Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@H:2]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:3]([NH:5][C@H:6]([C:11]([O:13]C)=[O:12])[CH2:7][CH:8]([CH3:10])[CH3:9])=[O:4].[Li+].[OH-]>C1COCC1.Cl>[OH:1][C@@H:2]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:3]([NH:5][C@H:6]([C:11]([OH:13])=[O:12])[CH2:7][CH:8]([CH3:10])[CH3:9])=[O:4]
Reactant: COC(=O)[C@H](CC(C)C)NC(=O)[C@@H](O)CC(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)C[C@H](NC(=O)[C@@H](O)CC(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.9 %

Procedure:
To a solution of methyl N-[(2S)-2-hydroxy-4-methylpentanoyl]-L-leucinate (7a) (2.13 g) dissolved in THF (21 mL) was added an aqueous 2.3 M LiOH solution (17 mL). The reaction mixture was stirred for 2 hours at room temperature, diluted with 1.2 N HCl (100 mL) and extracted with EtOAc. The organic layer was washed with brine and concentrated to give the desired product (1.75 g, 87%). 1H NMR (300 MHz, CDCl3) δ 0.92-0.96 (m, 12H), 1.50-1.71 (m, 5H), 1.82-1.90 (m, 1H), 4.17-4.22 (m, 1H), 4.50-4.57 (m, 1H), 7.26 (d, 1H).
Reaction SMILES: [CH3:1][CH:2]([CH:9]=[C:10]([CH3:12])[CH3:11])[CH2:3][CH2:4][CH2:5][CH2:6][CH:7]=[O:8].[BH4-].[Na+].CC(C)=O>C(O)C>[CH3:1][CH:2]([CH:9]=[C:10]([CH3:11])[CH3:12])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8]
Reactant: CC(C)=CC(C)CCCCC=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(C)=O
Product: CC(C)=CC(C)CCCCCO
Temperature: 25 °C
Reaction time: 16 h
Yield: 72.7 %

Procedure:
18 g (0.11 mol) of 6,8-dimethylnon-7-enal (1) and 96.0 g of ethanol are placed in a 500 ml round-bottomed flask equipped with a thermometer. Cooling is carried out to 5° C. and 2.0 g of sodium borohydride are added in small portions without exceeding a bulk temperature of 10° C. The mixture is stirred at ambient temperature for 16 hours. Cooling is carried out to 5° C. and 20.0 g (1.36 mol) of acetone are added dropwise to destroy the excess reducing agent without exceeding a bulk temperature of 10° C. The reaction medium is acidified with 20.0 g of 10% hydrochloric acid without exceeding a bulk temperature of 10° C. 40 g of water are also added, followed by 70 g of toluene, with vigorous stirring. The phases are separated and the organic phase is washed once with 50 g of saturated aqueous NaHCO3 solution and twice with 50 g of water. The organic phase is dried and filtered, and the toluene is evaporated at reduced pressure. After distillation, 13.4 g (0.08 mol) of (B.p.: 105° C./10 torr) are obtained. The yield is 72.7%. The analyses of the infrared, NMR and mass spectra correspond to the expected alcohol.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:12](OC(=O)C)(=[O:14])[CH3:13].OS(O)(=O)=O>>[C:12]([O:1][C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])(=[O:14])[CH3:13]
Reactant: O=C(O)c1cc(Br)ccc1O
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Product: CC(=O)Oc1ccc(Br)cc1C(=O)O
Temperature: 100 °C
Yield: 93.3 %

Procedure:
To a mixture of 2-hydroxy-5-bromo-benzoic acid (5.0 g, 23.0 mmol) in acetic anhydride (7.1 mL, 75.4 mmol) was added conc. H2SO4 (0.35 mL) at rt. Resulting suspension was heated in a 100° C. oil bath for 25 min. After cooled to about 50° C., the reaction mixture was poured onto ice (100 g) with stirring. The precipitated product was collected, rinsed with water, and dried in vacuo to give the title compound (5.56 g). 1H NMR (200 MHz, CDCl3): δ (ppm)=8.21 (d, J=2.3 Hz, 1H), 7.71 (dd, J=8.6, 2.3 Hz, 1H), 7.01 (d, J=8.6 Hz, 1H), 2.34 (s, 3H).
Reaction SMILES: C([O:3][C:4]([C:6]1([CH2:9][N:10]([CH3:12])[CH3:11])[CH2:8][CH2:7]1)=[O:5])C.[OH-].[Na+].Cl>C(O)C>[CH3:11][N:10]([CH2:9][C:6]1([C:4]([OH:5])=[O:3])[CH2:8][CH2:7]1)[CH3:12]
Reactant: CCOC(=O)C1(CN(C)C)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CN(C)CC1(C(=O)O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42 %

Procedure:
To a solution of 222 mg of 1-dimethylaminomethyl-cyclopropane carboxylic acid ethyl ester in 0.4 mL of ethanol was added 0.1 mL of 5N sodium hydroxide aqueous solution, and stirred overnight at room temperature. The reaction solution was added with 0.5 mL of 1N hydrochloric acid, and the solvent and water were evaporated, to give 78 mg of a mixture of the title compound and sodium chloride as a white powder.
Reaction SMILES: [H-].[Na+].[CH3:3][NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1.[S:11](Cl)(=[O:14])(=[O:13])[NH2:12]>C1COCC1>[CH3:3][N:4]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1)[S:11]([NH2:12])(=[O:14])=[O:13]
Reactant: CNc1ccccn1
Reactant: NS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(c1ccccn1)S(N)(=O)=O
Reaction time: 1 h

Procedure:
To a stirred solution of NaH (60%) (0.112 g, 2.78 mmol) in THF (6 ml), N-methylpyridin-2-amine (prepared by N-methylation of 2-aminopyridine) (0.3 g, 2.78 mmol) in THF (2 ml) was added and stirred for 1 h. To this a solution of Sulfamoyl chloride (0.32 g, 2.78 mmol) in THF (1 ml) was added and stirred for 2 h at RT. Reaction mass was quenched with methanol (0.6 ml) at ice cold condition and concentrated to dryness to get crude which was purified using neutral alumina column, eluent ethyl acetate in n-Hexane 0 to 85% to afford N-methyl-N-(pyridin-2-yl)sulfamide as off white solid (0.12 g, 23% yield)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:16][OH:17])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1.Cl[C:19]1[CH:20]=[C:21]2[N:28]([CH3:29])[C@@H:27]([CH3:30])[CH2:26][N:22]2[C:23](=[O:25])[N:24]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)[CH2:16][O:17][C:19]1[CH:20]=[C:21]2[N:28]([CH3:29])[C@@H:27]([CH3:30])[CH2:26][N:22]2[C:23](=[O:25])[N:24]=1
Reactant: C[C@H]1Cn2c(cc(Cl)nc2=O)N1C
Reactant: OCc1ccc(Oc2ccc(F)cc2)c(F)c1
Product: C[C@H]1Cn2c(cc(OCc3ccc(Oc4ccc(F)cc4)c(F)c3)nc2=O)N1C

Procedure:
The title compound was prepared by a procedure similar to that described for E9 starting from (3-fluoro-4-(4-fluorophenoxy)phenyl)methanol and (S)-7-chloro-1,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH:14]1[CH2:19][CH2:18][CH:17]([CH3:20])[CH2:16][CH2:15]1)[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C[CH2:22][N:23]=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CN.CCO>C(Cl)Cl>[CH3:22][NH:23][C:10]([C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:13][CH:14]1[CH2:19][CH2:18][CH:17]([CH3:20])[CH2:16][CH2:15]1)=[O:11]
Reactant: CC1CCC(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)CC1
Reactant: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CNC(=O)[C@H](CC1CCC(C)CC1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 21 h
Yield: 46.7 %

Procedure:
A mixture of (S)-2-(tert-butoxycarbonylamino)-3-(4-methylcyclohexyl)propanoic acid (2.080 g, 7.29 mmol, 1.0 equiv), EDC.HCl (3.308 g, 2.37 equiv), HOBt (1.752 g, 1.78 equiv), DIEA (7.6 mL, 6 equiv) and 33% wt. methylamine in EtOH (2.771 g, 4 equiv) in CH2Cl2 (80 mL) was stirred at rt for 21 h. The solvents were removed in vacuo and 1 N aq HCl (200 mL) was added. The mixture was extracted with EtOAc (3×). The combined organic extracts were washed with brine and dried over Na2SO4. After the solvents were removed in vacuo, the residue was purified by reversed-phase HPLC (Phenomenex® Luna 5μ C18(2) 100 A, 250×21.20 mm, 5 micron, 10%→90% CH3CN/H2O, 0.1% CF3COOH over 13 min and then 90% CH3CN/H2O, 0.1% CF3COOH over 3.5 min, flow rate 25 mL/min) to give tert-butyl (S)-1-(methylcarbamoyl)-2-(4-methylcyclohexyl)-ethylcarbamate (1.0167 g, 47%). LC-MS (3 min) tR=1.72 min, m/z 321 (M+Na+), 243, 199; 1H NMR (400 MHz, CDCl3) δ 6.27 (br s, 1H), 4.91 (br s, 1H), 4.11-4.07 (m, 1H), 2.802, 2.798 (d, J=4.8 Hz, 3H), 1.85-1.20 (m, 21H), 0.886, 0.851 (d, J=6.4 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[C:5]([C:16]#[N:17])=[C:4]([SH:18])[N:3]=1.Cl[CH2:20][C:21]1[N:22]=[C:23]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)[S:24][CH:25]=1.C(=O)(O)[O-].[Na+]>CN(C=O)C>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH:10]2[CH2:11][CH2:12][O:13][CH2:14][CH2:15]2)[C:5]([C:16]#[N:17])=[C:4]([S:18][CH2:20][C:21]2[N:22]=[C:23]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[S:24][CH:25]=2)[N:3]=1
Reactant: N#Cc1c(N)nc(S)c(C#N)c1C1CCOCC1
Reactant: ClCc1csc(-c2ccc(Cl)cc2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1c(N)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1C1CCOCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
100 mg (0.34 mmol) of the compound from Example 34A, 83 mg (0.34 mmol) of 4-(chloromethyl)-2-(4-chlorophenyl)-1,3-thiazole and 57 mg (0.68 mmol) of sodium bicarbonate are initially charged in 5 ml of dry DMF. The reaction mixture is stirred at RT for 16 h. After removal of the solvent on a rotary evaporator the residue is triturated with about 2 ml of acetonitrile. This results in the formation of a precipitate which is filtered off with suction and dried.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH:24]([CH2:25][OH:26])[CH2:23][N:22]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:21][CH:20]2[OH:34])=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:35]1([C:41]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)Cl)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>N1C=CC=CC=1>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH:24]([CH2:25][O:26][C:41]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)([C:49]3[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=3)[C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=3)[CH2:23][N:22]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[CH2:21][CH:20]2[OH:34])=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC(O)C(c2ccc(OCCCOCc3ccccc3)cc2)C(CO)C1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CC(O)C(c2ccc(OCCCOCc3ccccc3)cc2)C(COC(c2ccccc2)(c2ccccc2)c2ccccc2)C1

Procedure:
In an analogous manner to that described in Example 22(h), by reacting tert-butyl (3RS,4RS,5SR)-4-[4-(3-benzyloxy-propoxy)-phenyl]-3-hydroxy-5-hydroxymethyl-piperidine-1-carboxylate with triphenylchloromethane in pyridine there was obtained tert-butyl (3RS,4RS,5SR)-4-[4-(3-benzyloxy-propoxy)-phenyl]-3-hydroxy-5-trityloxymethyl-piperidine-1-carboxylate, [MS: 731 (M+NH4)+ ], as a colourless foam, alkylation of which with 2-bromomethyl-naphthalene analogously to Example 62(h) gave tert-butyl (3RS,4RS,5SR)-4-[4-(3-benzyloxy-propoxy)-phenyl]-3-(naphthalen-2-ylmethoxy)-5-trityloxymethyl-piperidine-1-carboxylate, [MS: 871 (M+NH4)+ ], as a colourless foam. Subsequent selective cleavage of the trityl group by means of a mixture of trifluoroacetic acid and trifluoroacetic anhydride in methylene chloride analogously to Example 86(u) yielded tert-butyl (3SR,4RS,5RS)-4-[4-(3-benzyloxy-propoxy)-phenyl]-3-hydroxymethyl-5-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a colourless solid; MS: 612 (M+H)+. Subsequent alkylation with methyl iodide analogously to Example 62(h) gave tert-butyl (3SR,4RS,5RS)-4-[4-(3-benzyloxy-propoxy)-phenyl]-3-methoxymethyl-5-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a colourless solid; MS: 626 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[S:10][CH:9]=2)=[CH:3][CH:2]=1.[H-].[Na+].S(OCC)(O[CH2:23][CH3:24])(=O)=O>CN(C)C=O>[CH2:23]([N:7]([C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1)[C:8]1[C:16]2[C:11](=[N:12][CH:13]=[CH:14][CH:15]=2)[S:10][CH:9]=1)[CH3:24]
Reactant: c1cnc2scc(Nc3ccncc3)c2c1
Reactant: CCOS(=O)(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(c1ccncc1)c1csc2ncccc12
Temperature: 0 °C
Yield: 46.7 %

Procedure:
A solution of 3-(4-pyridinylamino)thieno[2,3-b]pyridine (4 g) in 25 mL of dimethylformamide was added to an ice-cooled suspension of sodium hydride (60% oil dispersion, 0.8 g, washed with heptane) in 5 mL of dimethylformamide. After anion formation was completed a solution of diethyl sulfate (3 g) in 5 mL of dimethylformamide was added. After one hour the reaction mixture was poured into ice-water and extracted with ethyl acetate. The organic extract was washed with water and saturated sodium chloride, and then was dried (anhydrous magnesium sulfate), filtered and evaporated to 5 g of an oil. Elution through silica with 10% methanol in ethyl acetate via flash column chromatography afforded 2.1 g of a solid. Recrystallization from acetonitrile afforded 1.4 g of crystals, m.p. 123°-125° C.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][N:7]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[C:8]=1[C:9]([NH2:11])=[O:10])([OH:3])=[O:2].[CH2:19](O)[CH3:20]>>[NH2:11][C:9]([C:8]1[N:7]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[N:6]=[CH:5][C:4]=1[C:1]([O:3][CH2:19][CH3:20])=[O:2])=[O:10]
Reactant: NC(=O)c1c(C(=O)O)cnn1-c1cccc(Cl)c1
Reactant: CCO
Product: CCOC(=O)c1cnn(-c2cccc(Cl)c2)c1C(N)=O

Procedure:
A 2.5 g. portion of 4-carboxy-1-(3-chlorophenyl)-5-pyrazolecarboxamide was suspended in 50 ml. of absolute ethanol, made acid, and esterified and isolated as described in Example 14 above. The product was 1.64 g. of the desired product, m.p. 132°, and its elemental analysis was as follows.
Reaction SMILES: [Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[C:4]([N+:14]([O-])=O)[CH:3]=1.O1CC[CH2:19][CH2:18]1>>[N:14]1([C:4]2[CH:3]=[C:2]([Cl:1])[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]=2[C:6]([NH2:8])=[O:7])[CH2:19][CH2:18]1
Reactant: NC(=O)c1cc([N+](=O)[O-])c(Cl)cc1[N+](=O)[O-]
Reactant: C1CCOC1
Product: NC(=O)c1cc([N+](=O)[O-])c(Cl)cc1N1CC1
Reaction time: 2 h

Procedure:
Reaction of 4-chloro-2,5-dinitrobenzamide [Goldstein and Schaaf, Helv. Chim Acta. 1957, 40, 369-376] in tetrahydrofuran as described in Example C except that the reaction time was 2 hours, gave 2-(aziridin-1-yl)-4-chloro-5-nitrobenzamide (15) as a yellow powder, mp 155° C. 1H NMR [(CD3)2SO] δ8.15 (s, 1H, H-6), 7.83, 7 81 (2 br s, 2H, CONH2), 7.40 (s, 1H, H-3),2.33 (s, 4H, aziridin-H). 13NMR δ165.68 (s), 156 66 (s), 140.39 (s), 128 46 (s), 127 87 (s), 127 02 (d), 123.94 (d), 29.35 (t). Found: C,44.70;H, 3.14; N, 17.41. C9H8ClN3O3 requires C, 44 73;H, 3.33; N, 17.39%
Reaction SMILES: [CH2:1]([O:4][CH:5]1[C:10](=O)[CH2:9][CH2:8][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6]1)[CH:2]=[CH2:3].[CH2:19]([NH2:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:19]([NH:26][C@H:10]1[CH2:9][CH2:8][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][C@H:5]1[O:4][CH2:1][CH:2]=[CH2:3])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: C=CCOC1CN(C(=O)OC(C)(C)C)CCC1=O
Reactant: NCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: C=CCO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1NCc1ccccc1
Yield: 83.7 %

Procedure:
The same operation as in Example (90c) was performed using tert-butyl 3-allyloxy-4-oxopiperidine-1-carboxylate obtained in Example (113b) (4.37 g, 17.1 mmol), benzylamine (2.02 g, 18.9 mmol), sodium (triacetoxy)borohydride (6.36 g, 30 mmol) and 1,2-dichloroethane (40 mL). The resulting residue was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate=4/1, 1/1, 1/3, 0/1) to obtain 4.96 g of the title compound as a colorless oily substance (84%).
Reaction SMILES: NC(N)=O.CO[CH:7]([O:28]C)[CH2:8][N:9]1[C:17]2[C:12](=[CH:13][C:14]([O:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH2:26][NH2:27])=[CH:15][CH:16]=2)[CH:11]=[N:10]1.[C:30]([C:34]1[CH:38]=[C:37]([NH:39][C:40](=O)[O:41]CC(Cl)(Cl)Cl)[N:36]([C:48]2[CH:53]=[CH:52][C:51]([CH3:54])=[CH:50][CH:49]=2)[N:35]=1)([CH3:33])([CH3:32])[CH3:31].C(N(CC)C(C)C)(C)C>CN(C)C(=O)C>[C:30]([C:34]1[CH:38]=[C:37]([NH:39][C:40]([NH:27][CH2:26][C:20]2[CH:21]=[C:22]([F:25])[CH:23]=[CH:24][C:19]=2[O:18][C:14]2[CH:13]=[C:12]3[C:17](=[CH:16][CH:15]=2)[N:9]([CH2:8][CH2:7][OH:28])[N:10]=[CH:11]3)=[O:41])[N:36]([C:48]2[CH:53]=[CH:52][C:51]([CH3:54])=[CH:50][CH:49]=2)[N:35]=1)([CH3:33])([CH3:32])[CH3:31]
Reactant: COC(Cn1ncc2cc(Oc3ccc(F)cc3CN)ccc21)OC
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Agent: NC(N)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)NCc2cc(F)ccc2Oc2ccc3c(cnn3CCO)c2)cc1
Temperature: 80 °C

Procedure:
Preparation of 1-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)-3-(241-(2,2-dimethoxyethyl)-1H-indazol-5-yloxy)-5-fluorobenzyl)urea 70: (2-(1-(2,2-dimethoxyethyl)-1H-indazol-5-yloxy)-5-fluorophenyl)methanamine (2.00 g, 5.791 mmol), 2,2,2-trichloroethyl 3-tert-butyl-1-p-tolyl-1H-pyrazol-5-ylcarbamate (3.516 g, 8.686 mmol) and N,N-diisopropylethylamine (3.026 mL, 17.37 mmol) were suspended in N,N-dimethylacetamide (50 mL) and heated at 80° C. overnight. The reaction mixture was concentrated under reduced pressure and the residue diluted with EtOAc and saturated aqueous NH4Cl. The organics were washed with water (3×), brine, dried (MgSO4) and then concentrated under reduced pressure to afford the crude material, which was purified by flash column chromatography (eluant 35-45% EtOAc/Hexanes). After evaporation of the solvent, the desired product was obtained as a pale yellow foam (2.57 g, 74%). MS (APCI+) m/z 602 (M+1) was detected. 1H NMR (400 MHz, DMSO-d6) δ 7.88 (s, 1H), 7.43 (d, 1H, J=9 Hz), 6.72-7.30 (m, 9H), 6.18 (s, 1H), 6.01 (br, 1H), 5.47 (t, 1H, J=6.1 Hz), 4.76 (t, 1H, J=5.3 Hz), 4.44 (t, 4H, J=5.6 Hz), 3.38 (s, 6H), 2.37 (s, 3H), 1.30 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]3[N:14]=[CH:15][C:16]([C:17]#[CH:18])=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.Br[C:20]1[CH:21]=[C:22]([S:26]([NH2:29])(=[O:28])=[O:27])[CH:23]=[N:24][CH:25]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][N:11]3[N:14]=[CH:15][C:16]([C:17]#[C:18][C:20]4[CH:21]=[C:22]([S:26]([NH2:29])(=[O:28])=[O:27])[CH:23]=[N:24][CH:25]=4)=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: NS(=O)(=O)c1cncc(Br)c1
Reactant: C#Cc1cnn2ccc(-c3ccc(Cl)cc3)nc12
Product: NS(=O)(=O)c1cncc(C#Cc2cnn3ccc(-c4ccc(Cl)cc4)nc23)c1

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-3-ethynyl-pyrazolo[1,5-a]pyrimidine (example C.6) (63 mg, 0.25 mmol) and 5-bromo-pyridine-3-sulfonic acid amide (59 mg, 0.25 mmol) according to general procedure II. Obtained as a yellow solid (59 mg, 58%). MS (ISP) 410.3 [(M+H)+]; mp 248-249° C.
Reaction SMILES: [CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][N:21]([C:24](=[O:30])[CH:25]=[CH:26][CH2:27][CH2:28][CH3:29])[CH2:20][CH2:19]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)(=[O:7])=[O:6])[CH2:3][CH2:2]1.[NH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>>[CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][N:21]([C:24](=[O:30])[CH2:25][CH:26]([N:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)[CH2:27][CH2:28][CH3:29])[CH2:20][CH2:19]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:15])([F:16])[F:17])[CH:9]=2)(=[O:6])=[O:7])[CH2:3][CH2:2]1
Reactant: C1CCNCC1
Reactant: CCCC=CC(=O)N1CCC(N(C2CC2)S(=O)(=O)c2cccc(C(F)(F)F)c2)CC1
Product: CCCC(CC(=O)N1CCC(N(C2CC2)S(=O)(=O)c2cccc(C(F)(F)F)c2)CC1)N1CCCCC1

Procedure:
By following the procedure described above, N-cyclopropyl-N-(1-hex-2-enoyl-piperidin-4-yl)-3-trifluoromethylbenzenesulfonamide (30) was reacted with piperidine and N-cyclopropyl-N-{1-[3-(piperidin-1-yl)hexanoyl]piperidin-4-yl}-3-trifluoromethylbenzenesulfonamide (32) was obtained as a white solid. 1H NMR (CDCl3): δ 8.15 (S, 1H), 8.06 (d, 1H), 7.87 (d, 1H), 7.71 (t, 1H), 4.71 (d, 1H), 4.09 (m, 1H), 3.95 (d, 1H), 3.02 (m, 2H), 2.39 (m, 6H), 2.15 (m, 1H), 1.96 (m, 1H), 1.80 (m, 3H), 1.40 (m, 11H), 0.96 (m, 1H), 0.80 (m, 6H). LC: 100%. MS (M+H+): 530.
Reaction SMILES: C([C:3]([CH2:16][CH3:17])([C:13]([O-:15])=[O:14])[C:4](CC)([C:8]([O-:10])=[O:9])C([O-])=O)C.[CH2:18](Br)[CH2:19][CH2:20]CC>>[CH2:16]([CH:3]([CH2:4][C:8]([OH:10])=[O:9])[C:13]([OH:15])=[O:14])[CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCC(CC)(C(=O)[O-])C(CC)(C(=O)[O-])C(=O)[O-]
Reactant: CCCCCBr
Product: CCCCCC(CC(=O)O)C(=O)O
Reaction time: 19 h
Yield: 153 %

Procedure:
A method similar to that described by Devlin, et al, J. Chem. Soc., Perkin Transactions I, page 830 (1975) was used. Sodium ethoxide was formed by the addition of sodium metal (2.25 g, 91.59 mmol) to anhydrous EtOH (150 ml) under an N2 atmosphere. To the resultant solution was added triethyl-1,1,2-ethanetricaboxylate (obtained from Aldrich; 21 ml, 91.59 mmol) followed by dropwise addition of n-pentyl bromide (11.4 ml, 91.59 mmol). The mixture was brought to reflux and stirred overnight (19 hr). After the reaction had cooled, it was filtered and concentrated. The residue was treated with H2O and extracted with Et2O (three times). The combined organic extracts were dried (MgSO4), concentrated and purified by vacuum distillation (85° C./22.66 Pascals) to yield a colorless liquid (26.37 g, 91% yield).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]([CH3:23])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[N:20]=[C:19]([CH2:21]Cl)[O:18][N:17]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH:25]([NH:28][CH:29]([CH3:31])[CH3:30])([CH3:27])[CH3:26]>CN(C)C=O>[Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]([CH3:23])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[N:20]=[C:19]([CH2:21][N:28]([CH:29]([CH3:31])[CH3:30])[CH:25]([CH3:27])[CH3:26])[O:18][N:17]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)NC(C)C
Reactant: CN1Cc2c(-c3noc(CCl)n3)ncn2-c2cccc(Cl)c2C1=O
Solvent: CN(C)C=O
Product: CC(C)N(Cc1nc(-c2ncn3c2CN(C)C(=O)c2c(Cl)cccc2-3)no1)C(C)C
Yield: 65.7 %

Procedure:
1.82 g (5 mmol) of 7-chloro-3-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one were stirred at 80° overnight with 3 ml (21.3 mmol) of diisopropylamine and 20 ml of N,N-dimethylformamide. By evaporation of the reaction mixture and chromatography of the residue on silica gel while eluting with cyclohexane/ether/isopropanol/ammonia 15/15/5/0.5 there were obtained 1.41 g (66%) of 7-chloro-3-(5-diisopropylaminomethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one of m.p. 58°-63°, which was converted into the hydrochloride of m.p. 230°-231°.
Reaction SMILES: C1([C:7]2C=CC=C[C:8]=2[CH2:9][OH:10])C=CC=CC=1.[C:15]1([C:21]2[CH:28]=[CH:27][C:24]([CH2:25][OH:26])=[CH:23][CH:22]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[C:9]([O:26][CH2:25][C:24]1[CH:23]=[CH:22][C:21]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:28][CH:27]=1)(=[O:10])[CH:8]=[CH2:7]
Reactant: OCc1ccc(-c2ccccc2)cc1
Reactant: OCc1ccccc1-c1ccccc1
Product: C=CC(=O)OCc1ccc(-c2ccccc2)cc1

Procedure:
The same process as in Synthetic Example 1 was conducted except that the ortho-phenylbenzyl alcohol in Synthetic Example 1 was changed to para-phenylbenzyl alcohol. Consequently, 22.4 g of para-phenylbenzyl acrylate was obtained. The obtained para-phenylbenzyl acrylate was solid at ordinary temperature and had a melting point of 32° C. and a refractive index of 1.5920 at 40° C. The measurement result of 1H-NMR is shown below.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:13])[C:9]([O:11][CH3:12])=[O:10].[Br:14]N1C(=O)CCC1=O>ClC(Cl)(Cl)Cl.[Hg]>[Br:14][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:13])[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)C(=O)c1ccccc1C
Reactant: O=C1CCC(=O)N1Br
Agent: [Hg]
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C(=O)c1ccccc1CBr
Yield: 49.3 %

Procedure:
5.34 g (30 millimoles) of methyl 2-methylphenylglyoxylate and 5.34 g (30 millimoles) of N-bromosuccinimide in 1,000 ml of tetrachloromethane are exposed to a 300 W mercury vapor lamp for one hour. Thereafter, the organic phase is washed once with water and three times with sodium bicarbonate solution, dried over sodium sulfate/sodium carbonate and evaporated down, and the crude product is then chromatographed over silica gel using 1:9 methyl tert-butyl ether/n-hexane. 3.8 g (49%) of the abovementioned compound are obtained as a yellow oil.