Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][C:5]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([C:7]#[CH:8])[CH3:6])[CH:2]=C.F[P-](F)(F)(F)(F)F.[C:22]1(C)C=CC=CC=1>>[CH3:6][C:5]1([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:7]([CH:8]=[CH2:22])=[CH:2][CH2:1][O:4]1
Reactant: Cc1ccccc1
Reactant: C#CC(C)(OCC=C)c1ccccc1
Agent: F[P-](F)(F)(F)(F)F
Product: C=CC1=CCOC1(C)c1ccccc1

Procedure:
A solution of 2-allyloxy-2-phenylbut-3-yne (368 mg, 1.97 mmol) and the allenylidene complex (p-cymene)RuCl(PCy3)(═C═C═CPh2)+PF6− (43 mg, 0.0485 mmol, 2.5 mol %) in toluene (10 ml) is stirred for 24 hours at 80° C. under nitrogen. The solvent is evaporated and the crude product is purified by flash chromatography using ether:pentane (1:10) as the eluent. The title compound was obtained as a yellowish liquid (283 mg, 77%). 1H NMR (200 MHz, CDCl3): d=1.79 (s, 3H, CH3); 4.76 (m, 2H, J=0.8, OCH2); 5.02 (d, 1H, J=11.2, ═CH2); 5.06 (d, 1H, J=17.8, ═CH2); 5.98 (m, 1H, C═CH); 6.21 (ddd, 1H, J=17.8, 11.2 and 0.8, ═CH); 7.20-7.47 (m, 5H, Ph). 13C NMR (50 MHz, CDCl3): d=24.4 (CH3); 73.1 (OCH2); 89.8 (C); 117.1 (═CH2); 124.3 (═CH); 126.1 (Ph); 128.3. (═CH); 128.6, 128.9 (Ph); 144.5 (C); 144.7 (C Ph). IR (NaCl windows): 3088, 3060, 3029, 2979, 2832, 2837, 1821, 1644, 1620, 1596, 1492, 1448,1370, 1344, 1239, 1201, 1139, 1068, 1021, 991, 913, 865, 807, 763, 701. MS (rel. Intensity): 186 ([M+], 8); 172 (19); 171 (100); 153 (15); 144 (7); 143 (43); 142 (19); 128 (50); 127 (11); 115 (27); 109 (19); 105 (23); 91 (20); 81 (12); 79 (14); 78 (11); 77 (54); 76 (7); 66 (15); 65 (26); 63 (13); 55 (13); 53 (10); 52 (7); 51 (33); 50 (9); 43 (49); 40 (12); 39 (30); 27 (11). C13H14O (186.27): calcd. C, 83.83, H, 7.66; found: C, 83.54, H, 7.58.
Reaction SMILES: Cl.[CH2:2]1[C:4]2([CH2:9][CH2:8][CH2:7][CH2:6][NH:5]2)[CH2:3]1.N1C=CC=CC=1.CCN(C(C)C)C(C)C.[Cl:25][C:26](Cl)([O:28]C(=O)OC(Cl)(Cl)Cl)Cl.Cl>C(Cl)Cl>[CH2:3]1[C:4]2([CH2:9][CH2:8][CH2:7][CH2:6][N:5]2[C:26]([Cl:25])=[O:28])[CH2:2]1
Reactant: C1CCC2(CC2)NC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: c1ccncc1
Product: O=C(Cl)N1CCCCC12CC2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a vigorously stirred pale yellow solution of 4-azaspiro[2.5]octane hydrochloride (ABCR, 443 mg, 3.00 mmol), pyridine (0.36 mL, 4.5 mmol) and DIPEA (0.52 mL, 3.0 mmol) in DCM (10 mL) at 0° C. was added a solution of triphosgene (594 mg, 2.00 mmol) in DCM (5 mL) dropwise over 5 min. The resulting orange solution was stirred at 0° C. for 30 min, and at RT for 66 h. Aq. HCl solution (1M, 15 mL) was added and the mixture stirred for 30 min. The aqueous was extracted with DCM (4×15 mL), then the combined organics passed through a hydrophobic fit and concentrated in vacuo to leave the title compound as a red-brown oil (100% yield). 1H NMR (300 MHz, CDCl3): ˜2:1 ratio of rotamers, 0.71-0.76 (1.33H, m), 0.82 (0.67H, br s), 1.00-1.04 (1.33H, m), 1.09 (0.67H, br s), 1.53-1.59 (2H, m), 1.64-1.72 (2H, m), 1.75-1.83 (2H, m), 3.61-3.74 (2H, m).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Si:6]([O:13][C:14]1([CH2:20][CH2:21][CH2:22][OH:23])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].C(N(CC)CC)C>ClCCl.C(=O)(O)[O-].[Na+]>[CH3:1][S:2]([O:23][CH2:22][CH2:21][CH2:20][C:14]1([O:13][Si:6]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)(=[O:4])=[O:3]
Reactant: CC(C)(C)[Si](C)(C)OC1(CCCO)CCCCC1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC1(CCCOS(C)(=O)=O)CCCCC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Methanesulfonyl chloride (2.1 mL, 27.4 mmol) was added dropwise to a solution of 3-(1-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)propan-1-ol (6.80 g, 24.9 mmol) and triethylamine (4.20 mL, 29.9 mmol) in dichloromethane (100 mL) at 0° C. The solution was stirred for 2 h at 0° C., then was diluted with dichloromethane (20-25 mL) and saturated aqueous sodium bicarbonate (70 mL). The layers were separated and the aqueous layer was extracted with dichloromethane (40 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated to afford 3-(1-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)propyl methanesulfonate as a pale oil that was used directly in the next step.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH3:7])[C:2]=1[CH3:8].Cl[C:10]([O:12][CH2:13][CH3:14])=[O:11].[CH3:15][Mg]Cl>[Cu]I.O1CCCC1>[CH3:8][C:2]1[N:1]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:6]=[CH:5][CH:4]([CH3:15])[C:3]=1[CH3:7]
Reactant: C[Mg]Cl
Reactant: Cc1cccnc1C
Reactant: CCOC(=O)Cl
Agent: [Cu]I
Solvent: C1CCOC1
Product: CCOC(=O)N1C=CC(C)C(C)=C1C

Procedure:
A solution of 6.75 g of 2,3-lutidine and 475 mg of copper(I) iodide in 150 ml of abs. tetrahydrofuran is cooled to -20° and treated under argon with 3.4 ml of ethyl chloroformate. The reaction mixture is heated to 30° and treated dropwise within 10 minutes with 14 ml of methylmagnesium chloride (3 molar, in tetrahydrofuran). The ethyl 2,3,4-trimethyl-l (4H)-pyridinecarboxylate obtained as the intermediate can be isolated as follows: The reaction mixture is cooled to -10° and treated with 38 ml of aqueous (20%) ammonium chloride solution, whereupon 100 ml of ether are added and the organic solution is washed several times with a 20% ammonium chloride/ammonia (1:1) solution, 2N hydrochloric acid and 10% sodium carbonate solution. The organic solution is dried and concentrated, and the residue is purified on a silica gel column, the medium pressure flash chromatography method (solvent: n-hexane/ether [20:1]) being used and the pressure being produced with nitrogen gas.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[CH3:8].[N+:10]([O-])([OH:12])=[O:11]>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[C:5]([N+:10]([O-:12])=[O:11])=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(O)cc1Cl
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: Cc1cc([N+](=O)[O-])c(O)cc1Cl
Temperature: 0 °C
Reaction time: 5 h

Procedure:
245.0 g of 2A was mixed with 1.6 liters of glacial acetic acid, and the resulting solution was stirred at 8°-10° C. while 109.6 g of 90% aqueous nitric acid was added (two hours). The mixture was stirred at 10°-15° C. for five hours, poured into ice water and extracted with ether/hexane. The extract was washed with water, dried and stripped to dryness. The residue was stirred with 3 liters of hexane and the hexane solution was filtered through silica gel. The filtrate was held at -30° to -35° C. for 16 hours and filtered to give 3-chloro-4-methyl-6-nitrophenol (2B), as a solid.
Reaction SMILES: O[CH:2]([CH3:34])[CH2:3][N:4]([S:25]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1)(=[O:27])=[O:26])[C:5]1[CH:22]=[C:21]([CH3:23])[C:20]([CH3:24])=[CH:19][C:6]=1[O:7][CH2:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=1.C(N(S(F)(F)[F:41])CC)C.O>ClCCl>[F:41][CH:2]([CH3:34])[CH2:3][N:4]([S:25]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1)(=[O:27])=[O:26])[C:5]1[CH:22]=[C:21]([CH3:23])[C:20]([CH3:24])=[CH:19][C:6]=1[O:7][CH2:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: COC(=O)c1ccc(COc2cc(C)c(C)cc2N(CC(C)O)S(=O)(=O)c2ccccn2)cc1
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1ccc(COc2cc(C)c(C)cc2N(CC(C)F)S(=O)(=O)c2ccccn2)cc1
Yield: 23.6 %

Procedure:
460 mg of methyl 4-({2-[(2-hydroxypropyl)(pyridin-2-ylsulfonyl)amino]-4,5-dimethylphenoxy}methyl)benzoate was dissolved in 4.00 mL of dichloromethane, and 161 mg of diethylaminosulfur trifluoride was added dropwise thereto under ice-cooling, followed by stirring under ice-cooling for 30 minutes. To the reaction liquid was added water, followed by extraction with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1 to 1:1) to obtain 109 mg of methyl 4-({2-[(2-fluoropropyl)(pyridin-2-ylsulfonyl)amino]-4,5-dimethylphenoxy}methyl)benzoate.
Reaction SMILES: [O:1]=[CH:2][CH:3]=[CH:4][C:5]([O:7][CH3:8])=[O:6].[CH3:9][N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11]1.C(O)(C(F)(F)F)=O.C([C@@H]1N[C@H](C(C)(C)C)N(C)C1=O)C1C=CC=CC=1>C(Cl)Cl.C(O)(C)C>[CH3:8][O:7][C:5](=[O:6])[C@@H:4]([C:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:10]([CH3:9])[CH:11]=1)[CH2:3][CH:2]=[O:1]
Reactant: COC(=O)C=CC=O
Reactant: Cn1ccc2ccccc21
Agent: CN1C(=O)[C@H](Cc2ccccc2)N[C@@H]1C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)O
Solvent: ClCCl
Product: COC(=O)[C@H](CC=O)c1cn(C)c2ccccc12
Yield: 88.9 %

Procedure:
Prepared according to the general procedure from methyl 4-oxo-butenoate (171 mg, 1.50 mmol), 1-methyl-1H-indole (64 μL, 0.50 mmol), TFA (7.7 μL, 0.10 mmol) and (2S,5S)-5-benzyl-2-tert-butyl-3-methyl-imidazolidin-4-one (24.6 mg, 0.100 mmol) in CH2Cl2 (0.90 mL) and isopropanol (0.10 mL) at −85° C. for 21 h to provide, after silica gel chromatography (5:47:47 acetone/CH2Cl2/hexanes), the title compound as a colorless oil (109 mg, 89% yield, 91% ec). IR (film) 2937, 2833, 2729, 1732, 1623, 1545, 1477, 1436, 1379, 1332, 1228, 1171, 1042, 1016, 980, 773, 742 cm−1; 1H NMR (300 MHz, CDCl3) δ 9.81 (s, 1H, CHO), 7.67 (d, J=8.4 Hz, 1H, ArH), 7.33-7.23 (m, 2H, ArH), 7.15 (ddd, J=1.2, 7.6, 7.8 Hz, 1H, ArH), 6.98 (s, 1H, NCH), 4.44 (dd, J=5.4, 9.3 Hz, 1H, ArH), 3.76 (s, 3H, NCH3), 3.69 (s, 3H, OCH3), 3.47 (dd, J=9.3, 18.6 Hz, 1H, CH2CO); 2.94 (dd, J=5.1, 18.3 Hz, 1H, CH2CO); 13C NMR (75 MHz, CDCl3) δ 200.1, 173.8, 137.0, 126.9, 126.5, 122.1, 119.5, 119.1, 110.8, 109.6, 52.5, 46.8, 36.5, 33.0; HRMS (CI) exact mass calcd for (C14H15NO3) requires m/z 245.1048, found m/z 153.1151. [α]D=−123.6 (c=1.0, CHCl3). The enantiomeric ratio was determined by HPLC analysis of the alcohol, obtained by NaBH4 reduction of the aldehyde, using a Chiracel AS and AS guard column (3:97 isopropanol/hexanes, 1 mL/min); S isomer tr=71.7 min and R isomer tr=76.3 min.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:11][O:10][CH2:9][CH:8]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)[C:6]=2[N:7]=1.Cl.[CH3:21][NH2:22]>>[Cl:1][C:2]1[N:3]=[C:4]([NH:22][CH3:21])[C:5]2[CH2:11][O:10][CH2:9][CH:8]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)[C:6]=2[N:7]=1
Reactant: CN
Reactant: Clc1ccc(C2COCc3c(Cl)nc(Cl)nc32)cc1
Agent: Cl
Product: CNc1nc(Cl)nc2c1COCC2c1ccc(Cl)cc1
Yield: 30.6 %

Procedure:
2,4-dichloro-8-(4-chlorophenyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine (Preparation K) (500 mg, 1.584 mmol) and methanamine hydrochloride (160 mg, 2.377 mmol) were combined and purified as per Preparation Ha to give 2-chloro-8-(4-chlorophenyl)-N-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-amine (150 mg, 0.484 mmol, 30.5% yield). LC-MS (M+H)+=310.0. 1H NMR (500 MHz, CDCl3) δ ppm 7.22-7.31 (2 H, m), 7.13 (2 H, d, J=8.55 Hz), 4.46-4.64 (1 H, m), 4.43 (1 H, br. s.), 3.97-4.14 (1 H, m), 3.91 (1 H, d, J=3.36 Hz), 3.09 (3 H, d, J=4.88 Hz).
Reaction SMILES: C(OC([N:8]1[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Br:20])[CH:15]=2)([CH3:13])[CH2:11][O:10][S:9]1(=[O:22])=[O:21])=O)(C)(C)C.C(Cl)Cl>C(O)(C(F)(F)F)=O>[Br:20][C:16]1[CH:15]=[C:14]([C:12]2([CH3:13])[CH2:11][O:10][S:9](=[O:22])(=[O:21])[NH:8]2)[CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)N1C(C)(c2cccc(Br)c2)COS1(=O)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(c2cccc(Br)c2)COS(=O)(=O)N1
Reaction time: 3 h
Yield: 91 %

Procedure:
3-(tert-Butoxycarbonyl)-4-(3-bromophenyl)-4-methyl-[1,2,3]-oxathiazolidine-2,2-dioxide (DC4; R6=Me) (10.8 g, 28 mmol) was dissolved in 25% TFA in DCM (40 mL, 5 eq) and the mixture was left standing at RT for 3 h. The mixture was concentrated in vacuo to give 7.3 g (91%) of 4-(3-bromophenyl)-4-methyl-[1,2,3]-oxathiazolidine-2,2-dioxide as a yellow oil. 1H NMR (CDCl3) δ 7.59 (t, J=1.8 Hz, 1H), 7.48-7.52 (m, 1H), 7.39-7.42 (m, 1H), 7.30 (t, J=8.1 Hz, 1H), 4.59 (m, 2H), 1.82 (s, 3H).
Reaction SMILES: C([O:4][CH2:5][C@@H:6]([NH:32][C:33]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:34])[C:7]([N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]([N:16]1[CH2:20][CH2:19][CH2:18][C@H:17]1[C:21]([NH:23][C@@H:24]([C@H:29]([OH:31])C)[C:25]([O:27][CH3:28])=[O:26])=[O:22])=[O:15])=[O:8])(=O)C.CN1CCOCC1>C(Cl)Cl.CN(C=O)C>[CH2:36]([O:35][C:33]([NH:32][C@@H:6]([CH2:5][OH:4])[C:7]([N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]([N:16]1[CH2:20][CH2:19][CH2:18][C@H:17]1[C:21]([NH:23][C@@H:24]([CH2:29][OH:31])[C:25]([O:27][CH3:28])=[O:26])=[O:22])=[O:15])=[O:8])=[O:34])[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: COC(=O)[C@@H](NC(=O)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)[C@@H](COC(C)=O)NC(=O)OCc1ccccc1)[C@@H](C)O
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CO)NC(=O)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)[C@H](CO)NC(=O)OCc1ccccc1
Reaction time: 0.5 h
Yield: 14.3 %

Procedure:
(S)-1-((S)-3-Acetoxy-2-(benzyloxycarbonylamino)-propanoyl)-pyrrolidine-2-carboxylic acid (5) (400 mg, 1.05 mmol) was dissolved in CH2Cl2 (2 mL), NMM (0.13 mL) and IBCF (0.14 mL) were added at −15° C. and stirred for 30 minutes under inert atmosphere. A mixture of(S)-methyl-3-hydroxy-2-((S)-pyrrolidine-2-carboxamido)-propanoate hydrochloride (4) (293 mg, 1.16 mmol) and NMM (0.13 mL) in DMF (2 mL) were added drop wise to the reaction mixture and stirring was continued for another 3 h at RT. The reaction mixture was diluted with DCM (200 mL), washed with water (20 mL) and brine (10 mL). The separated organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The obtained crude material was purified by silica gel column chromatography eluting with 5% CH3OH/CH2Cl2 to afford compound 6 (80 mg, 13%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:13]=[C:12]([OH:14])[C:11]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:10]([CH3:22])[N:9]=2)=[N:6][CH:7]=1.C(N(CC)CC)C.[Cl:30][CH2:31][C:32](Cl)=[O:33]>C1COCC1>[CH2:15]([C:11]1[C:12]([OH:14])=[N:13][C:8]([C:5]2[N:6]=[CH:7][C:2]([NH:1][C:32](=[O:33])[CH2:31][Cl:30])=[CH:3][CH:4]=2)=[N:9][C:10]=1[CH3:22])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: Cc1nc(-c2ccc(N)cn2)nc(O)c1Cc1ccccc1
Reactant: O=C(Cl)CCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1nc(-c2ccc(NC(=O)CCl)cn2)nc(O)c1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a cold (0° C.) solution of compound of example 54 (0.050 g, 0.17 mmol) in THF (3 mL), was added triethylamine (0.025 g, 0.25 mmol) and chloroacetylchloride (0.029 g, 0.25 mmol), and the reaction mixture was stirred at room temperature for 30 minutes. THF was removed under reduced pressure, and reaction mixture was quenched with water and extracted with ethyl acetate (3×10 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain the crude product, which was purified by column chromatography (silica gel, 5% methanol in chloroform as an eluent) to obtain the title compound.
Reaction SMILES: Br[CH2:2][C:3](Br)=[O:4].[CH2:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1)[CH3:7].[C:16]([C:20]1[CH:25]=[CH:24][C:23]([S:26]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=2)(=[O:28])=[O:27])=[CH:22][CH:21]=1)([CH3:19])([CH3:18])[CH3:17]>>[C:16]([C:20]1[CH:21]=[CH:22][C:23]([S:26]([N:29]([C:30]2[CH:31]=[CH:32][C:33]([CH3:36])=[CH:34][CH:35]=2)[CH2:2][C:3]([N:8]([CH2:6][CH3:7])[CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[O:4])(=[O:28])=[O:27])=[CH:24][CH:25]=1)([CH3:19])([CH3:18])[CH3:17]
Reactant: CCNCc1ccncc1
Reactant: Cc1ccc(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Reactant: O=C(Br)CBr
Product: CCN(Cc1ccncc1)C(=O)CN(c1ccc(C)cc1)S(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
prepared by reaction of 2-bromoacetyl bromide with N-ethyl-N-pyridin-4-ylmethylamine and 4-tert-butyl-N-p-tolyl-benzenesulfonamide
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[N:10][CH:11]=1.[N:19]1(CC2N=CC(O)=CC=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.BrCCCCl.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[N:13]1([CH2:12][C:9]2[CH:8]=[CH:7][C:6]([O:5][CH2:4][CH2:3][CH2:2][N:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[CH:11][N:10]=2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: Oc1ccc(CN2CCCCC2)nc1
Reactant: ClCCCOc1ccc(CN2CCCCC2)nc1
Agent: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: c1cc(CN2CCCCC2)ncc1OCCCN1CCCCC1
Temperature: 25 °C
Yield: 80 %

Procedure:
5-(3-Chloro-propoxy)-2-Piperidin-1ylmethyl-pyridine. A solution of 6-piperidin-1-ylmethyl-pyridin-3-ol (0.225 g, 1.17 mmol), 1-bromo-3-chloro propane (0.23 mL, 2.34 mmol), and K2CO3 (0.483 g, 3.50 mmol) in acetone (10 mL) was heated to reflux temperature. After 10 h the reaction mixture was cooled to rt, diluted with acetone (50 mL) and filtered through a pad of diatomaceous earth. The filtrate was concentrated, giving the crude title compound as an oil (0.250 g, 80%).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[ClH:9].CN.[CH2:12]([N:14](CC)CC)C>ClCCCl>[ClH:9].[CH3:12][NH:14][CH:5]1[CH2:6][CH2:7][CH:2]([CH3:1])[CH2:3][CH2:4]1
Reactant: CCN(CC)CC
Reactant: CC1CCC(=O)CC1
Agent: CN
Agent: Cl
Solvent: ClCCCl
Product: CNC1CCC(C)CC1
Temperature: 25 °C

Procedure:
In 1,2-dichloroethane (35 ml) were suspended 4-methylcyclohexanone (2.5 g), methylamine hydrochloride (1.6 g) and triethylamine (3.3 ml), and to the suspension was added sodium triacetoxy boron hydride (6.6 g) under ice-cooling. The mixture was stirred under nitrogen atmosphere at room temperature over night. The solvent was evaporated, and the residue was neutralized with sodium hydroxide. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated. To the residue was added 4N hydrochloric acid-ethyl acetate, and the solvent was evaporated to give N, 4-dimethyl-cyclohexylamine hydrochloride (2.6 g) as colorless crystals.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([NH:14][NH2:15])=[O:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[C:16](OCC)(OCC)(OCC)[CH3:17]>>[CH3:16][C:17]1[O:13][C:12]([C:8]2[CH:7]=[C:6]3[C:11]([C:2](=[O:1])[NH:3][CH:4]=[N:5]3)=[CH:10][CH:9]=2)=[N:14][N:15]=1
Reactant: CCOC(C)(OCC)OCC
Reactant: NNC(=O)c1ccc2c(O)ncnc2c1
Product: Cc1nnc(-c2ccc3c(=O)[nH]cnc3c2)o1

Procedure:
4-Hydroxy quinazoline-7-hydrazide (0.41 g) was treated with triethyl orthoacetate (10 ml) at reflux under nitrogen for 24 hours. The mixture was cooled, filtered and purified by chromatography to give the title compound (0.09 g); m/z (M+1+) 229.
Reaction SMILES: [CH2:1]([C:13]1[N:14]=[N:15][N:16]([CH:18]([CH:24]([CH3:26])[CH3:25])[C:19]([O:21]CC)=[O:20])[N:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(C1N=NN(C(C2C=CC=CC=2)C(OCC)=O)N=1)CCCCCCCCC>>[CH2:1]([C:13]1[N:14]=[N:15][N:16]([CH:18]([CH:24]([CH3:25])[CH3:26])[C:19]([OH:21])=[O:20])[N:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCc1nnn(C(C(=O)OCC)C(C)C)n1
Agent: CCCCCCCCCCc1nnn(C(C(=O)OCC)c2ccccc2)n1
Product: CCCCCCCCCCCCc1nnn(C(C(=O)O)C(C)C)n1

Procedure:
When in the general procedure of Example 79 an appropriate amount of ethyl (±)-5-dodecyl-α-(1-methylethyl)-2H-tetrazole-2-acetate was substituted for ethyl (±)-5-decyl-α-phenyl-2H-tetrazole-2-acetate, the title compound was obtained, mp 39°-42° C.
Reaction SMILES: [ClH:1].[CH2:2]([O:4][C:5](=[O:8])[CH2:6]N)[CH3:3].Cl.[N:10]([O-:12])=O.[Na+]>O>[Cl:1][C:6](=[N:10][OH:12])[C:5]([O:4][CH2:2][CH3:3])=[O:8]
Reactant: O=N[O-]
Reactant: CCOC(=O)CN
Reactant: Cl
Agent: [Na+]
Solvent: O
Product: CCOC(=O)C(Cl)=NO
Reaction time: 1 h
Yield: 50.1 %

Procedure:
69.8 g of glycine ethyl ester hydrochloride are initially introduced into 120 ml of water and 41 ml of concentrated hydrochloric acid. 38 g of NaNO2 in 60 ml of water are then added dropwise at -10° C. in the course of 1 hour. After half an hour, a further 42.5 ml of concentrated hydrochloric acid are added, and then, in the course of 1 hour, a further 38 g of NaNO2 in 60 ml of water. Stirring is continued for 1 hour at -10° C. The mixture is subsequently extracted with ether, and the ether phase is washed several times with water. The ether is distilled off, and the crystals are dried. In this way, 38 g (50% of theory) of ethyl 2-chloro-2-hydroximinoacetate of a melting point of 81°-82° C. are obtained.
Reaction SMILES: Br[C:2]1[CH:19]=[CH:18][C:5]2[CH2:6][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1.O>C(O)C.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1.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>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C:2]2[CH:19]=[CH:18][C:5]3[CH2:6][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:8][CH2:9][O:10][C:4]=3[CH:3]=2)=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCOc2cc(Br)ccc2C1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCOc2cc(-c3ccc(Cl)cc3)ccc2C1
Yield: 96.5 %

Procedure:
A mixture of tert-butyl 8-bromo-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (200 mg, 0.605 mmol), a solution of 4-chlorophenylboronic acid (143 mg, 0.912 mmol) in ethanol (0.7 ml), 2N aqueous sodium carbonate solution (2.5 ml), and tetrakis(triphenylphosphine)palladium(0) (84.0 mg, 0.0730 mmol) in toluene (5 ml) was stirred under a nitrogen atmosphere at 95° C. for 12 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give the desired product (210 mg, 95.9%) as an oil.
Reaction SMILES: [NH2:1][CH:2]([CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].C(N(CC)CC)C.[C:32]([O:36][C:37](ON1C(=O)CCC1=O)=[O:38])([CH3:35])([CH3:34])[CH3:33]>CN(C)C=O>[CH2:18]([O:17][C:15]([NH:14][CH2:13][CH2:12][CH2:11][CH2:10][CH:2]([NH:1][C:37]([O:36][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:38])[C:3]([O:5][C:6]([CH3:9])([CH3:7])[CH3:8])=[O:4])=[O:16])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)C(N)CCCCNC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)ON1C(=O)CCC1=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC(CCCCNC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
tert-Butyl 2-amino-6-benzyloxycarbonylamino-hexanoate (1.0 g, 2.68 mmol) was dissolved in N,N-dimethylformamide (50 mL) and then triethylamine (5.35 mmol, 0.75 mL) followed by N-(tert-butoxycarbonyloxy)succinimide (0.72 g, 3.35 mmol) was added to the solution. The mixture was stirred overnight and then concentrated. The product was purified from the residue by silica gel chromatography (20% MeOH/chloroform) to give tert-butyl 6-benzyloxycarbonylamino-2-tert-butoxycarbonylamino-hexanoate. The tri-protected product was reduced on a Parr hydrogenator (50 psi) to remove the benzyloxycarbonyl protecting group. The solvents were removed to give tert-butyl 6-amino-2-tert-butoxycarbonylamino-hexanoate (0.65 g, 80%).