Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([C:13](=[O:29])[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:16][CH:15]=1)=[C:8](OS(C(F)(F)F)(=O)=O)[CH:7]=[CH:6]2.[F:38][C:39]1[CH:44]=[CH:43][CH:42]=[C:41]([F:45])[C:40]=1B(O)O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>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.CN(C=O)C>[F:38][C:39]1[CH:44]=[CH:43][CH:42]=[C:41]([F:45])[C:40]=1[C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[C:9]=1[C:13]([C:14]1[CH:15]=[CH:16][C:17]([O:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:18][CH:19]=1)=[O:29]
Reactant: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(OS(=O)(=O)C(F)(F)F)ccc2c1
Reactant: OB(O)c1c(F)cccc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(-c3c(F)cccc3F)ccc2c1
Temperature: 100 °C

Procedure:
Charge a flask with trifluoromethanesulfonic acid 6-methoxy-1-[4-(2-piperidin-1-yl-ethoxy)-benzoyl]-naphthalen-2-yl ester (2.0 g, 3.7 mmol), 2,6-difluorophenyl boronic acid (1.17 g, 7.4 mmol), tetrakis(triphenylphosphine)palladium (0) (855 mg, 0.74 mmol) and potassium phosphate (4.7 g, 22.2 mmol) add 100 mL of dry DMF and heat under nitrogen at 100° C. for two hours. Cool the reaction and filter. Purify on an SCX column eluting with 2N ammonia/methanol. Purify further on a silica gel column eluting with a gradient of 0-10% methanol/methylene chloride. The yield is 1.5 g (81%). 1H-NMR (CDCl3, 400 MHz) δ7.90 (d, J=8.4 Hz, 1H); 7.63 (d, J=8.4 Hz, 1H); 7.62 (d, J=9.2 Hz, 2H); 7.39 (d, J=8.4 Hz, 1H); 7.23 (d, J=2.8 Hz, 1H); 7.18-7.08 (m, 2H); 6.78 (d, J=10.4 Hz, 2H); 6.74 (s, 2H); 4.11-4.08 (m, 2H); 3.95 (s, 3H); 2.75 (t, J=6.4 Hz, 2H); 2.49-2.49 (m, 4H); 1.63-1.58 (m, 4H); 1.47-1.44 (m, 2H).
Reaction SMILES: [NH:1]1[C:9]2[C:4]3[C:5](=[CH:10][CH:11]=[CH:12][C:3]=3[C:2]1=[O:13])[CH:6]=[CH:7][CH:8]=2.[Br:14]Br.O>ClC(Cl)Cl>[Br:14][C:6]1[C:5]2[C:4]3[C:9](=[CH:8][CH:7]=1)[NH:1][C:2](=[O:13])[C:3]=3[CH:12]=[CH:11][CH:10]=2
Reactant: BrBr
Reactant: O=C1Nc2cccc3cccc1c23
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=C1Nc2ccc(Br)c3cccc1c23
Temperature: 0 °C
Yield: 95.4 %

Procedure:
Benz[cd]indol-2(1H)-one (2.1 g, 12.4 mmol) was dissolved in 50 ml trichloromethane and cooled to 0° C. To this stirred and cooled solution was added dropwise bromine (0.64 ml, 12.4 mmol) within 5 minutes. The reaction was allowed to warm up to room temperature for 24 hours. The reaction mixture was then poured into water and extracted with trichloromethane. The organic layer was dried over sodium sulfate, filtered and concentrated to give 2.935 g product (95% yield).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]2[O:12][CH2:11][CH2:10][NH:9][CH2:8]2)=[CH:3][CH:2]=1.[C:13](Cl)(=[O:17])[CH2:14][CH2:15][CH3:16].C(N(CC)CC)C>ClCCl>[N:1]1[CH:6]=[CH:5][C:4]([CH:7]2[CH2:8][N:9]([C:13](=[O:17])[CH2:14][CH2:15][CH3:16])[CH2:10][CH2:11][O:12]2)=[CH:3][CH:2]=1
Reactant: c1cc(C2CNCCO2)ccn1
Reactant: CCCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCC(=O)N1CCOC(c2ccncc2)C1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 2-(pyridin-4-yl)morpholine in dry dichloromethane are added 1.5 eq butanoyl chloride and 2.5 eq triethylamine. After stirring for 6 hours at room temperature the solvent is removed in vacuo and the residue redisolved in ethyl acetate. The organic solution is subsequently washed with 1 M KHSO4, 5% NaHCO3 and brine. After drying over Na2SO4, ethyl acetate is removed in vacuo and the crude 1-(2-(pyridin-4-yl)morpholino)butan-1-one is purified by column chromatography.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]1([C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=2)[C:16]([OH:18])=O)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH:22]1([NH2:28])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>C1COCC1.CN(C=O)C>[CH:22]1([NH:28][C:16](=[O:18])[C:15]2[CH:19]=[CH:20][CH:21]=[C:13]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:14]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: O=C(O)c1cccc(-c2ccccc2)c1
Reactant: NC1CCCCC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C(NC1CCCCC1)c1cccc(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Oxalyl chloride (132 μL, 1.5 mmol) was added over a 10 minute period to a mixture of 3-phenylbenzoic acid (200 mg, 1 mmol) dissolved in a mixture THF/DMF (3.5 mL/58 μL). After the addition, the reaction was stirred at room temperature for 2.5 hours. Cyclohexylamine (286 μL, 2.5 mmol) was then added into half of the acid chloride solution at 0° C. The reaction was then stirred at room temperature for 18 hours. The reaction was concentrated and water was added to the residue. The aqueous phase was extracted 3 times with CH2Cl2 and the combined organic layers were washed with 2N HCl, saturated NaHCO3, brine, dried over Na2SO4 and concentrated. Diethyl ether was added to the residue and a white solid precipitated which was collected by filtration and rinsed with a small amount of diethyl ether. The white solid was then dried under vacuum (108 mg, 80%). NMR 1H (ppm, CDCl3): 7.95 (s, 1H), 7.68 (d, J3=7.82 Hz, 2H), 7.59 (d, J3=7.13 Hz, 2H), 7.49-7.33 (m, 4H), 6.05 (br. d., J3=6.58 Hz, 1H), 3.75-3.70 (m, 1H), 2.06-2.01 (m, 2H), 1.78-1.61 (m, 3H), 1.49-1.36 (m, 2H), 1.30-1.14 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][NH2:11].[N:12]([C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[CH:17]=[CH:18][NH:19]2)=[C:13]=[O:14]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][NH:11][C:13]([NH:12][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[CH:17]=[CH:18][NH:19]2)=[O:14]
Reactant: NCCc1ccc(Cl)cc1Cl
Reactant: O=C=Nc1cccc2[nH]ccc12
Product: O=C(NCCc1ccc(Cl)cc1Cl)Nc1cccc2[nH]ccc12

Procedure:
2-(2,4-Dichlorophenyl)ethylamine (0.21 g, 1.1 mmol) and the product of Example 80A (0.16 g, 1. mmol) were treated as described in Example 80B to provide the title compound. mp 170° C.; 1H NMR (300 MHz, DMSO-d6) δ 2.90 (m, 2H), 3.31 (m, 2H), 6.47 (m, 2H), 6.93 (m, 2H), 7.23 (m, 1H), 7.40 (m, 2H), 7.60 (m, 2H), 8.15 (s, 1H), 11.02 (s, 1H). MS (DCI+) m/z 347 (M+H). Anal. Calcd. for C17H15N3Cl20: C, 58.63; H, 4.34; N, 12.07. Found: C, 58.49; H, 4.49; N, 12.38.
Reaction SMILES: [CH2:1]([O:3][CH:4]([C:9]1[CH:10]=[N:11][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)=[CH:13][CH:14]=1)[CH2:5][C:6]([OH:8])=[O:7])[CH3:2].C(O)(C)C.CCCCCC.C(O)(C)C.FC(F)(F)C(O)=O>CCCCCC>[CH2:1]([O:3][C@H:4]([C:9]1[CH:10]=[N:11][C:12]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][C:20]([C:23]([F:26])([F:24])[F:25])=[CH:21][CH:22]=2)=[CH:13][CH:14]=1)[CH2:5][C:6]([OH:8])=[O:7])[CH3:2]
Reactant: CCOC(CC(=O)O)c1ccc(OCc2ccc(C(F)(F)F)cc2)nc1
Solvent: CCCCCC
Solvent: CC(C)O
Solvent: O=C(O)C(F)(F)F
Product: CCO[C@@H](CC(=O)O)c1ccc(OCc2ccc(C(F)(F)F)cc2)nc1
Yield: 23 %

Procedure:
3-Ethoxy-3-(6-{[4-(trifluoromethyl)benzyl]oxy}pyridin-3-yl)propionic acid (200 mg) produced in Example 17 (17D) was dissolved in hexane (6 mL) and isopropanol (3 mL) and the resulting solution was subjected to optical resolution by high-performance liquid chromatography using a Chiralpak AD semi-preparative column (2.0 cm×25.0 cm, manufactured by Daicel Chemical Industries, Ltd.) (conditions: flow rate: 20 mL/min, solvent: hexane/isopropanol/trifluoroacetic acid=90/10/0.1 (v/v), detection wavelength: 220 nm). The solvent in the solution having been subjected to optical resolution was distilled off under reduced pressure, and a compound with a retention time of 7 minutes was obtained as (3S)-3-ethoxy-3-(6-{[4-(trifluoromethyl)benzyl]oxy}pyridin-3-yl)propionic acid (a white solid, 45 mg, yield: 23%), and a compound with a retention time of 10 minutes was obtained as (3R)-3-ethoxy-3-(6-{[4-(trifluoromethyl)benzyl]oxy}pyridin-3-yl)propionic acid (a white solid, 47 mg, yield: 24%).
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[O:12][C:13]([CH3:16])=[N:14][N:15]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[O-].[Na+].[C:20]1(=[O:25])[CH2:24][CH2:23][CH:22]=[CH:21]1>CO.[NH4+].[Cl-]>[C:1]1([S:7]([CH:10]([C:11]2[O:12][C:13]([CH3:16])=[N:14][N:15]=2)[CH:22]2[CH2:23][CH2:24][C:20](=[O:25])[CH2:21]2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1C=CCC1
Reactant: Cc1nnc(CS(=O)(=O)c2ccccc2)o1
Agent: C[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: Cc1nnc(C(C2CCC(=O)C2)S(=O)(=O)c2ccccc2)o1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 85.8 %

Procedure:
To 650 mg (2.73 mmol) of 2-benzenesulfonylmethyl-5-methyl-[1,3,4]oxadiazole in 35 mL of MeOH at 0° C., 50 μL (0.27 mmol, 0.1 eq) of a solution of sodium methoxide (5.4 M in MeOH) were added. After 15 min, 246 mg (3.0 mmol, 1.1 eq) of cyclopent-2-enone were added. The reaction mixture was stirred at 0° C. and was allowed to reach RT within 4 hours, diluted with saturated aqueous NH4Cl and extracted with EtOAc. The combined organic phases were dried over Na2SO4, filtered and evaporated. Column chromatography on silica gel with EtOAc gave 750 mg (86%) of 3-[benzenesulfonyl-(5-methyl-[1,3,4]oxadiazol-2-yl)-methyl]-cyclopentanone as a racemic mixture of diastereomers, white solid, MS: 321 (MH+).
Reaction SMILES: [C:1]1([C:7](=[N:14][CH:15]([CH2:23][CH2:24][CH:25]=[CH2:26])[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1COCC1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].I[CH2:43][CH2:44][CH2:45][CH2:46][B:47]1[O:51][C:50]([CH3:53])([CH3:52])[C:49]([CH3:55])([CH3:54])[O:48]1>C(OCC)C>[C:1]1([C:7](=[N:14][C:15]([CH2:43][CH2:44][CH2:45][CH2:46][B:47]2[O:51][C:50]([CH3:53])([CH3:52])[C:49]([CH3:54])([CH3:55])[O:48]2)([CH2:23][CH2:24][CH:25]=[CH2:26])[C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C=CCCC(N=C(c1ccccc1)c1ccccc1)C(=O)OC(C)(C)C
Reactant: CC1(C)OB(CCCCI)OC1(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=CCCC(CCCCB1OC(C)(C)C(C)(C)O1)(N=C(c1ccccc1)c1ccccc1)C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 16 h
Yield: 79.7 %

Procedure:
While under an atmosphere of argon, a solution of tert-butyl 2-(diphenylmethyleneamino)hex-5-enoate (7.00 g, 20.06 mmol) in freshly distilled (THF 50 mL) was cooled to −78° C. and treated with sodium bis(trimethylsilyl)amide (60 mL, 1.0 M in THF). After stirring for 10 min 2-(4-iodobutyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (12.4 g, 40.0 mmol) was added and the reaction was warmed to room temperature and stirred for 16 h. Next, the reaction mixture was cooled to 0° C., diluted with ethyl ether and washed successively with saturated aqueous NaHCO3 and saturated aqueous NaCl, dried over MgSO4, filtered and concentrated. Purification by MPLC (1-20% ethyl acetate in heptane with 0.5% triethylamine over 6 CV) gave tert-butyl 2-(diphenylmethyleneamino)-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)butyl)hex-5-enoate as a colorless oil (8.50 g, 80%). Rf 0.55 (30% ethyl acetate in heptane). ESI MS found for C33H46BNO4 m/z [532.5 (M+1)].
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([F:10])=[CH:4][C:3]=1[O:11][CH2:12][CH:13]1[CH2:15][CH2:14]1.C([Li])CCC.C(O[B:25]1[O:29][C:28]([CH3:31])([CH3:30])[C:27]([CH3:33])([CH3:32])[O:26]1)(C)C>C(OC)(C)(C)C>[CH:13]1([CH2:12][O:11][C:3]2[CH:4]=[C:5]([F:10])[C:6]([O:8][CH3:9])=[CH:7][C:2]=2[B:25]2[O:29][C:28]([CH3:31])([CH3:30])[C:27]([CH3:33])([CH3:32])[O:26]2)[CH2:15][CH2:14]1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: COc1cc(Br)c(OCC2CC2)cc1F
Agent: [Li]CCCC
Solvent: COC(C)(C)C
Product: COc1cc(B2OC(C)(C)C(C)(C)O2)c(OCC2CC2)cc1F
Reaction time: 1 h

Procedure:
A stirred solution of 1-bromo-2-cyclopropylmethoxy-4-fluoro-5-methoxy-benzene from example B.b7 (27.51 g; 0.10 mol) in dry tert. butylmethylether (500 mL) is cooled to −20° C. before addition of n-butyl lithium (1.6 M in hexane; 68.8 mL; 0.11 mol) via syringe. After complete addition stirring is continued for one hour. Neat 2-iso-propoxy-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane is added via syringe into the reaction mixture at −40° C. After 30 min the reaction is quenched with 1M citric acid (200 mL) at 0° C. and stirred for one hour at ambient temperature. The organic layer is separated. The aqueous layer is extracted with tert. butylmethylether (100 mL). The combined organic layers are washed with brine (200 mL) dried over MgSO4 and filtered through a plug of neutral alumina containing 5 wt % of water. The product is completely eluted with several small portions of tert. butylmethylether. The solvent is removed under reduced pressure. The crude is purified by short path distillation at 3×10−3 mbar (160° C.) to give the title compound as a colorless oil that solidifies at ambient temperature.
Reaction SMILES: CC(C)(C)C([NH:5][C:6]1[C:19]([C:20]([O:22][CH3:23])=[O:21])=[C:18]2[C:9]([C:10]3[CH:11]=[CH:12][N:13]=[N:14][C:15]=3[CH2:16][O:17]2)=[CH:8][CH:7]=1)=O>CO.S(=O)(=O)(O)O>[NH2:5][C:6]1[C:19]([C:20]([O:22][CH3:23])=[O:21])=[C:18]2[C:9]([C:10]3[CH:11]=[CH:12][N:13]=[N:14][C:15]=3[CH2:16][O:17]2)=[CH:8][CH:7]=1
Reactant: COC(=O)c1c(NC(=O)C(C)(C)C)ccc2c1OCc1nnccc1-2
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)c1c(N)ccc2c1OCc1nnccc1-2
Yield: 49.9 %

Procedure:
A solution of methyl 7-(2,2-dimethylpropionylamino)-10H-9-oxa-1,2-diazaphenanthrene-8-carboxylate (Intermediate 7, 0.702 g) in methanol (50 mL) and sulphuric acid (4 mL) was stirred and heated at reflux for 16 hours. After cooling, the solution was evaporated in vacuo and the residue was partitioned between ethyl acetate and water. The mixture was basified with 5M sodium hydroxide, then stirred and heated until all the solid had dissolved. The layers were separated and the aqueous layer was extracted six times with ethyl acetate. The combined extracts were dried (Na2SO4), filtered and the filtrate was evaporated in vacuo. The residue was triturated with DCM and the solid was collected by filtration to give methyl 7-amino-10H-9-oxa-1,2-diazaphenanthrene-8-carboxylate (0.264 g) as a yellow solid.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1([F:27])[O:25][C:8]2=[CH:9][C:10]3[N:14]=[C:13]([S:15][CH2:16][C:17]4[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][N:18]=4)[NH:12][C:11]=3[CH:24]=[C:7]2[O:6][CH:5]1[F:26].Cl[O-].[Na+].S(S([O-])=O)([O-])=[O:32].[Na+].[Na+].P([O-])(O)(O)=O.[Na+]>O1CCOCC1.O>[F:27][C:4]1([F:3])[O:25][C:8]2=[CH:9][C:10]3[N:14]=[C:13]([S:15]([CH2:16][C:17]4[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][N:18]=4)=[O:32])[NH:12][C:11]=3[CH:24]=[C:7]2[O:6][CH:5]1[F:26]
Reactant: Cc1ccc(CSc2nc3cc4c(cc3[nH]2)OC(F)C(F)(F)O4)nc1
Reactant: O=S([O-])S(=O)[O-]
Agent: O=P([O-])(O)O
Agent: [Na+]
Agent: [O-]Cl
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(CS(=O)c2nc3cc4c(cc3[nH]2)OC(F)C(F)(F)O4)nc1
Temperature: 30 °C
Reaction time: 0.83 h
Yield: 87 %

Procedure:
2.4 ml of 2M sodium hydroxide solution and 0.8 ml of water are added to a solution of 1.75 g of 6,6,7-trifluoro-6,7-dihydro-2-[(5-methyl-2-pyridyl)methylthio]-1H-[1,4]-dioxino[2,3-f]benzimidazole in 18 ml of dioxane. A mixture of 4.6 ml of sodium hypochlorite solution (8.9 g of active chlorine per ml) and 2.9 ml of 2M sodium hydroxide solution is added to the above solution at 30° C. in the course of 15 min. The mixture is stirred at 30° C. for 50 min., some drops of 2M sodium dithionite solution are added and the solution is concentrated in vacuo. 100 ml of water and 20 ml of ethyl acetate are added to the residue, and the title compound (1.6 g, 87% yield of m.p. 186°-187° C.) is precipitated by addition of sodium dihydrogen phosphate solution up to pH 7.
Reaction SMILES: [CH:1]1([C:4]2[N:9](N3CC3C)[C:8]3=[C:14]([CH3:18])[NH:15][N:16]([CH3:17])[C:7]3=[CH:6][N:5]=2)[CH2:3][CH2:2]1.[I-].[Na+]>CC(C)=O>[CH:1]1([C:4]2[N:5]3[CH2:7][CH:8]([CH3:14])[N:9]=[C:6]3[C:7]3[N:16]([CH3:17])[N:15]=[C:14]([CH3:18])[C:8]=3[N:9]=2)[CH2:2][CH2:3]1
Reactant: CC1=C2C(=CN=C(C3CC3)N2N2CC2C)N(C)N1
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: Cc1nn(C)c2c1N=C(C1CC1)N1CC(C)N=C21
Yield: 51 %

Procedure:
The above aziridine (12 g, 0.05 mol) is dissolved in 100 ml of acetone and refluxed with 10 g of sodium iodide for 2.5 hours. The mixture is evaporated in vacuo. The residue is dissolved in methylene dichloride and washed with a saturated solution of NaHCO3. The organic solution is dried (MgSO4) and evaporated in vacuo. The residual oil is crystallized from ethyl acetate ether to give 3.1 g (30%) of title compound, mp 107°-110° C.
Reaction SMILES: [CH2:1]([CH:4]([CH2:7][OH:8])[CH2:5][OH:6])[CH:2]=[CH2:3].[C:9]([O:12]C=C)(=[O:11])[CH3:10]>>[CH3:10][C:9]([O-:12])=[O:11].[CH2:1]([CH:4]([CH2:7][OH:8])[CH2:5][OH:6])[CH:2]=[CH2:3]
Reactant: C=COC(C)=O
Agent: C=CCC(CO)CO
Product: CC(=O)[O-]
Reaction time: 48 h

Procedure:
A mixture of 2-allyl-1,3-propanediol (0.116 g, 1 mmol), whole cells containing C. oxydans (0.1 g) and vinyl acetate saturated water (20 mL) was shaken at 30° C. and 300 RPM for 48 hours. The optically active monoacetate of 2-allyl-1,3-propanediol was obtained in 85% yield. Structure determination was done by nuclear magnetic resonance.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7](Cl)=[N:8][CH:9]=1)([O-:3])=[O:2].[C@H:11]1([NH2:18])[CH2:16][CH2:15][C@H:14]([NH2:17])[CH2:13][CH2:12]1.O1CCCC1>C(O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:17][C@H:14]2[CH2:15][CH2:16][C@H:11]([NH2:18])[CH2:12][CH2:13]2)=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: N[C@H]1CC[C@H](N)CC1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Solvent: CCO
Solvent: C1CCOC1
Product: N[C@H]1CC[C@H](Nc2ccc([N+](=O)[O-])cn2)CC1

Procedure:
A solution of 5-nitro-2-chloropyridine (2.50 g) and trans-1,4-cyclohexanediamine (5.40 g) in ethanol (15 ml)-tetrahydrofuran (10 ml) was stirred at room temperature for 5 days. The precipitates were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (solvent: chloroform-methanol-concentrated aqueous ammonia (20:4:1)) and crystallized from ethyl acetate to obtain N-(5-nitro-2-pyridyl)-trans-1,4-cyclohexanediamine (Reference Example 3-1 in Table 5).
Reaction SMILES: C([NH:4][C:5]1[N:10]=[C:9]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20]([NH:22][CH3:23])=[S:21])=[CH:15][CH:14]=2)[CH:8]=[CH:7][N:6]=1)(=O)C.BrBr>C(Cl)(Cl)Cl>[NH2:4][C:5]1[N:10]=[C:9]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]3[N:19]=[C:20]([NH:22][CH3:23])[S:21][C:15]=3[CH:14]=2)[CH:8]=[CH:7][N:6]=1
Reactant: CNC(=S)Nc1ccc(CCc2ccnc(NC(C)=O)n2)cc1
Agent: BrBr
Solvent: ClC(Cl)Cl
Product: CNc1nc2ccc(CCc3ccnc(N)n3)cc2s1
Yield: 13.1 %

Procedure:
To a solution of 2-acetamido-4-[2-{4-(3-methylthioureido)phenyl}ethyl]pyrimidine (5.8 g) in chloroform (100 ml) was dropwise added a solution of bromine (3.1 g) in chloroform (3 ml) at ambient temperature under stirring and the mixture was stirred at the same temperature for one hour. Further, the resultant mixture was refluxed for 2 hours with stirring. The reaction mixture was evaporated in vacuo and the residue was heated with 10% hydrochloric acid (100 ml) for one hour at 70° to 80° C. The resultant mixture was washed with ethyl acetate. The separated aqueous layer was adjusted to pH 8.0 with aqueous 20% potassium carbonate and extracted with ethyl acetate. The extract was washed with brine and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was subjected to column chromatography on silica gel. The column was eluted with a mixture of ethyl acetate and tetrahydrofuran (9:1 V/V), and the fraction containing the desired product was evaporated in vacuo and the crystalline residue was washed with ethyl acetate to give 6-[2-(2-amino-4-pyrimidinyl)ethyl]-2-methylaminobenzothiazole (0.66 g).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[Br:10][CH2:11][CH2:12]Br>>[Br:10][CH2:11][CH2:12][O:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1
Reactant: BrCCBr
Reactant: N#Cc1ccc(O)cc1
Product: N#Cc1ccc(OCCBr)cc1

Procedure:
The procedure is as for Example 53, Step A, using as substrate 4-hydroxybenzonitrile and 1,2-dibromoethane.
Reaction SMILES: C([O:4][CH:5]([CH:27]1[CH2:29][CH2:28]1)[C@H:6]1[O:10][C@@H:9]([N:11]2[C:15]3[N:16]=[C:17]([NH2:21])[NH:18][C:19](=[O:20])[C:14]=3[S:13][C:12]2=[O:22])[C@@H:8](CC([O-])=O)[CH2:7]1)(=O)C.C(OC([C@H]1O[C@@H](N2C3N=C(N)NC(=O)C=3SC2=O)[C@@H](CC([O-])=O)C1)CC)(=[O:32])C>>[NH2:21][C:17]1[NH:18][C:19](=[O:20])[C:14]2[S:13][C:12](=[O:22])[N:11]([C@H:9]3[C@H:8]([OH:32])[CH2:7][C@@H:6]([CH:5]([CH:27]4[CH2:29][CH2:28]4)[OH:4])[O:10]3)[C:15]=2[N:16]=1
Reactant: CC(=O)OC(C1CC1)[C@@H]1C[C@H](CC(=O)[O-])[C@H](n2c(=O)sc3c(=O)[nH]c(N)nc32)O1
Reactant: CCC(OC(C)=O)[C@@H]1C[C@H](CC(=O)[O-])[C@H](n2c(=O)sc3c(=O)[nH]c(N)nc32)O1
Product: Nc1nc2c(sc(=O)n2[C@@H]2O[C@H](C(O)C3CC3)C[C@H]2O)c(=O)[nH]1

Procedure:
The title compound was prepared in analogy to Example 1, by using [(2R,3R,5S)-5-[acetoxy(cyclopropyl)methyl]-2-(5-amino-2,7-dioxo-6H-thiazolo[4,5-d]pyrimidin-3-yl)tetrahydrofuran-3-yl]acetate (compound 14b) instead of [(2R,3R,5S)-5-(1-acetoxypropyl)-2-(5-amino-2,7-dioxo-6H-thiazolo[4,5-d]pyrimidin-3-yl)tetrahydrofuran-3-yl]acetate (compound 1g). Example 14 was purified and separated by preparative HPLC to afford Example 14-A and Example 14-B as white solid.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7]2[C:10]([C:14]#[N:15])=[C:11]([NH2:13])[S:12][C:6]=2[CH2:5]1)(=[O:3])[CH3:2].[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21](Cl)=[O:22]>>[C:1]([N:4]1[CH2:9][CH2:8][C:7]2[C:10]([C:14]#[N:15])=[C:11]([NH:13][C:21](=[O:22])[C:20]3[CH:24]=[CH:25][CH:26]=[C:18]([O:17][CH3:16])[CH:19]=3)[S:12][C:6]=2[CH2:5]1)(=[O:3])[CH3:2]
Reactant: COc1cccc(C(=O)Cl)c1
Reactant: CC(=O)N1CCc2c(sc(N)c2C#N)C1
Product: COc1cccc(C(=O)Nc2sc3c(c2C#N)CCN(C(C)=O)C3)c1

Procedure:
Prepared according to general procedure A starting from 6-acetyl-2-amino-3-cyano4,5,6,7-tetrahydro-thieno[2,3-c]pyridine (compound A3) and 3-methoxybenzoyl chloride.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28]([OH:30])=O)[CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[OH:65][C:66]([CH3:70])([CH3:69])[CH2:67][NH2:68]>C(Cl)Cl>[OH:65][C:66]([CH3:70])([CH3:69])[CH2:67][NH:68][C:28]([CH:9]1[CH:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=2[F:31])[C:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[NH:10]1)=[O:30]
Reactant: CC(C)(O)CN
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)CC1NC(C(=O)NCC(C)(C)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (80 mg, 0.14 mmol) in methylene chloride (10 mL), HATU (Aldrich, 105 mg, 0.28 mmol) was added followed by the addition of DIPEA (0.34 mmol) and 2-hydroxy-2-methyl-propylamine (Matrix, 25 mg, 028 mmol). The mixture was stirred at rt 1 hr. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2×10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on an ISCO machine (40 g column, eluent, 35-50% EtOAc/hexanes) to give a white solid. 50 mg.