitrile (0.5 g, 2.13 mmol), 3-methyl-N-(2,2-diphenylacetyl)-L-phenylalanine (see example 1, 0.80 g, 2.13 mmol) and diisopropylethylamine (1.1 mL, 6.39 mmol) in CH2Cl2 (15 mL) is added benzotriazol-1-yloxy-tris-(pyrrolidino)-phosphonium hexafluorophosphate (PyBop, 1.22 g, 2.34 mmol) in one portion. After stirring 1.5 hour, an additional portion of PyBop (0.61 g, 1.2 mmol) is added, and the solution is stirred overnight. The reaction mixture is washed with 1 N HCl (50 mL), saturated aqueous NaHCO3 (1×50 mL), water (1×50 mL) and brine (1×50 mL), dried over MgSO4, and evaporated. The residue is chromatographed (silica, 50% EtOAc/hexane) to yield N-[3-(3-(methoxycarbonyl)-phenoxy)-1-cyanopropyl]-3-methyl-Nα-(2,2-diphenylacetyl)-L-phenylalaninamide as a white solid, m.p. 152-153° C.
Reaction SMILES: [CH2:1]([S:8][C:9]1[C:14]2[N:15]=[C:16](OC3C=CC=CC=3)[N:17]=[C:18]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[C:13]=2[N:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:32][CH2:33][CH2:34][NH2:35]>>[CH2:1]([S:8][C:9]1[C:14]2[N:15]=[C:16]([NH:35][CH2:34][CH2:33][OH:32])[N:17]=[C:18]([N:19]3[CH2:20][CH2:21][O:22][CH2:23][CH2:24]3)[C:13]=2[N:12]=[CH:11][N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CSc2ncnc3c(N4CCOCC4)nc(Oc4ccccc4)nc23)cc1
Reactant: NCCO
Product: OCCNc1nc(N2CCOCC2)c2ncnc(SCc3ccccc3)c2n1

Procedure:
The same substance was also obtained in analogous manner by heating 8-benzylthio-4-morpholino-2-phenoxypyrimido[5,4-d]pyrimidine (melting point: 159°-161° C.) at 90° C. with 2-hydroxyethyl-amine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[CH2:11][C:12]([O:14][CH3:15])=[O:13].[NH4+].[Cl-]>C(O)C.O.[Fe]>[NH2:8][C:6]1[CH:5]=[CH:4][C:3]([CH2:11][C:12]([O:14][CH3:15])=[O:13])=[C:2]([Cl:1])[CH:7]=1
Reactant: COC(=O)Cc1ccc([N+](=O)[O-])cc1Cl
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: COC(=O)Cc1ccc(N)cc1Cl
Reaction time: 1 h
Yield: 83.2 %

Procedure:
To a solution of methyl 2-(2-chloro-4-nitrophenyl)acetate (step 3, 3.6 g, 15.6 mmol) in ethanol/water (4/1) were added Fe (4.4 g, 78.0 mmol) and NH4Cl (409 mg, 7.8 mmol). The mixture was stirred for 1 h under reflux temperature. The solvent was removed and the residue was diluted with CH2Cl2. The mixture was washed with brine, dried (MgSO4) and concentrated to give 2.59 g (83%) of title compound as orange oil.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]([C:9]([NH:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:10])[NH:6][C:7]=1[CH3:8].Br[C:19]1[S:20][C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[N:23]=1>>[S:20]1[C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[N:23]=[C:19]1[N:15]1[CH2:14][CH2:13][CH:12]([NH:11][C:9]([C:5]2[NH:6][C:7]([CH3:8])=[C:3]([Br:2])[CH:4]=2)=[O:10])[CH2:17][CH2:16]1
Reactant: Brc1nc2ccccc2s1
Reactant: Cc1[nH]c(C(=O)NC2CCNCC2)cc1Br
Agent: Cl
Product: Cc1[nH]c(C(=O)NC2CCN(c3nc4ccccc4s3)CC2)cc1Br

Procedure:
Title compound was synthesized by an analogous method to Example 123 by coupling 4-bromo-5-methyl-N-piperidin-4-yl-1H-pyrrole-2-carboxamide hydrochloride (Intermediate 57) with 2-bromo-1,3-benzothiazole (commercially available).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([CH3:12])[CH2:10][OH:11])[C:5]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)=[CH:4][N:3]=1.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([CH3:38])(=[N:27][C:28](=[O:37])[NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[CH:31]=2)=[O:26])=[CH:21][CH:20]=1>>[Cl:36][C:32]1[CH:31]=[C:30]([NH:29][C:28]([N:27]=[S:25]([C:22]2[CH:21]=[CH:20][C:19]([NH:18][C:2]3[N:7]=[C:6]([NH:8][C@H:9]([CH3:12])[CH2:10][OH:11])[C:5]([C:13]4[S:14][CH:15]=[CH:16][CH:17]=4)=[CH:4][N:3]=3)=[CH:24][CH:23]=2)([CH3:38])=[O:26])=[O:37])[CH:35]=[CH:34][CH:33]=1
Reactant: C[C@H](CO)Nc1nc(Cl)ncc1-c1cccs1
Reactant: CS(=O)(=NC(=O)Nc1cccc(Cl)c1)c1ccc(N)cc1
Product: C[C@H](CO)Nc1nc(Nc2ccc(S(C)(=O)=NC(=O)Nc3cccc(Cl)c3)cc2)ncc1-c1cccs1
Yield: 26 %

Procedure:
In the reaction of (R)-2-(2-chloro-5-(2-thienyl)pyrimidine-4-ylamino)propan-1-ol (115.5 mg, 0.43 mmol) with (RS)—S-(4-aminophenyl)-N-(3-chloro-phenylcarbamoyl)-S-methylsulphoximide (126 mg, 0.39 mmol) according to procedure 5c, the desired product is obtained in 26% yield (56 mg) after chromatographic purification (silica gel, dichloromethane/ethanol (0%-20% ethanol)).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[C:4]#[N:5].[NH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>CN(C=O)C>[F:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:2]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[C:3]=1[C:4]#[N:5]
Reactant: N#Cc1c(F)cccc1F
Reactant: C1CCNCC1
Solvent: CN(C)C=O
Product: N#Cc1c(F)cccc1N1CCCCC1
Yield: 43.8 %

Procedure:
2,6-Difluorobenzonitrile (250 mg; 1.8 mmol) and piperidine (145 mg; 1.7 mmol) were mixed in DMF (5 mL) for 3 hours at RT. The solvent is removed under vacuum, and the resulting oil is dried under vacuum at 30° C. overnight to yield 152 milligrams of 2-fluoro-6-(piperidin-1-yl)benzonitrile.
Reaction SMILES: [CH3:1][C:2]([O:4][C@H:5]1[C:14]2[C@@:15]3([CH3:30])[C@@H:26]([CH2:27][O:28][CH3:29])[O:25][C:23](=[O:24])[C:17]4=[CH:18][O:19][C:20]([C:21](=[O:22])[C:13]=2[C@@H:8]2[CH2:9][CH2:10][C@H:11]([OH:12])[C@@:7]2([CH3:31])[CH2:6]1)=[C:16]34)=[O:3].[CH2:32]([N:34]([CH2:40][CH3:41])[CH2:35][CH2:36][NH:37][CH2:38][CH3:39])[CH3:33]>C(Cl)Cl>[CH2:32]([N:34]([CH2:40][CH3:41])[CH2:35][CH2:36][N:37]([CH:18]=[C:17]1[C:16]2[C:15]([CH3:30])([C:14]3[CH:5]([O:4][C:2](=[O:3])[CH3:1])[CH2:6][C:7]4([CH3:31])[CH:8]([C:13]=3[C:21](=[O:22])[C:20]=2[OH:19])[CH2:9][CH2:10][CH:11]4[OH:12])[CH:26]([CH2:27][O:28][CH3:29])[O:25][C:23]1=[O:24])[CH2:38][CH3:39])[CH3:33]
Reactant: COC[C@H]1OC(=O)c2coc3c2[C@@]1(C)C1=C(C3=O)[C@@H]2CC[C@H](O)[C@@]2(C)C[C@H]1OC(C)=O
Reactant: CCNCCN(CC)CC
Solvent: ClCCl
Product: CCN(C=C1C(=O)OC(COC)C2(C)C1=C(O)C(=O)C1=C2C(OC(C)=O)CC2(C)C(O)CCC12)CCN(CC)CC
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 100 mg (0.23 mmol) 17-hydroxywortmannin in 2 mL CH2Cl2 is added N,N-Diethyl-N′-ethyl-ethane-1,2-diamine (50 μL). The reaction mixture is stirred at room temperature for 12 hours and then concentrated in vacuo. The residue is dissolved in EtOAc and precipitated with hexane. The precipitate is washed two times with hexane to give the product as a yellow solid. MS (ESI) m/z 575 (M+H).
Reaction SMILES: O=[C:2]([OH:11])[C@@H:3]([C@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4].[O:12]=[CH:13][C@@H]([C@H]([C@@H](CO)O)O)O>>[O:12]=[CH:13][C@@H:2]([C@H:3]([C@@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4])[OH:11]
Reactant: O=C(O)[C@H](O)[C@@H](O)[C@H](O)CO
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)CO
Product: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
When the P. ananatis NA1 strain was cultured with the mixed carbon source of glucose and xylose (MSII-GX medium), the glutamic acid yield was 25.7% (Table 2). In this case, accumulation of xylonic acid was observed, and thus it was suggested that most of xylose was converted into xylonic acid. It is estimated that the accumulation of xylonic acid with the P. ananatis NA1 strain was provided by the activity of glucose dehydrogenase of P. ananatis.
Reaction SMILES: O.[NH2:2][C:3]1[CH:8]=[C:7]([OH:9])[N:6]=[C:5]([SH:10])[N:4]=1.[Cl:11][C:12]1[C:13]([F:20])=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH2:15]Br>>[NH2:2][C:3]1[N:4]=[C:5]([S:10][CH2:15][C:14]2[CH:17]=[CH:18][CH:19]=[C:12]([Cl:11])[C:13]=2[F:20])[NH:6][C:7](=[O:9])[CH:8]=1
Reactant: Nc1cc(O)nc(S)n1
Reactant: Fc1c(Cl)cccc1CBr
Solvent: O
Product: Nc1cc(=O)[nH]c(SCc2cccc(Cl)c2F)n1

Procedure:
The subtitle compound was prepared according to the procedure of Example 1 step i) treating 4-amino-6-hydroxy-2-mercaptopyrimidine monohydrate (8.4 g) with 3-chloro-2-fluorobenzyl bromide (11.0 g) to afford the subtitle compound as a white solid. Yield: 14.1 g.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:3]=1[NH2:4].F[C:11]1[CH:12]=[N:13][CH:14]=[CH:15][C:16]=1[C:17]([OH:19])=[O:18].[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:3]=1[NH:4][C:15]1[CH:14]=[N:13][CH:12]=[CH:11][C:16]=1[C:17]([OH:19])=[O:18]
Reactant: Nc1ccc(Cl)cc1Cl
Reactant: O=C(O)c1ccncc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(O)c1ccncc1Nc1ccc(Cl)cc1Cl
Temperature: -78 °C
Yield: 72 %

Procedure:
2,4-Dichloraniline (162 mg, 1.00 mmol) and 3-fluoropyridine-4-carboxylic acid (141 mg, 1.00 mmol) were dissolved in dry THF (6.0 ml) under argon and the mixture was cooled to −78° C. A solution of LiHMDS (1.0M in THF, 3.5 ml) was added and the reaction mixture was allowed to warm to ambient temperature. After 18 h the reaction was quenched by adding a solution of HCl in dioxane (4.0M, 2.0 ml). The volatiles were removed in vacuo and the crude material was purified by flash chromatography using silica gel and a gradient of 0-10% methanol in DCM as eluent to give 204 mg (721 μmol; 72% yield) of pure desired product.