Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C@H:12]([N:17]2[C:25](=[O:26])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][C:23]=3[NH:27][C:28](=[O:32])[CH:29]([CH3:31])[CH3:30])[CH2:18]2)[CH2:13][CH2:14][NH:15][OH:16])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].[O-:33][C:34]#[N:35].[K+]>O>[NH2:35][C:34]([N:15]([CH2:14][CH2:13][C@@H:12]([N:17]1[C:25](=[O:26])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][C:23]=2[NH:27][C:28](=[O:32])[CH:29]([CH3:31])[CH3:30])[CH2:18]1)[C:6]1[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=1)[OH:16])=[O:33]
Reactant: CCOc1cc([C@@H](CCNO)N2Cc3cccc(NC(=O)C(C)C)c3C2=O)ccc1OC
Reactant: N#C[O-]
Agent: [K+]
Solvent: O
Product: CCOc1cc([C@@H](CCN(O)C(N)=O)N2Cc3cccc(NC(=O)C(C)C)c3C2=O)ccc1OC
Reaction time: 1 h
Yield: 55.6 %

Procedure:
To a solution of (1R)—N-{2-[1-(3-ethoxy-4-methoxy-phenyl)-3-hydroxyamino-propyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-isobutyramide (1.3 g, 2.6 mmol) in water (30 mL) was added a solution of potassium cyanate (442 mg, 5.5 g) in water (10 mL) at room temperature. After 1 h, the mixture was extracted with ethyl acetate (50 mL). The organic layer was washed with HCl (1N, 25 mL), brine (25 mL) and dried over MgSO4. The solvent was removed in vacuo and the residue was purified by prep HPLC to give (1R)—N-{2-[3-(N-aminocarbonyl-N-hydroxy-amino)-1-(3-ethoxy-4-methoxy-phenyl)-propyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-isobutyramide as a white solid (0.70 g, 55% yield): mp: 137-139° C. 1H NMR (DMSO-d6) δ 1.18 (d, J=7 Hz, 6H, 2CH3), 1.31 (t, J=7 Hz, 3H, CH3), 2.25-2.34 (m, 2H, CH2), 2.51-2.66 (m, 1H, CH), 3.22-3.40 (m, 2H, CH2), 3.73 (s, 3H, CH3), 3.95-4.06 (m, 2H, CH2), 4.10 (d, J=18 Hz, 1H, NCHH), 4.55 (d, J=18 Hz, 1H, NCHH), 5.26 (t, J=8 Hz, 1H, NCH), 6.34 (s, 2H, NH2), 6.92-6.98 (m, 3H, Ar), 7.18 (d, J=8 Hz, 1H, Ar), 7.50 (t, J=8 Hz, 1H, Ar), 8.29 (d, J=8 Hz, 1H, Ar), 9.34 (s, 1H, CH), 10.48 (s, 1H, NH); 13C NMR (DMSO-d6) δ 14.70, 19.18, 28.73, 35.94, 46.25, 47.22, 52.04, 55.43, 63.76, 111.94, 112.40, 116.55, 117.52, 117.60, 119.58, 131.99, 132.73, 137.12, 142.20, 147.89, 148.43, 161.57, 168.34, 174.93; Anal Calcd for C25H32N4O6+0.9 H2O: C, 59.96; H, 6.80; N, 11.19; H2O, 3.24. Found: C, 60.16; H, 6.58; N, 10.81; H2O, 3.24.
Reaction SMILES: [CH3:1][Si:2]([CH3:5])(Cl)Cl.[NH3:6]>C1C=CC=CC=1>[CH3:1][Si:2]1([CH3:5])[NH:6][Si:2]([CH3:5])([CH3:1])[NH:6][Si:2]([CH3:5])([CH3:1])[NH:6]1
Reactant: C[Si](C)(Cl)Cl
Reactant: N
Solvent: c1ccccc1
Product: C[Si]1(C)N[Si](C)(C)N[Si](C)(C)N1

Procedure:
This method involves reacting dimethyldichlorosilane with ammonia in benzene at 30° C., removing ammonia chloride by-product by filtration through a glass filter or the like, and distilling the reaction product to isolate hexamethylcyclotrisilazane.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:13]1[CH:14]=[C:15]([C:21]2[CH:22]=[C:23]3[C:32](I)=[CH:31][N:30]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C:24]3=[N:25][C:26]=2[CH:27]2[CH2:29][CH2:28]2)[CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[S:9]([CH3:12])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:41][C:42]1[CH:43]=[C:44]([CH:62]=[C:63]([F:65])[CH:64]=1)[CH2:45][N:46]1[C:50]([CH3:51])=[C:49](B2OC(C)(C)C(C)(C)O2)[C:48]([CH3:61])=[N:47]1.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.COCCOC.O>[C:1]([O:5][C:6]([N:8]([C:13]1[CH:14]=[C:15]([C:21]2[CH:22]=[C:23]3[C:32]([C:49]4[C:48]([CH3:61])=[N:47][N:46]([CH2:45][C:44]5[CH:62]=[C:63]([F:65])[CH:64]=[C:42]([F:41])[CH:43]=5)[C:50]=4[CH3:51])=[CH:31][N:30]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C:24]3=[N:25][C:26]=2[CH:27]2[CH2:29][CH2:28]2)[CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[S:9]([CH3:12])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1nn(Cc2cc(F)cc(F)c2)c(C)c1B1OC(C)(C)C(C)(C)O1
Reactant: COc1ccc(-c2cc3c(I)cn(C(=O)OC(C)(C)C)c3nc2C2CC2)cc1N(C(=O)OC(C)(C)C)S(C)(=O)=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1ccc(-c2cc3c(-c4c(C)nn(Cc5cc(F)cc(F)c5)c4C)cn(C(=O)OC(C)(C)C)c3nc2C2CC2)cc1N(C(=O)OC(C)(C)C)S(C)(=O)=O
Yield: 42.9 %

Procedure:
Using similar reaction conditions as described in step-ii of example-1, tert-butyl 5-(3-(N-(tert-butoxycarbonyl)methylsulfonamido)-4-methoxyphenyl)-6-cyclopropyl-3-iodo-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (intermediate 33) (150 mg, 0.21 mmol) was coupled with 1-(3,5-difluorobenzyl)-3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (intermediate 24) (91.69 mg, 0.24 mmol) in sodium carbonate (66.77 mg, 0.483 mmol), Pd(PPh3)2Cl2 (7.36 mg, 0.01 mmol), 1,2-dimethoxyethane/water (10/2 ml) to give 70 mg (41% yield) of titled compound. MS: m/z=778.0 (M+1).
Reaction SMILES: [NH2:1][C:2]1([C:15]([NH:17][CH3:18])=[O:16])[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[O:19]1[C:24]2[CH:25]=[CH:26][C:27]([CH:29]=O)=[CH:28][C:23]=2[O:22][CH2:21][CH2:20]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.C(O)(=O)C.ClCCl>[O:19]1[C:24]2[CH:25]=[CH:26][C:27]([CH2:29][NH:1][C:2]3([C:15]([NH:17][CH3:18])=[O:16])[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:6][CH2:7]3)=[CH:28][C:23]=2[O:22][CH2:21][CH2:20]1
Reactant: O=Cc1ccc2c(c1)OCCO2
Reactant: CNC(=O)C1(N)CCN(C(=O)OC(C)(C)C)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CNC(=O)C1(NCc2ccc3c(c2)OCCO3)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 5 mL of a dichloromethane solution containing 0.30 g of tert-butyl 4-amino-4-((methylamino)carbonyl)piperidine-1-carboxylate, 0.16 g of 2,3-dihydro-1,4-benzodioxin-6-carbaldehyde and 57 μL of acetic acid were added, the mixture was stirred at room temperature for 2 hours. The reaction mixture was added with 0.32 g of sodium triacetoxyborohydride and stirred at the same temperature for 30 minutes. Thereto were added chloroform and an aqueous saturated sodium hydrogen carbonate solution. The organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, the resultant solution was washed sequentially with water and an aqueous saturated sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [eluent; chloroform:methanol=10:1] to obtain 0.31 g of a pale yellow oily substance, tert-butyl 4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)-4-((methylamino)carbonyl)piperidine-1-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11]N3CC4(CCN(C)CC4)C3)=[CH:8][C:6]=2[N:7]=1.[N:28]1([CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH:33]2[C:38]([NH2:40])=[O:39])[CH2:31][CH2:30][CH2:29]1>>[N:28]1([C@@H:32]2[CH2:37][CH2:36][N:35]([CH2:11][C:9]3[S:10][C:5]4[C:4]([N:22]5[CH2:27][CH2:26][O:25][CH2:24][CH2:23]5)=[N:3][C:2]([Cl:1])=[N:7][C:6]=4[CH:8]=3)[CH2:34][C@H:33]2[C:38]([NH2:40])=[O:39])[CH2:31][CH2:30][CH2:29]1
Reactant: NC(=O)C1CNCCC1N1CCC1
Reactant: CN1CCC2(CC1)CN(Cc1cc3nc(Cl)nc(N4CCOCC4)c3s1)C2
Product: NC(=O)[C@@H]1CN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC[C@H]1N1CCC1

Procedure:
Prepared according to the method used in the preparation of 2-chloro-6-(7-methyl-2,7-diaza-spiro[3.5]non-2-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine using 4-azetidin-1-yl-piperidine-3-carboxylic acid amide in place of 7-methyl-2,7-diaza-spiro[3.5]nonane. The title compounds were separated by column chromatography.
Reaction SMILES: [CH3:1][C:2]([CH:16]([CH3:22])[CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])=[CH:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([CH2:10][CH2:11][CH2:12][O:13]2)=[CH:8][CH:7]=1.C(OO)(=[O:25])C>>[O:25]1[C:19]([CH3:21])([CH3:20])[CH:18]1[CH2:17][CH:16]([CH3:22])[C:2]([CH3:1])=[CH:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([CH2:10][CH2:11][CH2:12][O:13]2)=[CH:8][CH:7]=1
Reactant: CC(C)=CCC(C)C(C)=CCOc1ccc2c(c1)OCCC2
Reactant: CC(=O)OO
Product: CC(=CCOc1ccc2c(c1)OCCC2)C(C)CC1OC1(C)C

Procedure:
Following the procedure of Example 17, 7-(3,4,7-trimethyl-2,6-octadienyloxy)-chromane and peracetic acid are reacted to form 7-(6,7-epoxy-3,4,7-trimethyl-2-octenyloxy)-chromane, nD20 = 1.5311.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([P-:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.[K+].C1COCC1.F[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[NH:28][C@@H:29]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C@H:30]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:31]=1>C1COCC1>[C:8]1([P:7]([C:4]2[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]2[NH:28][C@@H:29]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C@H:30]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[N:31]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: c1ccc([P-]c2ccccc2)cc1
Reactant: Fc1ccccc1C1=N[C@@H](c2ccccc2)[C@H](c2ccccc2)N1
Agent: [K+]
Solvent: C1CCOC1
Product: c1ccc([C@@H]2N=C(c3ccccc3P(c3ccccc3)c3ccccc3)N[C@H]2c2ccccc2)cc1
Temperature: 25 °C

Procedure:
13.9 ml of 0.5M potassium diphenylphosphide/THF (6.95 mmol, 1.1 eq.) was heated to 60° in a thermostated oil bath. To this warm solution was then added a solution of 2.00 g fluoride 8 (6.32 mmol, 1 eq.) in 5 ml THF via syringe over 2 minutes. The resulting solution was then heated at reflux for 1 hour, cooled to room temperature and quenched by the addition of 10 ml water. The resulting mixture was extracted with methylene chloride (2×25 ml), dried (MgSO4), and the solvents removed in vacuo to give an oil.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([C:8](=[O:24])[CH2:9][C:10]([C:16]2[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[CH:17]=2)(O)[C:11]([F:14])([F:13])[F:12])=[CH:4][CH:3]=1.S(Cl)(Cl)=O.N1C=CC=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[N:7]=[CH:6][C:5]([C:8](=[O:24])[CH:9]=[C:10]([C:16]2[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[CH:17]=2)[C:11]([F:12])([F:13])[F:14])=[CH:4][CH:3]=1
Reactant: O=C(CC(O)(c1cc(Cl)cc(Cl)c1)C(F)(F)F)c1ccc(Br)nc1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: O=C(C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F)c1ccc(Br)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.4 %

Procedure:
After adding 2.42 g of toluene to 0.81 g (1.82 mmol) of 1-(6-bromopyridin-3-yl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutan-1-one, 0.44 g (3.64 mmol) of thionyl chloride and 0.29 g (3.64 mmol) of pyridine were added at 80° C., and stirred for 3 hours. The reaction solution was cooled to room temperature, and separated by adding 15 ml of ethyl acetate and 10 ml of water. After washing the ethyl acetate phase with an aqueous solution of 0.15 g of sodium hydroxide dissolved into 10 ml of water, the phase was washed with water. The solvent was distilled off under reduced pressure to obtain 0.63 g of 1-(6-bromopyridin-3-yl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-buten-1-one (yield 81.4%).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH2:17]([NH2:31])[CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][CH2:29][NH2:30]>O>[NH2:30][CH2:29][CH2:28][CH2:27][O:26][CH2:25][CH2:24][O:23][CH2:22][CH2:21][O:20][CH2:19][CH2:18][CH2:17][NH:31][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: NCCCOCCOCCOCCCN
Solvent: c1ccncc1
Solvent: O
Product: NCCCOCCOCCOCCCNc1ccc([N+](=O)[O-])cc1
Temperature: 70 °C
Yield: 52.7 %

Procedure:
1.41 g (0.01 mol) of 1-fluoro-4-nitrobenzene and 1.62 ml (0.02 mol) of pyridine were introduced into a three-necked flask under nitrogen. 8.75 ml (0.04 mol) of 4,7,10-trioxatridecane-1,13-diamine were added dropwise with stirring. The mixture was heated to 70° C. After reaction for 24 hours, the reaction mixture was cooled and 40 ml of distilled water were then added with vigorous stirring. Next, the reaction mixture was extracted with dichloromethane, washed twice with water, dried over MgSO4 and then evaporated under vacuum. The crude product, isolated in the form of a yellow oil comprising about 90% of expected mono-nitro derivative, was purified on a column of silica, eluting with ethyl acetate (to separate out the dinitro derivative), and then with methanol (to recover the expected mono-nitro derivative). 1.8 g of expected product (19) were obtained in the form of a dark yellow oil.
Reaction SMILES: [CH:1]1([SH:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.CC(C)([O-])C.[K+].Cl[C:14]1[N+:19]([O-:20])=[C:18]2[CH2:21][CH2:22][CH2:23][C:17]2=[C:16]([Cl:24])[CH:15]=1>O1CCOCC1.C(Cl)Cl>[Cl:24][C:16]1[CH:15]=[C:14]([S:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[N+:19]([O-:20])=[C:18]2[CH2:21][CH2:22][CH2:23][C:17]=12
Reactant: SC1CCCC1
Reactant: [O-][n+]1c(Cl)cc(Cl)c2c1CCC2
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: [O-][n+]1c(SC2CCCC2)cc(Cl)c2c1CCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.2 %

Procedure:
To a solution of cyclopentyl mercaptan (0.112 g, 1.10 mmol) in dioxane (4 mL) at rt was added potassium tert-butoxide (0.100 g, 0.88 mmol). The mixture was stirred at rt for 1 h. After this time, 2,4-dichloro-6,7-dihydro-5H-cyclopenta[b]pyridine 1-oxide (0.150 g, 0.74 mmol) in dioxane (1 mL) was added and the mixture was heated to 100° C. for 1 h. Then, the mixture was diluted with methylene chloride and washed with water. The organic layer were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography (silica, dichloromethane/methanol) to afford the title compound (0.170 g, 86%) as a brown oil. MW=269.79. 1H NMR (CDCl3, 500 MHz) δ 6.99 (s, 1H) 3.60-3.52 (m, 1H), 3.22 (t, J=7.5 Hz, 2H), 3.01 (t, J=7.5 Hz, 2H), 2.26-2.15 (m, 4H), 1.88-1.79 (m, 2H), 1.77-1.64 (m, 4H); APCI MS m/z 270 [M+H]+.
Reaction SMILES: [CH3:1][CH:2]([NH2:13])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.Cl.[CH2:15]([C:22]1([N:36]([CH3:38])[CH3:37])[CH2:27][CH2:26][CH:25](NCC2C=CC=CC=2)[CH2:24][CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.O>[CH2:15]([C:22]1([N:36]([CH3:37])[CH3:38])[CH2:27][CH2:26][CH:25]([NH:13][CH:2]([CH3:1])[CH2:3][C:4]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][CH:5]=2)[CH2:24][CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(N)Cc1c[nH]c2ccccc12
Reactant: CN(C)C1(Cc2ccccc2)CCC(NCc2ccccc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: O
Product: CC(Cc1c[nH]c2ccccc12)NC1CCC(Cc2ccccc2)(N(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 152.4 %

Procedure:
348 mg DL-α-methyltryptamine were dissolved in dry 1,2-dichloroethane (10 ml) under argon (clear solution), 463 mg 4-benzyl-4-dimethylamino-cyclohexane (see example 3) and glacial acetic acid (229 μl) were added and the mixture was stirred for one hour at RT. 550 mg sodium triacetoxyborohydride were then added and the suspension was stirred for a further 72 hours at RT. For working up, water (20 ml) was added to the reaction mixture, the organic phase was separated off and the aqueous phase was extracted once with ether and then rendered strongly alkaline with sodium hydroxide solution (pH>10). A gelatinous precipitate which dissolved in ethyl acetate thereby precipitated out. The aqueous phase was extracted with ethyl acetate (4×10 ml). All the ethyl acetate phases were combined, dried with sodium sulfate and concentrated to dryness. 766 mg of a mixture of cis- and trans-1-benzyl-N′-[2-(1H-indol-3-yl)-1-methylethyl]-N,N-dimethylcyclohexane-1,4-diamine were obtained as a vitreous solid (m.p. 48-53° C.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[S:10])=[CH:4][CH:3]=1.[CH2:11]([NH2:16])[C:12]([CH3:15])([CH3:14])[CH3:13]>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:16][CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[S:10])=[CH:4][CH:3]=1
Reactant: Fc1ccc(N=C=S)cc1
Reactant: CC(C)(C)CN
Solvent: ClCCl
Product: CC(C)(C)CNC(=S)Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.5 %

Procedure:
To a solution of 4-fluoro-phenylisothiocyanate (1.00 g, 6.53 mmol) in dichloromethane (20 mL) at room temperature was added neopentylamine (1.00 mL, 8.5 mmol) and the reaction was stirred overnight at room temperature. The mixture was concentrated in vacuo and the resulting residue was triturated with diethyl ether and filtered to afford 1.42 g (90%) of 1-(4-fluoro-phenyl)-3-(2,2-dimethylpropyl)-thiourea as a white solid which was used without further purification.
Reaction SMILES: C(O)(=O)C.[NH2:5][CH2:6][C@@H:7]([C:9]1[CH:10]=[CH:11][C:12]([OH:20])=[C:13]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:14]=1)[OH:8].[O:21]=[C:22]1[N:26]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:25](=[O:33])[CH:24]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([N:41]3[CH2:46][CH2:45][C:44](=O)[CH2:43][CH2:42]3)=[CH:37][CH:36]=2)[S:23]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN(C=O)C>[CH2:31]([O:30][C:28](=[O:29])[CH2:27][N:26]1[C:25](=[O:33])[CH:24]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([N:41]3[CH2:42][CH2:43][CH:44]([NH:5][CH2:6][C@H:7]([OH:8])[C:9]4[CH:10]=[CH:11][C:12]([OH:20])=[C:13]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:14]=4)[CH2:45][CH2:46]3)=[CH:37][CH:36]=2)[S:23][C:22]1=[O:21])[CH3:32]
Reactant: CCOC(=O)CN1C(=O)SC(Cc2ccc(N3CCC(=O)CC3)cc2)C1=O
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CCOC(=O)CN1C(=O)SC(Cc2ccc(N3CCC(NC[C@H](O)c4ccc(O)c(NS(C)(=O)=O)c4)CC3)cc2)C1=O
Reaction time: 0.33 h
Yield: 73.5 %

Procedure:
Acetic acid (0.05 mL, 0.92 mmol) was added to a mixture of N-{5-[(1R)-2-amino-1-hydroxyethyl]-2-hydroxyphenyl}methanesulfonamide (which was obtained in Example 10) (113 mg, 0.46 mmol), ethyl 2-[2,4-dioxo-5-[4-(4-oxo-1-piperidineyl)benzyl]-1,3-thiazolidin-3-yl}acetate (which was obtained in Example 50) (180 mg, 0.46 mmol), and DMF (3 mL). The mixture was stirred for 20 minutes and then, sodium triacetoxyborohydride (117 mg, 0.55 mmol) was added, and the new mixture was stirred at room temperature for 24 hours. The volatiles were removed in vacuo and the residue was purified by flash chromatography (dichloromethane/methyl alcohol 5/1) to produce an off-white solid (210 mg, 74% yield); mp 153-155° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.18 (t, J=7.1 Hz, 3H), 1.30-1.60 (m, 2H), 1.80-1.83 (m, 2H), 2.50-2.65 (m, 4H), 2.80-2.85 (m, 4H), 3.40 (m, 2H), 3.60 (m, 1H), 4.13 (q, J=7.1 Hz, 2H), 4.47 (m, 1H), 5.04 (m, 1H), 6.80-6.90 (m, 3H), 6.97 (m, 1H), 7.1 (m, 2H), 7.19 (m, 1H); MS (ES) m/z: 621 (MH+); Anal. Calcd. for: C28H36N4O8S2×1CH3CO2H: C, 52.93; H, 5.92; N, 8.23. Found: C, 52.69; H, 5.63; N, 8.23.
Reaction SMILES: C(O[C:6]([C:8]1[N:9]=[C:10]([Cl:23])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][CH:20]([CH3:22])[CH3:21])=[CH:13][CH:12]=2)=[O:7])CCC.[CH3:24][N:25]([CH3:29])[CH2:26][CH2:27][NH2:28]>>[CH3:24][N:25]([CH3:29])[CH2:26][CH2:27][NH:28][C:6]([C:8]1[N:9]=[C:10]([Cl:23])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][CH:20]([CH3:21])[CH3:22])=[CH:13][CH:12]=2)=[O:7]
Reactant: CN(C)CCN
Reactant: CCCCOC(=O)c1nc(Cl)c2ccc(OC(C)C)cc2c1O
Product: CC(C)Oc1ccc2c(Cl)nc(C(=O)NCCN(C)C)c(O)c2c1

Procedure:
Synthesized from 1-chloro-4-hydroxy-6-isopropoxy-isoquinoline-3-carboxylic acid butyl ester (can be obtained according to U.S. Pat. No. 6,093,730, October 1998, Weidmann et al.) and N,N-dimethyl-ethane-1,2-diamine in analogy to example B-4, followed by deprotection in analogy to example B-1 f); MS-(+)-ion: M+1=352.1.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:33])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:31][CH3:32])=[C:16]([CH2:19][N:20]([C@@H:26]([CH3:30])[CH2:27][O:28][CH3:29])[C@@H:21]([C:23]([OH:25])=O)[CH3:22])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[Cl-].[NH4+:35]>>[Cl:1][C:2]1[C:3]([F:33])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:31][CH3:32])=[C:16]([CH2:19][N:20]([C@@H:26]([CH3:30])[CH2:27][O:28][CH3:29])[C@@H:21]([C:23]([NH2:35])=[O:25])[CH3:22])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: [NH4+]
Reactant: COC[C@H](C)N(Cc1cc2c(Nc3cccc(Cl)c3F)ncnc2cc1OC)[C@H](C)C(=O)O
Agent: [Cl-]
Product: COC[C@H](C)N(Cc1cc2c(Nc3cccc(Cl)c3F)ncnc2cc1OC)[C@H](C)C(N)=O

Procedure:
N-({4-[(3-Chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)-N-[(1S)-2-methoxy-1-methylethyl]-D-alanine was coupled with ammonium chloride using a procedure analogous to the equivalent step in Example 16 to give the title product; 1H NMR Spectrum: (DMSO-d6) 1.07 (d, 3H); 1.24 (d, 3H); 2.99 (m, 1H); 3.18 (m, 4H); 3.47 (m, 2H); 3.83 (d, 1H); 3.89 (d, 1H); 3.97 (s, 3H); 6.98 (m, 1H); 7.21 (s, 1H); 7.30 (dt, 1H); 7.50 (m, 1H); 7.60 (m, 2H); 8.37 (s, 1H); 8.44 (s, 1H); 9.64 (s, 1H); Mass Spectrum: (M+H)+ 476.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:17]([O-:19])=[O:18])=[C:9]([CH:16]=1)[O:10][CH:11]([CH3:15])[C:12](Cl)=[O:13].[OH:28][CH2:29][N:30]1[CH:34]=[CH:33][CH:32]=[N:31]1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:17]([O-:19])=[O:18])=[C:9]([CH:16]=1)[O:10][CH:11]([CH3:15])[C:12]([O:28][CH2:29][N:30]1[CH:34]=[CH:33][CH:32]=[N:31]1)=[O:13]
Reactant: CC(Oc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-])C(=O)Cl
Reactant: OCn1cccn1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(Oc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-])C(=O)OCn1cccn1
Temperature: 20 °C
Reaction time: 15 h
Yield: 70 %

Procedure:
A solution of 21.2 g (0.05 mol) of α-(5-(2-chloro-4-trifluoromethylphenoxy)-2-nitro-phenoxy)-propionic acid-chloride in 30 ml of toluene was added to a mixture, cooled to from 0° to 5° C., of 5.4 g (0.055 mol) of 1-hydroxymethylpyrazole, 6 g (0.06 mol) of triethylamine and 70 ml of toluene. The reaction mixture was stirred overnight (approx. 15 hours) at room temperature (approx. 20° C.). To work up the mixture, it was diluted with toluene and then washed with water, dilute sodium hydroxide solution and again with water, and the organic phase was dried, filtered and concentrated. 17.0 g (70% of theory) of pyrazol-1-yl-methyl α-(5-(2-chloro-4-trifluoromethyl-phenoxy)-2-nitrophenoxy)-propionate were obtained in the form of beige-colored crystals of melting point 75° C.
Reaction SMILES: O.[NH2:2][NH2:3].[CH2:4]([C:8]1[CH:18]=[CH:17][C:11]([C:12](OCC)=[O:13])=[CH:10][CH:9]=1)[CH:5]([CH3:7])[CH3:6]>O>[CH2:4]([C:8]1[CH:18]=[CH:17][C:11]([C:12]([NH:2][NH2:3])=[O:13])=[CH:10][CH:9]=1)[CH:5]([CH3:7])[CH3:6]
Reactant: CCOC(=O)c1ccc(CC(C)C)cc1
Reactant: NN
Solvent: O
Product: CC(C)Cc1ccc(C(=O)NN)cc1
Temperature: 25 °C
Yield: 71.6 %

Procedure:
Hydrazine monohydrate (2.43 g, 48.5 mmol) was added slowly to a heterogeneous solution of ethyl 4-isobutylbenzoate (5.0 g, 24.2 mmol) and H2O and stirred at reflux for 12 hours. The reaction mixture was cooled to room temperature and filtered. The yellow solid was washed with cold water (1×20 mL) and dried to provide the title compound (3.33 g, 78% yield) as a yellow solid.