Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].C(N(CC)CC)C.[CH3:13][N:14]1[C:23]2[C:22](=[O:24])[NH:21][C:20]3[CH:25]=[CH:26][CH:27]=[CH:28][C:19]=3[NH:18][C:17]=2[C:16]([CH3:29])=[N:15]1>O1CCOCC1>[Cl:1][CH2:2][C:3]([N:18]1[C:19]2[CH:28]=[CH:27][CH:26]=[CH:25][C:20]=2[NH:21][C:22](=[O:24])[C:23]2[N:14]([CH3:13])[N:15]=[C:16]([CH3:29])[C:17]1=2)=[O:4]
Reactant: Cc1nn(C)c2c1Nc1ccccc1NC2=O
Reactant: O=C(Cl)CCl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: Cc1nn(C)c2c1N(C(=O)CCl)c1ccccc1NC2=O
Reaction time: 3 h
Yield: 65.1 %

Procedure:
2 g of chloroacetyl chloride and 2 g of triethylamine are added dropwise at the same time over the course of 40 minutes to a boiling solution of 2.3 g of 1,3-dimethyl-1,4,9,10-tetrahydropyrazolo[4,3-b][1,5]benzodiazepin-10-one in 30 ml of absolute dioxane, and the mixture is stirred for a further 3 hours. It is then allowed to cool and is filtered; the filtrate is concentrated to dryness and chromatographed over a silica gel column by means of a 1:1 mixture of petroleum ether and ethyl acetate, and the product is recrystallized from toluene to yield 2.0 g of 4-chloroacetyl-1,3-dimethyl-1,4,9,10-tetrahydropyrazolo[4,3-b][1,5]benzodiazepin-10-one, mp 246° to 248° C. (dec.).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]2[CH:13]=[C:12]([S:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:11]=[CH:10][N:9]=2)[S:5][CH:6]=1.C1C=C(Cl)C=C(C(OO)=[O:29])C=1>ClCCl>[CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]2[CH:13]=[C:12]([S:14]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[O:29])[CH:11]=[CH:10][N:9]=2)[S:5][CH:6]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1csc(Nc2cc(Sc3ccccc3)ccn2)n1
Solvent: ClCCl
Product: Cc1csc(Nc2cc(S(=O)c3ccccc3)ccn2)n1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A 50 mL round bottom flask was charged with N-(4-methylthiazol-2-yl)-4-(phenylthio)pyridin-2-amine (0.050 g, 0.17 mmol) and dichloromethane (5 mL). The solution was cooled to 0° C., then MCPBA (0.029 g, 0.17 mmol) was added and the reaction mixture was stirred at room temperature for 2 hours. An additional 15 mg of MCPBA were added and the reaction mixture was stirred overnight. The reaction mixture was quenched with sodium bisulfite and extracted with dichloromethane. The organic layer was washed with a saturated solution of NaHCO3. The organic layer was dried over magnesium sulfate, filtered and concentrated. The residue was purified using preparative TLC with 35% EtOAc in hexanes as the solvent system to afford 4-methyl-N-(4-(phenylsulfinyl)pyridin-2-yl)thiazol-2-amine as a light yellow solid. 1H NMR (CDCl3) δ 8.34 (d, 1H), 7.48-7.73 (m, 5H), 7.25 (s, 1H), 6.93 (dd, 1H), 6.41 (s, 1H), 2.36 (d, 3H); Mass spectrum (apci) m/z=316 (100) (M+H).
Reaction SMILES: CC(C)([O-])C.[Na+].[CH3:7][C:8]([C:10]1[CH:11]=[CH:12][C:13]([OH:16])=[CH:14][CH:15]=1)=[O:9].C([O:19][C:20](=O)[CH2:21][CH2:22][CH2:23][CH3:24])C>C1COCC1>[OH:16][C:13]1[CH:14]=[CH:15][C:10]([C:8](=[O:9])[CH2:7][C:20](=[O:19])[CH2:21][CH2:22][CH2:23][CH3:24])=[CH:11][CH:12]=1
Reactant: CC(=O)c1ccc(O)cc1
Reactant: CCCCC(=O)OCC
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCC(=O)CC(=O)c1ccc(O)cc1
Temperature: 8 °C
Yield: 64.8 %

Procedure:
Sodium tert-butoxide, 1270 g, is slurried in 1390 g THF and the mixture heated to reflux temperature. A solution of 580 g 4-hydroxyacetophenone and 555 g ethylvalerate in 1390 g THF is added over 30 minutes. The solution is stirred at reflux temperature until the reaction is complete, ca 4.5 h, and then quenched by addition of the reaction mixture to 1270 g 37% HCl. The mixture is concentrated by distillation of THF at reduced pressure and to the residue is added 900 g toluene. The water phase is separated and the toluene phase washed with 900 g 10% aqueous NaCl. The toluene is stripped at reduced pressure and the residual oil diluted with 850 g acetic acid. The solution is cooled to 8° C. and 850 ml water added slowly. The formed slurry is stirred at 5-8° C. for 90 minutes and then filtered and washed with 608 g 20% aqueous acetic acid. Drying under vacuum at 40° C. gives 608 g 1-(4-hydroxyphenyl)-1,3-heptandione.
Reaction SMILES: CO.[CH:3]1([C:9]2[CH:18]=[C:17]3[C:12]([C:13]([CH3:47])=[CH:14][C:15](=[O:46])[N:16]3[CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][CH:24]([N:27]([CH2:35][C:36]4[CH:45]=[CH:44][C:39]5[O:40][CH2:41][CH2:42][O:43][C:38]=5[CH:37]=4)C(=O)OC(C)(C)C)[CH2:23][CH2:22]3)=[CH:11][CH:10]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[ClH:48].C(OCC)(=O)C>C(OCC)(=O)C>[ClH:48].[CH:3]1([C:9]2[CH:18]=[C:17]3[C:12]([C:13]([CH3:47])=[CH:14][C:15](=[O:46])[N:16]3[CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][CH:24]([NH:27][CH2:35][C:36]4[CH:45]=[CH:44][C:39]5[O:40][CH2:41][CH2:42][O:43][C:38]=5[CH:37]=4)[CH2:23][CH2:22]3)=[CH:11][CH:10]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: Cc1cc(=O)n(CCN2CCC(N(Cc3ccc4c(c3)OCCO4)C(=O)OC(C)(C)C)CC2)c2cc(C3CCCCC3)ccc12
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1cc(=O)n(CCN2CCC(NCc3ccc4c(c3)OCCO4)CC2)c2cc(C3CCCCC3)ccc12
Reaction time: 1.5 h

Procedure:
To 0.7 mL of methanol solution containing 73 mg of tert-butyl (1-(2-(7-cyclohexyl-4-methyl-2-oxo-1,2-dihydroquinolin-1-yl)ethyl)piperidin-4-yl)(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)carbamate, 0.7 mL of 4 mol/L hydrogen chloride/ethyl acetate solution was added at room temperature, and stirred for 1.5 hours. Ethyl acetate was added, and the resulting solid was filtered to give 43 mg of 7-cyclohexyl-1-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-4-methylquinolin-2(1H)-one hydrochloride as a white solid.
Reaction SMILES: [F:1][CH2:2][C:3]1([CH2:21][F:22])[CH:8]=[C:7]([C:9](=[S:12])OC)[C:6]2[CH:13]=[C:14]([C:17]([F:20])([F:19])[F:18])[CH:15]=[CH:16][C:5]=2[O:4]1.C1CC[N:31]2C(=[N:27][CH2:28][CH2:29][CH2:30]2)CC1.NCCC#N.C(OCC)(=O)C>O1CCCC1>[C:28]([CH2:29][CH2:30][NH:31][C:9]([C:7]1[C:6]2[CH:13]=[C:14]([C:17]([F:20])([F:19])[F:18])[CH:15]=[CH:16][C:5]=2[O:4][C:3]([CH2:21][F:22])([CH2:2][F:1])[CH:8]=1)=[S:12])#[N:27]
Reactant: C1CCC2=NCCCN2CC1
Reactant: COC(=S)C1=CC(CF)(CF)Oc2ccc(C(F)(F)F)cc21
Agent: N#CCCN
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: N#CCCNC(=S)C1=CC(CF)(CF)Oc2ccc(C(F)(F)F)cc21
Temperature: 25 °C
Reaction time: 7 h
Yield: 1334.9 %

Procedure:
O-methyl 2,2-bis(fluoromethyl)-6-trifluoromethyl-2H-1-benzopyran-4-carbothioate (0.34 g) and DBU (10 mg) were dissolved in tetrahydrofuran (5 ml); to the solution, 3-aminopropionitrile (0.2 ml) was added at room temperature in a nitrogen atmosphere and the resulting mixture was stirred for 7 hours at room temperature. Ethyl acetate was added to the reaction mixture, which was washed with water, dilute HCl, aqueous sodium bicarbonate and a saturated aqueous solution of sodium chloride. The mixture was dried with anhydrous sodium sulfate and concentrated under reduced pressure; the resulting residue was subjected to silica gel column chromatography (eluent; methylene chloride) to give the titled compound (0.33 g), which was identical to the authentic sample.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH2:13][CH2:14][NH2:15])[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2].[CH:16]([O:19][C:20]1[CH:21]=[C:22]([CH2:30][C:31](OCC)=[O:32])[CH:23]=[CH:24][C:25]=1[O:26][CH:27]([CH3:29])[CH3:28])([CH3:18])[CH3:17]>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH2:13][CH2:14][NH:15][C:31](=[O:32])[CH2:30][C:22]2[CH:23]=[CH:24][C:25]([O:26][CH:27]([CH3:28])[CH3:29])=[C:20]([O:19][CH:16]([CH3:18])[CH3:17])[CH:21]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2]
Reactant: CCOC(=O)Cc1ccc(OC(C)C)c(OC(C)C)c1
Reactant: CCOc1ccc(CCN)cc1OCC
Solvent: ClC(Cl)Cl
Product: CCOc1ccc(CCNC(=O)Cc2ccc(OC(C)C)c(OC(C)C)c2)cc1OCC
Temperature: 160 °C
Reaction time: 20 h
Yield: 74.6 %

Procedure:
A mixture of 2-(3,4-diethoxyphenyl)-ethylamine (40.7 g, 0.195 mole) and ethyl 3,4-diisopropoxyphenylacetate (55.7 g, 0.195 mole) was heated with stirring at 160° C. for 20 hours, allowed to cool and the resulting oil taken up in 700 ml of chloroform. The organic solution was washed 3 times with 100 ml of N hydrochloric acid and then with water to pH 7. The chloroform solution was dried over magnesium sulphate, the solvent removed under reduced pressure and purification effected by chromatography over silica gel. 64.5 g (yield 72%) of product was obtained sufficiently pure to be used in step (b) below.
Reaction SMILES: C[N:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([N+]([O-])=O)[C:3]1=O.[O:15]1[CH2:20]CC(=O)[CH2:17][CH2:16]1.N>CO>[N+:8]([C:6]1[CH:7]=[N:2][C:3]2[CH2:17][CH2:16][O:15][CH2:20][C:4]=2[CH:5]=1)([O-:10])=[O:9]
Reactant: Cn1cc([N+](=O)[O-])cc([N+](=O)[O-])c1=O
Reactant: O=C1CCOCC1
Agent: N
Solvent: CO
Product: O=[N+]([O-])c1cnc2c(c1)COCC2
Yield: 52.2 %

Procedure:
A mixture of 1-methyl-3,5-dinitro-2-pyridone (0.8 g, 4 mmol), tetrahydro-4H-pyran-4-one (0.4 g, 4 mmol) and ammonia solution in methanol (2.0 M, 40 mL) was refluxed for 4 h. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate. The soluble portion was flash chromatographed over silica gel (eluent: 90:10 v/v ethyl acetate-hexane) to give a yellow solid (0.376 g, 52% yield).
Reaction SMILES: ClCCl.[CH3:4][O:5][C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([O:17][CH3:18])[C:14]=1[O:15][CH3:16])[C:9](Cl)=[O:10].[NH2:19][C:20]1[N:25]2[N:26]=[CH:27][CH:28]=[C:24]2[N:23]=[C:22]([CH2:29][CH2:30][CH:31]([O:33][Si](C)(C)C)[CH3:32])[CH:21]=1.C([O-])(O)=O.[Na+]>N1C=CC=CC=1>[OH:33][CH:31]([CH3:32])[CH2:30][CH2:29][C:22]1[CH:21]=[C:20]([NH:19][C:9](=[O:10])[C:8]2[CH:7]=[C:6]([O:5][CH3:4])[C:14]([O:15][CH3:16])=[C:13]([O:17][CH3:18])[CH:12]=2)[N:25]2[N:26]=[CH:27][CH:28]=[C:24]2[N:23]=1
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Reactant: CC(CCc1cc(N)n2nccc2n1)O[Si](C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cc(C(=O)Nc2cc(CCC(C)O)nc3ccnn23)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.2 %

Procedure:
A dry dichloromethane solution (5 ml) containing 650 mg of 3,4,5-trimethoxybenzoyl chloride was slowly added dropwise to 5 ml of a pyridine solution containing 520 mg of the crystals obtained in step (7), and stirred at room temperature for 2 hours. After completion of the reaction, a saturated aqueous NaHCO3 solution was added and the reaction mixture was extracted with dichloromethane. The organic layer was collected and washed with a 1N aqueous hydrochloric acid until the pH of the water layer became about 1. The organic layer was allowed to stand for 2 hours, washed with water and a saturated saline solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was recrystallized from dichloromethane-n-hexane to provide 480 mg of the object compound as colorless crystals. Table 2 shows the structure and melting point of the compound obtained.
Reaction SMILES: S(Cl)([Cl:3])=O.[OH:5][C:6]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=O>C1C=CC=CC=1>[C:6]([Cl:3])([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:5]
Reactant: CCCCCCCCCC(=O)O
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: CCCCCCCCCC(=O)Cl

Procedure:
A mixture of 0.5 ml of thionyl chloride, 934 mg of capric acid and 4 ml of benzene was refluxed for 2 hours and then was evaporated to dryness to obtain capric acid chloride. The raw acid chloride was taken up in 5 ml of benzene and 1 ml of pyridine was added thereto. Then, a solution of 728 mg of ethyl 3'-(3'-α-hydroxy trans-1'-octenyl)-cyclopentane-2-carboxylate in 5 ml of benzene was slowly added to the mixture and after the addition of 66 mg of 4-dimethylaminopyridine, the mixture was stirred for 17 hours at 20° C. The mixture was poured into 1N hydrochloric acid and the mixture was extracted with ether. The ether extracts were washed with water, and aqueous sodium bicarbonate solution, dried and evaporated to dryness. The residue was chromatographed over silica gel and was eluted with an 8-2 cyclohexane-ethyl acetate mixture containing 0.1% of triethylamine to obtain 710 mg of ethyl (1RS, 5RS, 3'SR) (1'E) 2-oxo-5-(3'-decanoyloxy-1'-octenyl)-cyclopentanecarboxylate.
Reaction SMILES: [CH2:1]1[CH:7](O)[NH:6][P:4]([N:9]([CH2:13][CH2:14][Cl:15])[CH2:10][CH2:11][Cl:12])(=[O:5])[O:3][CH2:2]1.[CH:16]1([NH3+:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.[SH:23][CH2:24][CH2:25][S:26]([O-:29])(=[O:28])=[O:27].ClC(Cl)(Cl)C(O)=O>CO>[CH:16]1([NH3+:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.[Cl:12][CH2:11][CH2:10][N:9]([CH2:13][CH2:14][Cl:15])[P:4]1(=[O:5])[NH:6][CH:7]([S:23][CH2:24][CH2:25][S:26]([O-:29])(=[O:28])=[O:27])[CH2:1][CH2:2][O:3]1
Reactant: O=P1(N(CCCl)CCCl)NC(O)CCO1
Reactant: O=S(=O)([O-])CCS
Agent: O=C(O)C(Cl)(Cl)Cl
Agent: [NH3+]C1CCCCC1
Solvent: CO
Product: O=P1(N(CCCl)CCCl)NC(SCCS(=O)(=O)[O-])CCO1
Reaction time: 8 h

Procedure:
1.4 g (5 mmol) of 4-hydroxycyclophosphamide and 1.2 g (5 mmol) of cyclohexylammonium-2-mercaptoethanesulphonate were dissolved together with a trace of trichloroacetic acid in 25 ml of methanol and were left to stand overnight in a refrigerator at -25° C. The reaction solution was then concentrated to about 5 ml, ether was added until clouding commenced and the mixture was triturated. The crystallised material was filtered with suction after standing for 20 hours at 0° C., and was washed and dried.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].Br[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34].C(=O)([O-])[O-].[K+].[K+].Cl>C(Cl)(Cl)Cl.CN(C=O)C>[CH2:34]([O:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[CH2:4][OH:5])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH3:13]
Reactant: COc1ccc(C=O)c(O)c1
Reactant: CCCCCCCCCCCCCCCCCCCCCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCCCCCCCOc1cc(OC)ccc1CO
Temperature: 100 °C
Reaction time: 7 h
Yield: 64.4 %

Procedure:
2-Hydroxy-4-methoxybenzaldehyde (5 g, 32.9 mmol), 1-bromodocosane (16.6 g, 42.7 mmol) and potassium carbonate (14.8 g, 107 mmol) were mixed with DMF (150 ml), and the mixture was stirred at 100° C. for 7 hr. Chloroform (400 ml) and 1N hydrochloric acid (300 ml) were added to the reaction mixture, and the mixture was washed. The organic layer was washed successively with 1N hydrochloric acid and saturated brine. The organic layer was concentrated and slurry-washed with methanol. The precipitate was collected by filtration and dried under reduced pressure. The obtained dried crystals were dissolved in THF (150 ml), sodium borohydride (3.7 g) was added, and the mixture was stirred at 40° C. for 3 hr. 1N Hydrochloric acid was added to the reaction mixture, and the mixture was concentrated. The mixture was extracted with chloroform, and washed successively with aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was concentrated. The obtained residue was washed with acetonitrile, and the precipitate was collected by filtration and dried under reduced pressure to give 2-docosyloxy-4-methoxybenzyl alcohol (9.8 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[Br:8].[Li]CCCC.[CH3:14][CH:15]([CH3:34])[CH2:16][CH:17]([N:27]=[CH:28][C:29]1[S:30][CH:31]=[CH:32][N:33]=1)[C:18]12[O:25][CH2:24][C:21]([CH3:26])([CH2:22][O:23]1)[CH2:20][O:19]2>CCOCC>[Br:8][C:3]1[CH:4]=[CH:5][C:6]([CH:28]([NH:27][CH:17]([C:18]23[O:25][CH2:24][C:21]([CH3:26])([CH2:22][O:23]2)[CH2:20][O:19]3)[CH2:16][CH:15]([CH3:34])[CH3:14])[C:29]2[S:30][CH:31]=[CH:32][N:33]=2)=[CH:7][CH:2]=1
Reactant: CC(C)CC(N=Cc1nccs1)C12OCC(C)(CO1)CO2
Reactant: Brc1ccccc1Br
Agent: [Li]CCCC
Solvent: CCOCC
Product: CC(C)CC(NC(c1ccc(Br)cc1)c1nccs1)C12OCC(C)(CO1)CO2

Procedure:
To a solution of dibromobenzene (760 mg, 3.2 mmol) in dry ether was added 2.5 M solution of nBuLi in hexanes (1.3 mL, 3.2 mmol) at −30° C. After stirring forl h, a solution of [3-methyl-1-(4-methyl-2,6,7-trioxa-bicyclo[2.2.2]oct-1-yl)-butyl]-thiazol-2-ylmethylene-amine (500 mg, 1.6 mmol) in 5 mL of dry ether was added slowly. The reaction mixture was allowed to stir at the same temperature for 2 h and then the reaction was quenched with water and extracted with ethyl acetate. The organic layer was washed with saturated NaCl and dried over MgSO4. The solvent was evaporated in vacuo. The crude was flash column chromatographed using 2:1 hexanes:EtOAc as an eluant to get [(4-bromo-phenyl)-thiazol-2-yl-methyl]-[3-methyl-1-(4-methyl-2,6,7-trioxa-bicyclo[2.2.2]oct-1-yl)-butyl]-amine as a pale yellow solid.
Reaction SMILES: [CH2:1]([N:8]([CH2:12][C:13]1[C:18](Cl)=[N:17][C:16]([N:20]([CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH3:21])=[CH:15][N:14]=1)[CH2:9][CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].O>CN(C=O)C>[CH2:1]([N:8]1[CH2:12][C:13]2[N:14]=[CH:15][C:16]([N:20]([CH2:22][CH:23]3[CH2:25][CH2:24]3)[CH3:21])=[N:17][C:18]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(CC1CC1)c1cnc(CN(CCO)Cc2ccccc2)c(Cl)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(CC1CC1)c1cnc2c(n1)OCCN(Cc1ccccc1)C2
Reaction time: 2.5 h
Yield: 80.1 %

Procedure:
To a solution of 2-[benzyl({3-chloro-5-[(cyclopropylmethyl)(methyl)amino]pyrazin-2-yl}methyl)amino]ethanol (0.50 g) in DMF (3 mL) was added potassium tert-butoxide (0.19 g) at 0° C., and the mixture was stirred for 2.5 hr. Water (10 mL) was added, and the mixture was extracted with ethyl acetate. The aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with water and saturated brine, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (solvent gradient: 10-*40% ethyl acetate/hexane) to give the title compound (0.36 g, 79%) as a pale-yellow oil.
Reaction SMILES: [OH:1][CH2:2][CH:3]([N:15]1[C:21](=[O:22])[CH2:20][CH2:19][N:18]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=2)[CH2:17][CH2:16]1)[CH2:4][CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][C:10]([OH:14])([CH3:13])[CH2:9][CH2:8]1.I[CH3:34].[H-].[Na+]>>[OH:14][C:10]1([CH3:13])[CH2:9][CH2:8][N:7]([CH2:6][CH2:5][CH2:4][CH:3]([N:15]2[C:21](=[O:22])[CH2:20][CH2:19][N:18]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:31])([F:30])[F:32])[CH:24]=3)[CH2:17][CH2:16]2)[CH2:2][O:1][CH3:34])[CH2:12][CH2:11]1
Reactant: CI
Reactant: CC1(O)CCN(CCCC(CO)N2CCN(c3cccc(C(F)(F)F)c3)CCC2=O)CC1
Agent: [H-]
Agent: [Na+]
Product: COCC(CCCN1CCC(C)(O)CC1)N1CCN(c2cccc(C(F)(F)F)c2)CCC1=O
Yield: 25 %

Procedure:
In analogy to the procedure described in example 23B, (rac)-4-[1-hydroxymethyl-4-(4-hydroxy-4-methyl-piperidin-1-yl)-butyl]-1-(3-trifluoromethyl-phenyl)-[1,4]diazepan-5-one was treated with iodomethane and NaH to give the title compound in 25% yield as colorless oil. MS: 472.4 (MH+).
Reaction SMILES: [C:1]1(=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:7]([O:11][C:12]([NH:14][NH2:15])=[O:13])([CH3:10])([CH3:9])[CH3:8]>CO>[C:7]([O:11][C:12]([NH:14][N:15]=[C:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:13])([CH3:10])([CH3:9])[CH3:8]
Reactant: O=C1CCCC1
Reactant: CC(C)(C)OC(=O)NN
Solvent: CO
Product: CC(C)(C)OC(=O)NN=C1CCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.8 %

Procedure:
A mixture of cyclopentanone (20 g, 238 mmol) and hydrazinecarboxylic acid tert-butyl ester (31.4 g, 0.238 mol) in MeOH (300 mL) was stirred at RT for 2 h. The reaction mixture was concentrated in vacuo and the resulting solid was dried under vacuum to give 1-cyclopentylidenehydrazine-2-carboxylic acid tert-butyl ester (47.1 g, 100% yield).
Reaction SMILES: [CH3:1][S:2]([O:5][C@H:6]1[CH2:10][N:9]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)=[O:12])[C@H:8]([C:24]([NH:26][NH:27][C:28]([NH:30][CH3:31])=O)=O)[CH2:7]1)(=[O:4])=[O:3].O.N.[S:34](=O)(=O)(O)O>>[CH3:1][S:2]([O:5][C@H:6]1[CH2:10][N:9]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)=[O:12])[C@H:8]([C:24]2[S:34][C:28]([NH:30][CH3:31])=[N:27][N:26]=2)[CH2:7]1)(=[O:4])=[O:3]
Reactant: O=S(=O)(O)O
Reactant: CNC(=O)NNC(=O)[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: N
Solvent: O
Product: CNc1nnc([C@@H]2C[C@@H](OS(C)(=O)=O)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)s1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A suspension of (2S, 4R)-4-methanesulfonyloxy-2-(4-methylsemicarbazidocarbonyl)-1- (4-nitrobenzyloxycarbonyl)pyrrolidine (2.00 g) in concentrated sulfuric acid (20 ml) was stirred at 0°-5° C. for 3 hours. The reaction mixture was poured into ice-water (200 ml), adjusted to pH 9 with concentrated ammonia water, extracted with dichloromethane (100 ml), dried over magnesium sulfate and concentrated under reduced pressure to give a syrup. The syrup was subjected to a column chromatography on silica gel (20 g) and eluted with a mixture of methanol and chloroform (1:99,V/V) to give (2S, 4R)-4-methanesulfonyloxy-2-{5-(methylamino)-1,3,4-thiadiazol-2-yl }-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (1.94 g).
Reaction SMILES: C(O[C:6](=O)[N:7]([CH2:9][CH2:10][O:11][Si:12]([C:25]([CH3:28])([CH3:27])[CH3:26])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)C)(C)(C)C.Cl.O1CCOCC1>C(Cl)Cl>[C:25]([Si:12]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[O:11][CH2:10][CH2:9][NH:7][CH3:6])([CH3:28])([CH3:26])[CH3:27]
Reactant: CN(CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CNCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Yield: 24.3 %

Procedure:
[2-(tert-Butyl-diphenyl-silanyloxy)-ethyl]-methyl-carbamic acid tert-butyl ester (572 mg, 1.38 mmol) and 4M HCl/dioxane (3 mL) in CH2Cl2 (5 mL) were stirred at RT for 3 h. The reaction mixture was concentrated in vacuo and the crude material was purified by silica gel column chromatography, eluting with CH2Cl2 and increasing the polarity to 10% MeOH/CH2Cl2 to obtain [2-(tert-butyl-diphenyl-silanyloxy)-ethyl]-methyl-amine as a yellow solid (105 mg, 21%).
Reaction SMILES: CO[CH2:3][N:4]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:5][Si](C)(C)C.[O:17]=[C:18]([CH3:29])/[CH:19]=[CH:20]/[C:21]1[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[C:18]([CH:19]1[CH2:3][N:4]([CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:5][CH:20]1[C:21]1[CH:22]=[CH:23][C:24]([C:25]#[N:26])=[CH:27][CH:28]=1)(=[O:17])[CH3:29]
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: CC(=O)/C=C/c1ccc(C#N)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)C1CN(Cc2ccccc2)CC1c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 32.8 %

Procedure:
A solution of N-(methoxymethyl)-N-(phenylmethyl)-N-(trimethylsilyl)methylamine (22.46 g, 94.6 mmol) in CH2Cl2 (100 mL) was added dropwise, over a 30 minutes period, to a stirred solution of 4-((E)-3-oxo-but-1-enyl)-benzonitrile (10.8 g, 63.1 mmol) and trifluoroacetic acid (0.48 mL, 6.30 mmol) in CH2Cl2 (40 mL) at 0° C. The ice bath was removed, and the solution was stirred at 25° C. for an additional 48 h. It was then concentrated and purification by flash chromatography (SiO2, EtOac/Heptane 1:1) afforded 6.3 g (33%) of the title compound as a yellow oil. ES-MS m/e: 305.1 (M+H+).