Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])/[C:5](/[O:16][CH2:17][CH3:18])=[CH:6]/[C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[CH:10]2)[CH3:2].[H][H]>CCO.[Pd]>[CH2:1]([O:3][C:4](=[O:19])[CH:5]([O:16][CH2:17][CH3:18])[CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[CH:10]2)[CH3:2]
Reactant: CCOC(=O)/C(=C/c1ccc2[nH]ccc2c1)OCC
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C(Cc1ccc2[nH]ccc2c1)OCC
Reaction time: 2 h
Yield: 89 %

Procedure:
A suspension of 9.7 g of (Z)-2-ethoxy-3-(1H-indol-5-yl)-acrylic acid ethyl ester in 100 ml of EtOH and 1.0 g of Pd/C (10%) was hydrogenated at 22° C. for 2 h after which time hydrogen uptake ceased. The suspension was filtered, the filtrate evaporated and the residue chromatographed on silica (n-hexane/AcOEt, 2:1) to give 8.7 g of the title compound as a white solid. MS: (M)+ 261.2.
Reaction SMILES: Br[CH2:2][C@@H:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:7]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])[CH:6]=1)[OH:4].[Na+].[I-:25]>CC(C)=O>[I:25][CH2:2][C@@H:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:7]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])[CH:6]=1)[OH:4]
Reactant: [I-]
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CBr)ccc1OCc1ccccc1
Agent: [Na+]
Solvent: CC(C)=O
Product: CS(=O)(=O)Nc1cc([C@@H](O)CI)ccc1OCc1ccccc1
Yield: 91.7 %

Procedure:
A mixture of (R)-2-bromo-1-[4-phenylmethoxy-3-[(methylsulfonyl)amino]phenyl]ethanol (12.4 g, 31 mmol) and NaI (52 g, 346 mmol) were refluxed in acetone (190 mL) for 1.75 hours. After filtration, the filtrate was concentrated to a pasty red-brown solid which was partitioned between CH2Cl2 (150 mL) and H2O (190 mL). The organic phase was washed with 150 mL ~23.5% w/w aq. sodium bisulfite and with H2O (150 mL), dried over Na2SO4 and concentrated to give the title compound (12.72 g, 91%).
Reaction SMILES: [Br:1][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][NH:18][C:19]1[CH:34]=[CH:33][C:22]([C:23]([O:25][CH:26]=[CH:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[O:24])=[CH:21][CH:20]=1.[H][H]>[Pd].O1CCCC1>[Br:1][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][NH:18][C:19]1[CH:20]=[CH:21][C:22]([C:23]([O:25][CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[O:24])=[CH:33][CH:34]=1
Reactant: [H][H]
Reactant: CCOC(=O)C=COC(=O)c1ccc(NCCCCCCCCCCCCCCCCBr)cc1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCOC(=O)CCOC(=O)c1ccc(NCCCCCCCCCCCCCCCCBr)cc1

Procedure:
A solution of 4 g. 2-(ethoxycarbonyl)vinyl 4-(16-bromohexadecylamino)benzoate and 400 mg. 10% palladium-on-carbon in 100 ml. tetrahydrofuran is hydrogenated at 50 psi until hydrogen uptake stops. The catalyst is filtered, the solution is evaporated, and the residue is crystallized from acetonitrile to yield 2-(ethoxycarbonyl)ethyl 4-(16-bromohexadecylamino)benzoate.
Reaction SMILES: [NH2:1][NH2:2].[Cl:3][C:4]1[CH:5]=[C:6]([CH:10]2[C:16]3[CH:17]=[C:18]([CH:21]([C:28]4[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=4)[C:22]4[N:26]([CH3:27])[CH:25]=[N:24][CH:23]=4)[CH:19]=[CH:20][C:15]=3[NH:14][C:13](=S)[CH2:12][S:11]2)[CH:7]=[CH:8][CH:9]=1.[Na+].[Cl-]>C1COCC1>[Cl:3][C:4]1[CH:5]=[C:6]([CH:10]2[C:16]3[CH:17]=[C:18]([CH:21]([C:28]4[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=4)[C:22]4[N:26]([CH3:27])[CH:25]=[N:24][CH:23]=4)[CH:19]=[CH:20][C:15]=3[N:14]=[C:13]([NH:1][NH2:2])[CH2:12][S:11]2)[CH:7]=[CH:8][CH:9]=1
Reactant: Cn1cncc1C(c1ccc(Cl)cc1)c1ccc2c(c1)C(c1cccc(Cl)c1)SCC(=S)N2
Reactant: NN
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1cncc1C(c1ccc(Cl)cc1)c1ccc2c(c1)C(c1cccc(Cl)c1)SCC(NN)=N2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.9 %

Procedure:
Hydrazine (3.2 ml) was added at room temperature to a mixture of 5-(3-chlorophenyl)-7-[(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-1,5-dihydro-4,1-benzothiazepine-2(3H)-thione (described in Example B16a) (0.0063 mol) in THF (35 ml). The mixture was stirred at room temperature for 30 min, poured out into ice water, saturated with NaCl and extracted with DCM and a small amount of methanol. The organic layer was separated, dried, filtered and the solvent was evaporated, yielding 2.3 g (71.9%) of 5-(3-chlorophenyl)-7-[(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-2-hydrazino-3,5-dihydro-4,1-benzothiazepine.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH2:7][CH2:6][S:5]1(=[O:11])=[O:10].[I-:12].[Na+]>CC(C)=O>[I:12][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH2:7][CH2:6][S:5]1(=[O:11])=[O:10]
Reactant: [I-]
Reactant: O=S1(=O)CCCCN1CCCl
Agent: [Na+]
Solvent: CC(C)=O
Product: O=S1(=O)CCCCN1CCI
Temperature: 80 °C

Procedure:
To a solution of 2-(2-chloroethyl)tetrahydro-2H-1,2-thiazine 1,1-dioxide (1.3 g, 6.6 mmol) in acetone (13 mL) was added sodium iodide (4.9 g, 33 mmol). The reaction mixture was heated at 80° C. overnight. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated in vacuo. The solids were taken up in dichloromethane and filtered. The filtrate was concentrated and chromatographed (0 to 5%, methanol in dichloromethane) to provide 2-(2-iodoethyl)tetrahydro-2H-1,2-thiazine 1,1-dioxide as an orange solid. 1H NMR (400 MHz, CDCl3) δ 3.51-3.42 (m, 4 H), 3.25 (t, J=7.4 Hz, 2 H), 3.02 (t, J=6.0 Hz, 2 H), 2.20 (m, 2 H), 1.69 (m, 2 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=O)[CH2:6][CH2:5]2.[CH3:12][N:13]([CH3:15])[NH2:14].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[N:14][N:13]([CH3:15])[CH3:12])[CH2:6][CH2:5]2
Reactant: O=C1CCc2cc(Cl)ccc21
Reactant: CN(C)N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CN(C)N=C1CCc2cc(Cl)ccc21
Reaction time: 4 h

Procedure:
20 g of 5-chloroindan-1-one are dissolved in 600 ml of dry toluene and, after addition of 27.4 ml of N,N-dimethylhydrazine and 1 g of p-toluenesulfonic acid, boiled with a water trap for 4 h. The reaction mixture is concentrated in vacuo, and the residue is dissolved in ethyl acetate and washed with sodium bicarbonate solution and then with water. The organic phase is dried over sodium sulfate and concentrated in vacuo, and the residue is chromatographed on silica gel with ethyl acetate/heptane ½. N′-(5-chloroindan-1-ylidene)-N,N-dimethylhydrazine is obtained as an oil.
Reaction SMILES: S(=O)(=O)(O)O.[OH:6][C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:10]([O:12][CH3:13])=[O:11].[N+:19]([O-])([O:21]C(C)C)=[O:20]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl>[OH:6][C:7]1[C:8]([N+:19]([O-:21])=[O:20])=[C:9]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)c1ccc(OC)c(O)c1
Reactant: CC(C)O[N+](=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])O
Solvent: ClCCl
Product: COC(=O)c1ccc(OC)c(O)c1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
Sulfuric acid (3.0 mL, 56 mmol) was added dropwise over 2 min to a solution of methyl 3-hydroxy-4-methoxybenzoate (3.64 g, 20 mmol), tetrabutylammonium hydrogensulfate (340 mg, 1.0 mmol), isopropyl nitrate (5.0 mL, 50 mmol), and dichloromethane (40 mL) at 0° C. The reaction was allowed to warm to rt, maintained for 45 min, and then quenched with ice water (100 mL). This mixture was extracted with dichloromethane (250 mL×2). The combined extracts were dried, filtered, concentrated, and purified by silica gel chromatography (4:1→3:7; hexanes:ethyl acetate) to give methyl 3-hydroxy-4-methoxy-2-nitrobenzoate: MS (ESI): 228.4.
Reaction SMILES: [C:1]([C:3]1[C:8]([O:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[CH:7][C:6]([C:17]([F:20])([F:19])[F:18])=[CH:5][N:4]=1)#[N:2].[I-].[N:22]1([C:32](N2C=C[N+](C)=C2)=[O:33])[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25][CH2:24][CH2:23]1>ClCCl>[C:1]([C:3]1[C:8]([O:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][C:32]([N:22]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH2:25][CH2:24][CH2:23]3)=[O:33])=[CH:14][CH:15]=2)=[CH:7][C:6]([C:17]([F:20])([F:18])[F:19])=[CH:5][N:4]=1)#[N:2]
Reactant: C[n+]1ccn(C(=O)N2CCCc3ccccc32)c1
Reactant: N#Cc1ncc(C(F)(F)F)cc1Oc1ccc(O)cc1
Agent: [I-]
Solvent: ClCCl
Product: N#Cc1ncc(C(F)(F)F)cc1Oc1ccc(OC(=O)N2CCCc3ccccc32)cc1

Procedure:
The title compound was prepared from 4-(2-cyano-5-trifluoromethyl-pyridin-3-yloxy)-phenol and 3-(3,4-dihydro-2H-quinoline-1-carbonyl)-1-methyl-3H-imidazol-1-ium iodide. The crude product was subjected to flash chromatography (Quad flash 12, dichlormethane) (43%, oil).
Reaction SMILES: C1(P(=[CH:20][C:21]([O:23][CH3:24])=[O:22])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:25][C:26]1[O:30][C:29]([CH:31]=O)=[CH:28][CH:27]=1.O>C1(C)C=CC=CC=1>[Br:25][C:26]1[O:30][C:29]([CH:31]=[CH:20][C:21]([O:23][CH3:24])=[O:22])=[CH:28][CH:27]=1
Reactant: O=Cc1ccc(Br)o1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)C=Cc1ccc(Br)o1
Temperature: 80 °C
Reaction time: 1 h
Yield: 75.9 %

Procedure:
4.58 g (13.7 mmol, 1.2 eq) of methyl triphenylphosphoranylideneacetate are added to a solution of 2.0 g (11.4 mmol, 1.0 eq) of 5-bromofuran-2-carbaldehyde in 15 mL of toluene. The reaction mixture is stirred for 1 hour at 80° C. The reaction is stopped by adding 20 ml of water and is then extracted with ethyl acetate. The organic phases are combined and dried over sodium sulfate. The solvents are evaporated off and the residue is then chromatographed on silica gel (80/20 heptane/ethyl acetate). 2.0 g of methyl 3-(5-bromofuran-2-yl)acrylate are obtained. Yield=77%.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][C:14](Cl)=[N:15][OH:16])=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:18]([C:20]1[C:21]([NH2:27])=[N:22][C:23]([NH2:26])=[CH:24][CH:25]=1)#[CH:19].C(N(CC)CC)C>O1CCCC1>[CH:1]1([O:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][C:14]3[CH:19]=[C:18]([C:20]4[C:21]([NH2:27])=[N:22][C:23]([NH2:26])=[CH:24][CH:25]=4)[O:16][N:15]=3)=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C#Cc1ccc(N)nc1N
Reactant: ON=C(Cl)Cc1ccc(OC2CCCC2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Nc1ccc(-c2cc(Cc3ccc(OC4CCCC4)cc3)no2)c(N)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 48.3 %

Procedure:
To a tetrahydrofuran (3 mL) solution of (4-cyclopentyloxy-phenyl)-acetohydroximoyl chloride (150 mg, 0.592 mmol) described in Manufacturing Example 78-1-4 and 3-ethynyl-pyridin-2,6-diamine (50.3 mg, 0.378 mmol) described in Manufacturing Example 13-1-3 was added triethylamine (206 μL, 1.48 mmol). This reaction mixture was stirred for 1.5 hours at room temperature. This mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=1:1˜ethyl acetate) to obtain the title compound (64 mg, 31%).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[C:12]([O:13][CH3:14])=[CH:11][C:8]([CH:9]=O)=[C:7]([N+:15]([O-:17])=[O:16])[CH:6]=1.[C:18]([CH2:20][C:21]([O:23][CH3:24])=[O:22])#[N:19].N1CCCCC1>CO>[C:18](/[C:20](=[CH:9]\[C:8]1[CH:11]=[C:12]([O:13][CH3:14])[C:5]([O:4][CH2:3][CH2:2][Cl:1])=[CH:6][C:7]=1[N+:15]([O-:17])=[O:16])/[C:21]([O:23][CH3:24])=[O:22])#[N:19]
Reactant: COc1cc(C=O)c([N+](=O)[O-])cc1OCCCl
Reactant: COC(=O)CC#N
Solvent: CO
Solvent: C1CCNCC1
Product: COC(=O)/C(C#N)=C/c1cc(OC)c(OCCCl)cc1[N+](=O)[O-]
Yield: 27.1 %

Procedure:
To a mixture of 3.00 g (11.58 mmol) of 4-(2-chloroethoxy)-5-methoxy-2-nitrobenzaldehyde and 1.5 mL (16.95 mmol) of methyl cyanoacetate in 30 mL of methanol is added 0.3 mL of piperidine. The mixture is heated at reflux for 5 minutes then cooled slightly and the thick suspension is collected by filtration washing with ethyl acetate followed by diethyl ether to give 1.07 g (27%) of methyl (2E)-2-cyano-3-[4-(2-chloroethoxy)-5-methoxy-2-nitrophenyl]-2-propenoate as a yellow solid, mp softens at 121° C., melts at 157–160° C.
Reaction SMILES: [I-:1].[Na+].Br[C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][CH:8]=[CH:7]2>[Cu]I.O1CCOCC1>[I:1][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][CH:8]=[CH:7]2
Reactant: [I-]
Reactant: Brc1ccc2ncccc2c1
Agent: [Cu]I
Agent: [Na+]
Solvent: C1COCCO1
Product: Ic1ccc2ncccc2c1
Temperature: 110 °C
Reaction time: 15 h
Yield: 95.3 %

Procedure:
Sodium iodide (4.32 g, 28.8 mmol), copper (I) iodide (137 mg, 0.72 mmol), 6-bromo-quinoline (3 g, 14.4 mmol), N,N′-dimethyl-cyclohexane (0.227 mL, 1.44 mmol) and dioxane were charged in a microwave tube (25 mL). The tube was purged with nitrogen for 10 min and sealed with a Teflon septum. The reaction mixture was stirred at 110° C. for 15 h. After cooling, the mixture was poured onto ice-water and extracted with DCM. The crude was purified by silica gel column to give 6-iodo-quinoline as light green solid (3.5 g, 92%).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:68])[C@H:10]([CH2:62][CH:63]1[CH2:67][CH2:66][CH2:65][CH2:64]1)[NH:11]C(=O)[C@H](C(C)(C)C)NC(=O)[C@H](CC1C=CC=CC=1C)NC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1>N1CCCCC1.ClCCl>[CH2:1]([O:8][C:9](=[O:68])[C@H:10]([CH2:62][CH:63]1[CH2:64][CH2:65][CH2:66][CH2:67]1)[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccccc1C[C@H](NC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)N[C@H](C(=O)N[C@@H](CC1CCCC1)C(=O)OCc1ccccc1)C(C)(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: C1CCNCC1
Product: N[C@@H](CC1CCCC1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 520 mg (0.56 mmol) of N-[N-[N-[O-tert-butyl-N-[(9-fluorenyl)methoxycarbonyl]-L-α-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-3-cyclopentyl-L-alanine benzyl ester in 3 ml of piperidine and 12 ml of dichloromethane was stirred at room temperature for 30 minutes. The solvent was removed by evaporation and the residue was chromatographed on silica gel using firstly ethyl acetate/petrol (1:1) and then methanol/dichloromethane (1:9) for the elution. The resulting amine was added to a solution of 207 mg (0.504 mmol) of N-(9-fluorenylmethoxycarbonyl)-O-tert-butyl-L-α-aspartic acid, 78 mg (0.51 mmol) of 1-hydroxybenzotriazole and 134 mg (0.7 mmol) of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride in 10 ml of dichloromethane and stirred at room temperature for 18 hours. The solutionwas then extracted with 2M hydrochloric acid and saturated sodium bicarbonate solution and dried over anhydrous magnesium sulphate. Evaporation, trituration with diethyl ether and filtration gave 440 mg of N-[N-[N-[N-O-tert-butyl-N-[(9-fluorenyl)methoxycarbonyl]-L-α-aspartyl]-O-tert-butyl-L-α-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-3-cyclopentyl-L-alanine benzyl ester as a white solid; MS: m/e 1101 [M+H].
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:6]=[N:7][CH:8]=1)#[CH:2].I[C:18]1[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[CH:21]=[CH:20][C:19]=1[NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31]>>[C:30]([O:29][C:28]([NH:27][C:19]1[CH:20]=[CH:21][C:22]([N+:24]([O-:26])=[O:25])=[CH:23][C:18]=1[C:2]#[C:1][C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:15])[CH3:14])[CH:6]=[N:7][CH:8]=1)=[O:34])([CH3:33])([CH3:31])[CH3:32]
Reactant: CC(C)(C)OC(=O)Nc1ccc([N+](=O)[O-])cc1I
Reactant: C#Cc1cncc(NC(=O)OC(C)(C)C)c1
Product: CC(C)(C)OC(=O)Nc1cncc(C#Cc2cc([N+](=O)[O-])ccc2NC(=O)OC(C)(C)C)c1
Yield: 85 %

Procedure:
This compound was prepared according to the procedure of Example B19 step C, using tert-butyl (5-ethynylpyridin-3-yl)carbamate and tert-butyl (2-iodo-4-nitrophenyl)carbamate as the starting material in 85% yield. LCMS calculated for C23H27N4O6(M+H)+: m/z=455.1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[CH2:7][NH:8][CH:9]([C:13](C)(C)[O:14][SiH2]C(C)(C)C)[CH:10]([CH3:12])[CH3:11])([CH3:4])([CH3:3])[CH3:2].[CH:23](N(C(C)C)CC)(C)C.CI>CN(C=O)C>[C:1]([O:5][C:6](=[O:22])[CH2:7][N:8]([CH:9]([CH2:13][OH:14])[CH:10]([CH3:11])[CH3:12])[CH3:23])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)C(NCC(=O)OC(C)(C)C)C(C)(C)O[SiH2]C(C)(C)C
Reactant: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CI
Product: CC(C)C(CO)N(C)CC(=O)OC(C)(C)C

Procedure:
{[1-(tert-Butyl-dimethyl-silanyloxymethyl)-2-methyl-propyl]-amino}-acetic acid tert-butyl ester (1.9 g, 6.1 mmol) and diisopropylethylamine (4.2 mL, 24 mmol) were dissolved in DMF (15 mL). A solution of MeI (0.45 mL, 7.3 mmol) in DMF (100 mL) was slowly added over 15 min. The reaction was stirred for 2½ h. The solvent was removed in vacuo. The residue product was dissolved in EtOAc (100 mL) and the solution was washed with water (20 mL). The organic phase was dried over magnesium sulfate, filtered and the filtrate was evaporated in vacuo. The residue was dissolved in acetonitrile (45 mL) and Et3N 3HF (2 mL, 12.3 mmol) was added. The reaction was stirred for 16 h. The solvent was removed in vacuo. The crude product was dissolved in EtOAc (100 mL) and washed with saturated sodium bicarbonate solution (25 mL) and saturated sodium chloride solution (25 mL). The organic phase was dried over magnesium sulfate and the solution was slowly filtered through 5 g of silica gel. The filtrate was evaporated in vacuo. Yield: 1.1 g, 78%.
Reaction SMILES: [CH2:1]1[O:23][C:4]2[CH:5]=[C:6]([O:9][CH2:10][CH:11]=[C:12]([CH3:22])[CH2:13][CH2:14][CH:15]=[C:16]([CH3:21])[CH2:17][CH:18]([CH3:20])[CH3:19])[CH:7]=[CH:8][C:3]=2[O:2]1.ClC1C=CC=C(C(OO)=[O:32])C=1>C(Cl)Cl>[O:32]1[C:16]([CH3:21])([CH2:17][CH:18]([CH3:19])[CH3:20])[CH:15]1[CH2:14][CH2:13][C:12]([CH3:22])=[CH:11][CH2:10][O:9][C:6]1[CH:7]=[CH:8][C:3]2[O:2][CH2:1][O:23][C:4]=2[CH:5]=1
Reactant: CC(=CCOc1ccc2c(c1)OCO2)CCC=C(C)CC(C)C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(=CCOc1ccc2c(c1)OCO2)CCC1OC1(C)CC(C)C

Procedure:
To 10 g. of 1,2-(methylenedioxy)-4-[(3,7,9-trimethyl-2,6-decadienyl)oxy]-benzene dissolved in 100 ml. of methylene chloride are added portionwise, while stirring and cooling with ice at 1°-5° C., 6.85 g. of 80% m-chloroperbenzoic acid and the mixture is stirred for a further 2 hours while cooling with ice. The mixture is subsequently diluted with 200 ml. of ether and washed successively with ice-cold 1-N aqueous sodium hydroxide, water and saturated aqueous sodium chloride solution, dried over sodium sulphate and evaporated. By chromatography on silica gel with hexane/ether (4:1 parts by volume), there is obtained pure 4-[(6,7-epoxy-3,7,9-trimethyl-2-decenyl)-oxy]-1,2-(methylenedioxy)-benzene of boiling point (bulb tube) 135°-140° C./0.02 mm Hg.; nD22 = 1.5168.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[N:10]=[C:9]([CH:11]2[CH2:16][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([CH2:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[CH2:14][N:13]([C:28](OC3C=CC([N+]([O-])=O)=CC=3)=[O:29])[CH2:12]2)[O:8][N:7]=1.Cl.[OH:41][CH:42]1[CH2:45][NH:44][CH2:43]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[OH:41][CH:42]1[CH2:45][N:44]([C:28]([N:13]2[CH2:14][CH:15]([C:17]3[CH:18]=[CH:19][C:20]([CH2:23][C:24]([F:26])([F:25])[F:27])=[CH:21][CH:22]=3)[CH2:16][CH:11]([C:9]3[O:8][N:7]=[C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])[N:10]=3)[CH2:12]2)=[O:29])[CH2:43]1
Reactant: OC1CNC1
Reactant: COCCOc1noc(C2CC(c3ccc(CC(F)(F)F)cc3)CN(C(=O)Oc3ccc([N+](=O)[O-])cc3)C2)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCOc1noc(C2CC(c3ccc(CC(F)(F)F)cc3)CN(C(=O)N3CC(O)C3)C2)n1
Temperature: 150 °C

Procedure:
50.5 mg (0.064 mmol, purity 70%) of the compound from Example 67A, 30.2 mg (0.275 mmol) of 3-hydroxyazetidine hydrochloride and 31.7 mg (0.229 mmol) of potassium carbonate were added to 2.1 ml of DMF and heated in a single-mode microwave (Emrys Optimizer) at 150° C. for 20 min. For workup, the reaction solution was combined and filtered, and the residue was purified by means of preparative HPLC. Enantiomer separation of 100 mg of the racemic crude product according to Method 8D gave 7.8 mg of the title compound from Example 98 (enantiomer 1) and 8.0 mg of the title compound from Example 99 (enantiomer 2).
Reaction SMILES: [OH:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([OH:10])[CH2:4][C:3]1([CH3:12])[CH3:11].[C:13](#N)[CH3:14].Cl.OO>O.[Fe].C1CCCCC1>[CH:14]1([O:1][N:2]2[C:7]([CH3:8])([CH3:9])[CH2:6][CH:5]([OH:10])[CH2:4][C:3]2([CH3:12])[CH3:11])[CH2:13][CH2:5][CH2:4][CH2:3][CH2:11]1
Reactant: CC#N
Reactant: CC1(C)CC(O)CC(C)(C)N1O
Agent: [Fe]
Agent: Cl
Agent: OO
Solvent: O
Solvent: C1CCCCC1
Product: CC1(C)CC(O)CC(C)(C)N1OC1CCCCC1
Yield: 75 %

Procedure:
Nanosized activated iron powder in mineral oil (0.042 g) is rinsed successively with two 2 ml portions of cyclohexane. Most of the solvent is removed with a pipette. The iron is added to a mixture of 5.00 g (29.0 mmol) of 1-oxyl-2,2,6,6-tetramethylpiperidin-4-ol, 44 ml of acetonitrile, and 32 ml of cyclohexane that has been heated to 40 degrees. To this mixture is carefully added over several minutes a solution of 0.548 g of concentrated hydrochloric acid in 3 ml of water. The reaction temperature is brought to reflux and a solution of 7.81 g (115 mmol) of 50% aqueous hydrogen peroxide is added dropwise over a period of 2.25 hours. After about one-half of the peroxide solution is added, a second portion of nanosized activated iron powder in mineral oil (0.039 g), rinsed twice with cyclohexane, and a solution of 0.166 g of concentrated hydrochloric acid in 1 ml of water are added to the reaction mixture. The reaction mixture is heated at 60-62 degrees for 1.5 hours after the peroxide has been added. After work up and purification according to the procedure of Example 54, the yield of the title compound is 5.53 g (75% yield), GC assay 96%.
Reaction SMILES: [CH3:1][C:2]1([N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[C@@H:18]4[CH2:19][CH2:20][CH2:21][CH2:22][C@H:17]4[NH:16][C:15]3=[O:23])[CH2:10][CH2:9]2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(C(C)C)CC)(C)C.Cl[C:34]([O:36][CH:37]([CH3:39])[CH3:38])=[O:35].C([O-])(O)=O.[Na+]>ClCCl>[O:23]=[C:15]1[N:14]([CH:11]2[CH2:12][CH2:13][N:8]([C:2]3([CH3:1])[CH2:7][CH2:6][N:5]([C:34]([O:36][CH:37]([CH3:39])[CH3:38])=[O:35])[CH2:4][CH2:3]3)[CH2:9][CH2:10]2)[C@@H:18]2[CH2:19][CH2:20][CH2:21][CH2:22][C@H:17]2[NH:16]1
Reactant: CC1(N2CCC(N3C(=O)N[C@@H]4CCCC[C@H]43)CC2)CCNCC1
Reactant: CC(C)OC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)OC(=O)N1CCC(C)(N2CCC(N3C(=O)N[C@@H]4CCCC[C@H]43)CC2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 51 %

Procedure:
A solution of (3aR,7aR)-1-[1-(4-methyl-4-piperidyl)-4-piperidyl]-3a,4,5,6,7,7a-hexahydro-3H-benzoimidazol-2-one (HCl salt, 99 mg, 0.25 mmol) and diisopropylethylamine (129.3 mg, 1.0 mmol) in dry dichloromethane (5 mL) at 0° C. was added dropwise with a solution of 1.0 N isopropyl chloroformate in dichloromethane (0.3 mL, 0.3 mmol) and was stirred at room temperature for 3 h. Saturated NaHCO3 (5 mL) was added followed by dichloromethane (20 mL). The phases were separated and the aqueous phase was extracted with dichloromethane (2×10 mL). The combined organic phases were washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified with preparative LC/MS (high pH) to give the title compound (52 mg, 51%). 1H NMR (400 MHz, METHANOL-D4) δ ppm 0.98 (s, 3H), 1.21 (d, J=6.25 Hz, 6H), 1.30-1.51 (m, 6H), 1.61 (d, J=11.33 Hz, 1H), 1.67-1.89 (m, 7H), 1.95 (d, J=7.42 Hz, 1H), 2.13-2.34 (m, 3H), 2.85-3.16 (m, 4H), 3.28-3.41 (m, 2H), 3.47-3.68 (m, 3H), 4.77-4.85 (m, 1H). MS (M+1): 407.3.