Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([O:20][CH3:21])=[C:4]([CH:10]([NH:12]C(=O)OC(C)(C)C)[CH3:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].Cl.O1CCOCC1>C(=O)(O)[O-].[Na+]>[Br:1][C:2]1[C:3]([O:20][CH3:21])=[C:4]([CH:10]([NH2:12])[CH3:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8]
Reactant: COc1c(C(C)NC(=O)OC(C)(C)C)cc(Cl)c(C)c1Br
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1c(C(C)N)cc(Cl)c(C)c1Br

Procedure:
A mixture of tert-butyl [1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethyl]carbamate (0.84 g, 2.2 mmol) (second peak from chiral separation) was treated with 4.0 M hydrogen chloride in dioxane (3.0 mL, 12 mmol) at room temperature for 2 hours. The mixture was diluted with saturated sodium bicarbonate solution and extracted with dichloromethane. The combined organic layers were dried over MgSO4, filtered and concentrated to give 1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethanamine, which was combined with 6-bromo-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (0.82 g, 2.9 mmol, from Example 108, Step 1) and N,N-diisopropylethylamine (1.2 mL, 6.6 mmol) in ethanol (6 mL) and heated at 100° C. overnight. The reaction mixture was concentrated and purified on silica gel (eluting with 0-65% ethyl acetate in hexanes) to afford the desired product. LCMS calculated for C20H24BrClN5O2 (M+H)+: m/z=480.1, 482.1. found: 480.0, 482.0.
Reaction SMILES: [CH2:1]([CH:19]1[CH2:24][C:23](=[O:25])[N:22]([C:26]2[CH:31]=[CH:30][C:29]([N+:32]([O-])=O)=[CH:28][C:27]=2[OH:35])[C:20]1=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[H][H]>C(O)C.[Pd]>[CH2:1]([CH:19]1[CH2:24][C:23](=[O:25])[N:22]([C:26]2[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][C:27]=2[OH:35])[C:20]1=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: [H][H]
Reactant: CCCCCCCCCCCCCCCCCCC1CC(=O)N(c2ccc([N+](=O)[O-])cc2O)C1=O
Agent: [Pd]
Solvent: CCO
Product: CCCCCCCCCCCCCCCCCCC1CC(=O)N(c2ccc(N)cc2O)C1=O

Procedure:
In 2 liters of ethanol were suspended 150 g of 2-octadecylsuccinimido-5-nitro-phenol and 7.5 g of palladium/carbon were added to the suspension, which was subjected to catalytic reduction with hydrogen gas at room temperature under normal pressure. After about 10 hours of reaction period of time, palladium/carbon was filtered off and ethanol was removed by distillation. The residue was recrystallized from benzene to give white powdery crystal melting at 85°-90° C. in the yield of 90 g.
Reaction SMILES: [C:1]([OH:7])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH2:8]=[S:9]1[CH:15]2[N:12]([C:13](=[O:17])[C:14]2=O)[CH:11]([C:18]([OH:20])=[O:19])[C:10]1([CH3:22])[CH3:21].[CH3:23][S:24]([CH2:27][C:28]([CH:30]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:29])(=[O:26])=[O:25]>C1C=CC=CC=1>[C:1]([OH:7])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH2:8]=[S:9]1[C@H:15]2[N:12]([C:13](=[O:17])[C:14]2=[CH:30][C:28](=[O:29])[CH2:27][S:24]([CH3:23])(=[O:26])=[O:25])[C@@H:11]([C:18]([OH:20])=[O:19])[C:10]1([CH3:22])[CH3:21]
Reactant: CS(=O)(=O)CC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C=S1C2C(=O)C(=O)N2C(C(=O)O)C1(C)C
Agent: CC(C)(C)C(=O)O
Solvent: c1ccccc1
Product: C=S1[C@@H]2C(=CC(=O)CS(C)(=O)=O)C(=O)N2[C@@H](C(=O)O)C1(C)C
Reaction time: 0.17 h

Procedure:
A solution of 2.3 g of methylene-6,7-dioxo-3,3-dimethyl-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate pivalate in 75 ml of benzene is treated at room temperature with 4 g of methylsulphonylacetylmethylenetriphenylphosphorane. After 10 minutes, the reaction mixture is evaporated. The residue is chromatographed on silica gel while eluting with cyclohexane/ethyl acetate (1:1). There is obtained methylene-(2S,5R)-3,3-dimethyl-7-oxo-6-[3-methylsulphonyl-2-oxopropylidene]-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate pivalate as an orange oil [Rf: 0.23; cyclohexane/ethyl acetate (1:1); NMR (CDCl3), δ (ppm): 1.22 (9H); 1.5 (3H); 1.56 (3H); 3.03 (3H, CH3 --SO2); 4.24 (2H, --CH2 --SO2); 4.59 (1H); 6.02 (1H); 6.79 (1H)].
Reaction SMILES: Cl[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[CH:3]=1.P(=O)(O)(O)[OH:18].C>COCCO>[N:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:2][C:3]1=[O:18]
Reactant: Clc1cn(-c2ccccn2)c2ccccc12
Reactant: O=P(O)(O)O
Solvent: COCCO
Product: O=C1Cc2ccccc2N1c1ccccn1
Temperature: 100 °C

Procedure:
Dissolve the 3-chloro-1-(pyrid-2-yl)-indole in 1500 cm3 of 2-methoxyethanol and heat to 100° C. with stirring. Add 1100 cm3 of 70% phosphoric acid in a fine stream. Continue heating for 6 hours and then treat the reaction mixture with charcoal under reflux for 15 mins. Filter. Heat to 70° C. while adding 2000 cm3 of water. Cool the precipitated product for 12 hours at 5° C. Filter and dry.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[NH2:7][C:8]1[C:9]2[CH:16]=[C:15]([C:17]3[N:21]([CH:22]4[CH2:26][CH2:25][N:24]([C:27](OC(C)(C)C)=O)[CH2:23]4)[CH:20]=[N:19][C:18]=3[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[S:14][C:10]=2[N:11]=[CH:12][N:13]=1.O>C1COCC1.C(O)(C(F)(F)F)=O>[CH3:27][N:24]1[CH2:25][CH2:26][CH:22]([N:21]2[C:17]([C:15]3[S:14][C:10]4[N:11]=[CH:12][N:13]=[C:8]([NH2:7])[C:9]=4[CH:16]=3)=[C:18]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[N:19]=[CH:20]2)[CH2:23]1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cnc(-c3ccccc3)c2-c2cc3c(N)ncnc3s2)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CN1CCC(n2cnc(-c3ccccc3)c2-c2cc3c(N)ncnc3s2)C1
Yield: 19.8 %

Procedure:
A mixture of lithium aluminium hydride in THF (1M, 0.1 mL), THF (2 mL) and tert-butyl 3-[5-(4-aminothieno[2,3-d]pyrimidin-6-yl)-4-phenyl-1H-imidazol-1-yl]pyrrolidine-1-carboxylate (intermediate 102) (31 mg) was refluxed for 4 hours under an inert atmosphere. After addition of water and TFA (1 drop), the mixture was evaporated and the residue was purified by preparative RPHPLC (eluting with a gradient of MeCN and water containing 0.1% TFA) to afford the title compound as a colourless solid (5 mg, 28%).
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH2:14][CH:13]([N:16]3[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=4)=[O:22])[CH2:17]3)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)#[N:2].[NH4+:37].[Cl-]>O1CCOCC1>[C:1]([CH2:3][C:4]1[CH:5]=[CH:6][C:7]([CH:10]2[CH2:15][CH2:14][CH:13]([N:16]3[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:34])([F:35])[F:33])[CH:27]=4)=[O:22])[CH2:17]3)[CH2:12][CH2:11]2)=[CH:8][CH:9]=1)(=[NH:37])[NH2:2]
Reactant: [NH4+]
Reactant: N#CCc1ccc(C2CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)cc1
Agent: [Cl-]
Solvent: C1COCCO1
Product: N=C(N)Cc1ccc(C2CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)cc1

Procedure:
A solution of N-({1-[4-(4-cyanomethyl-phenyl)-cyclohexyl]-azetidin-3-ylcarbamoyl}-methyl)-3-trifluoromethyl-benzamide (as prepared in Example 21, 250 mg, 0.50 mmol) in dioxane (2 mL) and saturated NH4Cl (2 mL) was heated in a sealed tube to 120° C. overnight. The solvent was removed in vacuo and the residue was purified on a silica gel column using a CombiFlash® system using ethyl acetate and 7N NH3 in MeOH as eluent (from pure ethyl acetate to 5% 7N NH3 in MeOH in ethyl acetate) to afford the title compound as yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:12][NH:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:14]1[S:15][C:16]2[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:21][CH:20]=[CH:19][C:17]=2[N:18]=1.C(N(C(C)C)CC)(C)C>>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:10][N:11]([C:14]2[S:15][C:16]3[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:21][CH:20]=[CH:19][C:17]=3[N:18]=2)[CH2:12]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cccc2nc(Br)sc12
Reactant: CC(C)(C)OC(=O)NC1CNC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cccc2nc(N3CC(NC(=O)OC(C)(C)C)C3)sc12
Yield: 92 %

Procedure:
The same operation as in Example (217a) was performed using 3-tert-butoxycarbonylaminoazetidine (300 mg, 1.74 mmol), ethyl 2-bromo-1,3-benzothiazole-7-carboxylate obtained in Example (1f) (332 mg, 1.16 mmol) and diisopropylethylamine (0.40 mL, 2.32 mmol), to obtain 403 mg of the title compound as a pale yellow solid (92%).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH2:12]1[CH:16](O)[CH2:15][NH:14][CH2:13]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(/C(OC(C)(C)C)=O)=N\C(OC(C)(C)C)=O>O1CCCC1>[CH3:1][C:2]1[C:3]([N+:9]([O-:11])=[O:10])=[CH:4][CH:5]=[C:6]([O:8][CH:12]2[CH2:16][CH2:15][NH:14][CH2:13]2)[N:7]=1
Reactant: Cc1nc(O)ccc1[N+](=O)[O-]
Reactant: OC1CCNC1
Agent: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1nc(OC2CCNC2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 50 h

Procedure:
6-Methyl-5-nitropyridin-2-ol (5 g) was dissolved in tetrahydrofuran and DL-3-pyrrolidinol (2.83 g) and triphenylphosphine (12.76 g) were added. Di-tert-butyl (E)-diazene-1,2-dicarboxylate (11.21 g) dissolved in tetrahydrofuran (15 mL) was added dropwise over 15 min. The reaction mixture was stirred at room temperature for 50 h. The reaction mixture was concentrated in vacuo. The remaining residue was suspended in dichloromethane and trifluoroacetic acid (7.55 mL) was added dropwise. The reaction mixture was stirred for 12 h at room temperature. The reaction mixture was concentrated in vacuo, redissolved in dichloromethane and extracted several times with 1N hydrochloric acid. The combined aqueous extracts were treated with 1N NaOH to pH 10 and extracted with ethyl acetate (3×). The combined ethyl acetate extracts were successively washed with water and brine and dried (sodium sulfate). After concentration in vacuo, the crude product was purified by flash chromatography (silica, dichloromethane, 1-10% methanol gradient). Yield: 1.5 g (18.6%, pale yellow oil).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]2[C:15]3=[C:16]([CH2:18][CH2:19][N:14]3[C@@H:13]3[CH2:20][CH2:21][NH:22][CH2:23][C@H:12]23)[CH:17]=1.Cl[CH2:25][CH2:26][CH2:27][C:28]([C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=1)=[O:29].C([O-])([O-])=O.[K+].[K+]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]2[C:15]3=[C:16]([CH2:18][CH2:19][N:14]3[C@@H:13]3[CH2:20][CH2:21][N:22]([CH2:25][CH2:26][CH2:27][C:28]([C:30]4[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=4)=[O:29])[CH2:23][C@H:12]23)[CH:17]=1
Reactant: Clc1ccc(-c2cc3c4c(c2)[C@H]2CNCC[C@H]2N4CC3)c(Cl)c1
Reactant: O=C(CCCCl)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C(CCCN1CC[C@@H]2[C@H](C1)c1cc(-c3ccc(Cl)cc3Cl)cc3c1N2CC3)c1ccc(F)cc1
Yield: 37.2 %

Procedure:
The title compound (36 mg, 37%) was prepared by the method of Example 189 from (±)-cis-2-(2,4-dichlorophenyl)-4,5,6a,7,8,9,10,10a-octahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole (65.8 mg, 0.19 mmol), 4-chloro-4′-fluorobutyrophenone (50.0 mg, 0.25 mmol), KI (31.5 mg, 0.19 mmol), and K2CO3(50.0 mg, 0.57 mmol) after chromatographic purification as a white amorphous solid. 1H NMR (CDCl3, 300 MHz) δ 7.90–7.95 (m, 2H), 7.37 (s, 1H), 7.16 (s, 2H), 7.03 (t, 2H, J=8.8 Hz), 6.91 (s, 1H), 6.85 (s, 1H), 3.49 (bt, 1H, J=8.0 Hz), 3.25–3.45 (m, 2H), 3.02–3.22 (m, 2H), 2.90–3.02 (m, 3H), 2.50–2.88 (m, 2H), 2.10–2.45 (m, 4H), 1.70–2.00 (m, 4H) ppm. MS (CI, NH3): 509 (base, M+H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C@H:7](O)[CH3:8])=[CH:3][CH:2]=1.C([Li])CCC.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.C(NC(C)C)(C)C.[CH3:33][C:34]([C:36]12[CH2:45][CH:40]3[CH2:41][CH:42]([CH2:44][CH:38]([CH2:39]3)[CH2:37]1)[CH2:43]2)=[O:35]>C1COCC1.CCCCCC>[C:36]12([C:34](=[O:35])[CH2:33][C@H:7]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[CH3:8])[CH2:43][CH:42]3[CH2:41][CH:40]([CH2:39][CH:38]([CH2:44]3)[CH2:37]1)[CH2:45]2
Reactant: CC(=O)C12CC3CC(CC(C3)C1)C2
Reactant: C[C@@H](O)c1ccncc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: C[C@H](CC(=O)C12CC3CC(CC(C3)C1)C2)c1ccncc1
Yield: 17 %

Procedure:
The method followed that described in Example 9 but using (+)-(R)-1-(4-pyridyl)ethanol (1.84 g, 15.0 mmol) in THF (80 ml), butyllithium (1.6M; 9.4 ml, 15.0 mmol) in hexane, p-toluenesulfonyl chloride (2.86 g, 15.0 mmol), diisopropylamine (6.31 ml, 45.0 mmol) in THF (120 ml), butyllithium (1.6M; 28.12 ml, 45.0 mmol) in hexane and 1-adamantyl methyl ketone (8.0 g, 45 mmol). Chromatography, on elution with petrol-ether-triethylamine 100:50:1 gave the title compound (722 mg, 17%), which crystallised from hexane, m.p. 48°-49° C.; [α]D -6.6° (c 1.0, MeOH). IR, NMR and MS data were the same as given in Example 14.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:8]([NH:10][C@H:11]([C:16]([NH:18][C@H:19]([C:27]([O:29][CH3:30])=[O:28])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:17])[CH2:12][C:13](=[O:15])[NH2:14])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6].[ClH:41]>CO.O1CCOCC1.[C].[Pd]>[NH2:1][C@H:2]([C:8]([NH:10][C@H:11]([C:16]([NH:18][C@H:19]([C:27]([O:29][CH3:30])=[O:28])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:17])[CH2:12][C:13](=[O:15])[NH2:14])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6].[ClH:41]
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](N)CCC(N)=O

Procedure:
14.1 g of Z-Gln-Asn-Phe-OCH3 are hydrogenated at 45°C in 800 ml of methanol with the addition of 8.5 ml of 3N-hydrogen chloride in dioxan and 2.4 g of 10% palladium carbon. When the hydrogen uptake ceases, the batch is filtered and evaporated. The residue is processed without purification.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([N:14]1[CH:18]([C:19](OCC)=[O:20])[CH2:17][CH2:16][CH:15]1[C:24](OCC)=[O:25])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O>O1CCCC1>[CH2:7]([N:14]1[CH:18]([CH2:19][OH:20])[CH2:17][CH2:16][CH:15]1[CH2:24][OH:25])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCOC(=O)C1CCC(C(=O)OCC)N1Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCC1CCC(CO)N1Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 96.6 %

Procedure:
To a suspension of lithium aluminum hydride 10.25 g) in tetrahydrofuran (550 ml) was added dropwise a solution of 1-benzyl-2,5-bis(ethoxycarbonyl)pyrrolidine (55 g) in tetrahydrofuran (100 ml). The reaction mixture was stirred for 30 minutes at 0° C., allowed to warm to room temperature and then stirred at the same temperature for 1 hour. And then water was added carefully until excess lithium aluminum hydride was decomposed. After the precipitate was filtered off, the filtrate was evaporated under reduced pressure to give crude 1-benzyl-2,5-bis(hydroxymethyl)pyrrolidine (38.52 g).
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6]/[N:7]=[C:8](/[C:14]1[N:15]=[C:16]([NH:19][C:20]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[S:17][CH:18]=1)\[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N+]=[N-]>CO.[Pd]>[NH2:1][CH2:4][CH2:5][O:6]/[N:7]=[C:8](/[C:14]1[N:15]=[C:16]([NH:19][C:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[S:17][CH:18]=1)\[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)/C(=N\OCCN=[N+]=[N-])c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)/C(=N\OCCN)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1

Procedure:
16.4 g of 2-(tritylamino)-4-thiazoleglyoxylic acid ethyl ester (Z)-O-(2-azidoethyl) oxime were hydrogenated for 3.5 hours under normal pressure in 300 ml of methanol in the presence of 2.5 g of palladium/carbon (5%). The catalyst was filtered off and the solvent was removed in a vacuum. The residue was crystallized from carbon tetrachloride/petroleum ether (low-boiling). There was obtained 2-(tritylamino)-4-thiazoleglyoxylic acid ethyl ester (Z)-O-(2-aminoethyl) oxime as white crystals having a melting point of 126°-144° C.
Reaction SMILES: [C:1]([CH:3]([CH:7]1[C:11]([Cl:12])=[C:10](Cl)C(=O)O1)[C:4]([NH2:6])=[O:5])#[N:2].Cl.[CH3:16][C:17]1[CH:18]=[CH:19][C:20]([S:25]([CH3:28])(=[O:27])=[O:26])=[C:21]([CH2:23][NH2:24])[CH:22]=1.C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+]>C(O)C>[ClH:12].[Cl:12][C:11]1[CH:7]=[C:3]([C:4]([NH2:6])=[O:5])[C:1](=[NH:2])[N:24]([CH2:23][C:21]2[CH:22]=[C:17]([CH3:16])[CH:18]=[CH:19][C:20]=2[S:25]([CH3:28])(=[O:27])=[O:26])[CH:10]=1
Reactant: N#CC(C(N)=O)C1OC(=O)C(Cl)=C1Cl
Reactant: Cc1ccc(S(C)(=O)=O)c(CN)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Cc1ccc(S(C)(=O)=O)c(Cn2cc(Cl)cc(C(N)=O)c2=N)c1
Yield: 60.9 %

Procedure:
(Step 2) 2-Cyano-2-(3,4-dichloro-5-oxo-2,5-dihydrofuran-2-yl)acetamide (2.49 g), 1-[5-methyl-2-(methylsulfonyl)phenyl]methanamine hydrochloride obtained in Step 1 (3.0 g) and potassium carbonate (4.4 g) were stirred in ethanol (30 ml) at 80° C. for 24 hr. The reaction mixture was treated with 1N sodium hydroxide solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate:hexane=4:1). The obtained residue was dissolved in methanol, 4N hydrogen chloride-ethyl acetate solution (5 ml) was added, and the mixture was crystallized from methanol-ethyl acetate. The precipitated crystals were collected by filtration, and recrystallized to give the title compound (1.26 g).
Reaction SMILES: [Cl:1][C:2]1[N:13]=[C:12](Cl)[C:11]2[C:10]3[CH2:9][CH2:8][CH2:7][C:6]=3[S:5][C:4]=2[N:3]=1.[C@H:15]1([NH2:22])[CH2:20][CH2:19][C@H:18]([NH2:21])[CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+]>CC#N.CCOC(C)=O>[Cl:1][C:2]1[N:13]=[C:12]([NH:21][CH:18]2[CH2:19][CH2:20][CH:15]([NH2:22])[CH2:16][CH2:17]2)[C:11]2[C:10]3[CH2:9][CH2:8][CH2:7][C:6]=3[S:5][C:4]=2[N:3]=1
Reactant: Clc1nc(Cl)c2c3c(sc2n1)CCC3
Reactant: N[C@H]1CC[C@H](N)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: NC1CCC(Nc2nc(Cl)nc3sc4c(c23)CCC4)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
A 50-mL round-bottom flask placed a solution of 10,12-dichloro-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraene (500 mg, 2.04 mmol, 1.00 equiv) in anhydrous CH3CN (20 mL) was added trans-cyclohexane-1,4-diamine (280 mg, 2.45 mmol, 1.20 equiv) and potassium carbonate (844 mg, 6.11 mmol, 3.00 equiv) at room temperature. The resulting solution was stirred overnight at 80° C. under nitrogen. The resulting solution was diluted with EtOAc, washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted (520 mg, crude) of 1-N-[10-chloro-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]cyclohexane-1,4-diamine as a white solid which was used directly for next step without further purification.
Reaction SMILES: N1C=CC=CC=1.[C:7]1([CH3:17])[CH:12]=[CH:11][C:10]([S:13](Cl)(=[O:15])=[O:14])=[CH:9][CH:8]=1.[OH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1>ClCCl>[S:13]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)([C:10]1[CH:11]=[CH:12][C:7]([CH3:17])=[CH:8][CH:9]=1)(=[O:15])=[O:14]
Reactant: OCCCCCOc1ccccn1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCCCCOc2ccccn2)cc1
Reaction time: 4 h
Yield: 54.6 %

Procedure:
5 ml of pyridine and 7 g of p-toluenesulfonyl chloride were added to a solution of 6.5 g of the compound obtained in Example 3a in 20 ml of dichloromethane and then the mixture was stirred for 4 hours. The organic layer was washed with 10% aqueous citric acid and then with water and dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate) to obtain 6.57 g of the title compound (yield: 53%).
Reaction SMILES: N[CH2:2][C:3]1([OH:15])[C:12]2[C:7](=[C:8]([O:13][CH3:14])[CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][CH2:4]1.N([O-])=O.[Na+]>O1CCOCC1.C(O)(=O)C.O.C(OCC)(=O)C>[CH3:14][O:13][C:8]1[C:7]2[CH2:6][CH2:5][CH2:4][C:3](=[O:15])[CH2:2][C:12]=2[CH:11]=[CH:10][CH:9]=1
Reactant: COc1cccc2c1CCCC2(O)CN
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1cccc2c1CCCC(=O)C2
Reaction time: 2.5 h
Yield: 52 %

Procedure:
To a solution of 1-aminomethyl-5-methoxy-1,2,3,4-tetrahydronaphthalen-1-ol (26.6 g) in 1,4-dioxane (60 ml), acetic acid (24 ml) and water (210 ml) was added sodium nitrite (9.7 g) in water (60 ml) dropwise at 5° C., and the mixture was stirred at the same temperature for 2.5 hours. The resulting mixture was diluted with ethyl acetate and separated. The organic layer was washed with saturated aqueous sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was chromatographed (hexane-ethyl acetate) over silica gel to afford 1-methoxy-5,7,8,9-tetrahydro-6H-benzocyclohepten-6-one (12.7 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:20])[CH2:9][C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=2)[C:13]([O:15][CH3:16])=[O:14])=[CH:4][CH:3]=1.[CH2:21](Br)[CH:22]=[CH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[H-].[Na+].[NH4+].[Cl-]>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH:9]([C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=2)[C:13]([O:15][CH3:16])=[O:14])[CH2:21]/[CH:22]=[CH:23]/[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:20])=[CH:6][CH:7]=1
Reactant: BrCC=Cc1ccccc1
Reactant: COC(=O)c1cccc(CC(=O)c2ccc(F)cc2)c1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(C(C/C=C/c2ccccc2)C(=O)c2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 87.7 %

Procedure:
To a solution of the product from Step 1 (1.0 g, 3.7 mmol) and cinnamyl bromide (0.72 g, 3.7 mmol) in DMF (15 mL) at 0° C. under N2 was added the NaH (121 mg, 4.0 mmol, 80% in oil). After 20 min. at 0° C., the reaction was stirred for 1 h at r.t. Saturated NH4Cl (15 mL) was then added and the product was extracted with Et2O. The organic phase was washed with H2O and brine, and was then dried (MgSO4) filtered, and evaporated. The residue was purified by flash chromatography (1:10 EtOAc:hexane) to give a colourless oil (1.26 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C@@H:4](/[CH:5]=[C:6](\[Cl:14])/[C:7](=[O:13])[O:8][CH:9]([CH3:12])[CH2:10][CH3:11])[C@H:3]1[C:15]([OH:17])=[O:16].[C:19]([C@@H:21](O)[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:23]=1)#[N:20]>C(Cl)(Cl)Cl>[CH3:18][C:2]1([CH3:1])[C@@H:4](/[CH:5]=[C:6](\[Cl:14])/[C:7](=[O:13])[O:8][CH:9]([CH3:12])[CH2:10][CH3:11])[C@H:3]1[C:15]([O:17][C@H:21]([C:19]#[N:20])[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:23]=1)=[O:16]
Reactant: N#C[C@@H](O)c1cccc(Oc2ccccc2)c1
Reactant: CCC(C)OC(=O)/C(Cl)=C/[C@H]1[C@@H](C(=O)O)C1(C)C
Solvent: ClC(Cl)Cl
Product: CCC(C)OC(=O)/C(Cl)=C/[C@H]1[C@@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)C1(C)C

Procedure:
Using the procedure of Step B of Example 43, (1R,cis,Z) 2,2-dimethyl-3-[2-chloro-3-oxo-3-(1-methyl-propoxy)-1-propenyl]-cyclopropane carboxylic acid and (S)α-cyano-3-phenoxy-benzyl alcohol were reacted to form (S)α-cyano-3-phenoxy-benzyl (1R,cis,Z) 2,2-dimethyl-3-[2-chloro-3-oxo-3-(1-methyl-propoxy)-1-propenyl]-cyclopropanecarboxylate with a specific rotation of [α]D20 =+16.5°±2.° (c=0.65% in chloroform).