Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([N:8]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=1)[CH3:9])[CH2:5][O:6][CH3:7]>C(O)(=O)C>[CH3:7][O:6][CH2:5][CH:4]([N:8]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=1)[CH3:9])[CH2:3][O:2][CH3:1]
Reactant: COCC(COC)N(C)Cc1ccc([N+](=O)[O-])cc1
Solvent: CC(=O)O
Product: COCC(COC)N(C)Cc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.2 %

Procedure:
In acetic acid (100 ml) was dissolved N-(1,3-dimethoxypropan-2-yl)-N-methyl-4-nitrobenzylamine (3.1 g), and to the mixture was added reduced iron (3.2 g) little by little. The mixture was stirred at room temperature overnight, and the solvent was evaporated. To the residue was added ethyl acetate, and precipitates were filtered off. The filtrate was washed with sodium hydroxide solution, water and saturated brine, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue dissolved in ethyl acetate. To the mixture was added 4N hydrochloric acid-ethyl acetate, and precipitates were filtered and washed with diethylether. The mixture was dissolved in water, and the mixture was neutralized with 1N sodium hydroxide solution and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated to give 4-((N-(1,3-dimethoxypropan-2-yl)-N-methylamino)methyl)aniline (2.4 g) as red oil.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[C:7]([OH:12])(=[O:11])[C:8]([OH:10])=[O:9].[OH:13][C:14]1[CH:15]=[CH:16][C:17]2[C:21]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([CH2:29][N:30]4[CH2:34][CH2:33][CH2:32][CH2:31]4)=[C:25]([CH3:35])[CH:24]=3)=[C:20](C3C=CC(OCCC4CCCN4)=NC=3)[S:19][C:18]=2[CH:50]=1.[N:51]1([CH2:56][CH2:57][O:58][C:59]2[CH:64]=[CH:63][C:62](Br)=[CH:61][C:60]=2[O:66][CH3:67])[CH2:55][CH2:54][CH2:53][CH2:52]1>>[C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[C:7]([OH:12])(=[O:11])[C:8]([OH:10])=[O:9].[OH:13][C:14]1[CH:15]=[CH:16][C:17]2[C:21]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([CH2:29][N:30]4[CH2:34][CH2:33][CH2:32][CH2:31]4)=[C:25]([CH3:35])[CH:24]=3)=[C:20]([C:62]3[CH:63]=[CH:64][C:59]([O:58][CH2:57][CH2:56][N:51]4[CH2:55][CH2:54][CH2:53][CH2:52]4)=[C:60]([O:66][CH3:67])[CH:61]=3)[S:19][C:18]=2[CH:50]=1
Reactant: Cc1cc(Cc2c(-c3ccc(OCCC4CCCN4)nc3)sc3cc(O)ccc23)ccc1CN1CCCC1
Reactant: COc1cc(Br)ccc1OCCN1CCCC1
Agent: O=C(O)C(=O)O
Product: COc1cc(-c2sc3cc(O)ccc3c2Cc2ccc(CN3CCCC3)c(C)c2)ccc1OCCN1CCCC1
Yield: 30 %

Procedure:
The title compound was prepared from 6-benzyloxy-2-(dimethylamino)benzo[b]thiophen-3-yl 3-methyl-4-[(1-pyrrolidinyl)methyl]phenyl ketone (Example 124, Part C) and 4-bromo-2-methoxyphenyl 2-(1-pyrrolidinyl)ethyl ether (Part A) in 30% yield after PrepLC (SiO2; gradient of 80:15:5 to 70:25:5 hexanes-THF-TEA) by essentially following the procedure detailed in Example 123, Part A.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]1[CH2:13][C:12](=[O:14])[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-]#N.[Na+].[C:18](=[O:21])([O-])[O-].[NH4+:22].[NH4+:23]>O.C(O)C>[NH:22]1[CH2:13][C:12](=[O:14])[NH:23][C:18]1=[O:21].[CH2:1]([O:8][CH2:9][CH:10]1[CH2:13][C:12](=[O:14])[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: [NH4+]
Agent: O=C1CC(COCc2ccccc2)C1
Agent: [C-]#N
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=C1CNC(=O)N1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
3-(Benzyloxymethyl)cyclobutanone 4.0 g (21 mmol), sodium cyanide 2.1 g (42 mmol) and ammonium carbonate 10.1 g (105 mmol) were added into a 100-ml eggplant-shaped flask, and the mixture was dissolved in 50 ml of 50% water/ethanol. This eggplant-shaped flask was sealed and the mixture was stirred overnight at 60° C. After opening this flask with caution in a draft chamber, the reaction solution was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and filtered to remove insoluble inorganic salts. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography (hexane:ethyl acetate=50:50). Thus, 3-(benzyloxymethyl)cyclobutanone hydantoin was obtained as a white crystal (cis-form 2.8 g, 11 mmol, 50%; trans-form 1.1 g, 4.3 mmol, 21%).
Reaction SMILES: O=S(Cl)[Cl:3].[CH2:5]([C:7]([CH2:18][C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)([CH2:16][CH3:17])[CH:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)O)[CH3:6].CN(C)C=O.[OH-].[Na+]>C1(C)C=CC=CC=1>[Cl:3][CH:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:7]([CH2:16][CH3:17])([CH2:18][C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)[CH2:5][CH3:6]
Reactant: O=S(Cl)Cl
Reactant: CCC(CC)(Cc1cccnc1)C(O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CCC(CC)(Cc1cccnc1)C(Cl)c1ccccc1
Yield: 40 %

Procedure:
13.3 g (0.11 mol) of SOCl2 are added dropwise, at 80° C., to 5 g (0.018 mol) of 2-ethyl-1-phenyl-2-(pyrid-3-ylmethyl)-butanol in 100 ml of toluene and a catalytic amount (0.1 g) of dimethylformamide, and the mixture is left for 5 hours at this temperature. The mixture is cooled, poured onto ice water and then rendered alkaline with 30% strength NaOH solution. The aqueous phase is extracted with three times 50 ml of tert-butyl methyl ether and the combined organic phases are dried over MgSO4. After the solvent has been evaporated off, the residue is chromatographed over silica gel (1 : 1 toluene/ethyl acetate). 2.07 g (yield 40%) of the title compound are obtained as a viscous yellow oil (compound No. 581).
Reaction SMILES: O[CH2:2]CCNC1CCN(CC2C=CC=CC=2)CC1.[C:19]([C:22]1[CH:23]=[C:24]([N:28]([CH:45]2[CH2:49][CH2:48][CH2:47][CH2:46]2)[C:29]([NH:31][CH:32]2[CH2:37][CH2:36][N:35]([CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH2:34][CH2:33]2)=[O:30])[CH:25]=[CH:26][CH:27]=1)(=[NH:21])[NH2:20]>>[C:19]([C:22]1[CH:23]=[C:24]([N:28]([CH:45]2[CH2:49][CH2:48][CH2:47][CH2:46][CH2:2]2)[C:29]([NH:31][CH:32]2[CH2:33][CH2:34][N:35]([CH2:38][C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)[CH2:36][CH2:37]2)=[O:30])[CH:25]=[CH:26][CH:27]=1)(=[NH:21])[NH2:20]
Reactant: OCCCNC1CCN(Cc2ccccc2)CC1
Reactant: N=C(N)c1cccc(N(C(=O)NC2CCN(Cc3ccccc3)CC2)C2CCCC2)c1
Product: N=C(N)c1cccc(N(C(=O)NC2CCN(Cc3ccccc3)CC2)C2CCCCC2)c1

Procedure:
This material was prepared from 4-(3-hydroxypropyl)amino-1-benzylpiperidine by the same route employed in the synthesis of N-(3-amidinophenyl)-N'-(1-benzylpiperidin-4-yl)cyclopentylurea. There was obtained 26 mg of the desired product as the bis-tifluoroacetic acid salt after purification by reverse phase HPLC. LRMS (M+2H)2+ m/z 196.7, (M+H)+ m/z 392;1H NMR (CD3OD): d 2.23 (m, 6H), 3.21 (bt, 2H), 3.58 (t, 2H, J=5.12 Hz), 3.62 (m, 2H), 4.39 (m, 3H), 4.53 (t, 2H, J=5.12 Hz), 7.51 (m, 5H), 7.62-7.78 (m, 3H), 7.81 (s, 1H).
Reaction SMILES: [CH3:1][NH:2][C:3](=[S:17])[NH:4][C:5]1[S:6][CH:7]=[C:8]([C:10](=[O:16])[C:11]([O:13]CC)=[O:12])[N:9]=1.CNC(=S)NC1NC(C(=O)C(OCC)=O)=CS1.[OH-].[Na+].Cl>O.C(O)C>[CH3:1][NH:2][C:3](=[S:17])[NH:4][C:5]1[S:6][CH:7]=[C:8]([C:10](=[O:16])[C:11]([OH:13])=[O:12])[N:9]=1
Reactant: CCOC(=O)C(=O)c1csc(NC(=S)NC)n1
Agent: CCOC(=O)C(=O)C1=CSC(NC(=S)NC)N1
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CNC(=S)Nc1nc(C(=O)C(=O)O)cs1

Procedure:
To a mixture of ethyl 2-[2-[3-(methyl)thioureido]-1,3-thiazol-4-yl]glyoxylate, which can be represented as ethyl 2-[2-[3-(methyl)thioureido]-2,3-dihydro-1,3-thiazol-4-yl]glyoxylate, (21 g.), ethanol (200 ml) and water (100 ml.) was added 1 N sodium hydroxide aqueous solution (154 ml.) under ice-cooling and stirring. The mixture was further stirred for 10 minutes and then neutralized with 1 N hydrochloric acid (154 ml.). The precipitates were collected by filtration, washed with water and then dried to give 2-[2-[3-(methyl)thioureido]-1,3-thiazol-4-yl]glyoxylic acid, which can be represented as 2-[2-[3-(methyl)thioureido]-2,3-dihydro-1,3-thiazol-4-yl]glyoxylic acid, (17.8 g.), mp.>250° C.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]([S:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]3[C:19](=[O:20])[CH2:18][O:17][C:16]3=[O:21])=[CH:8][CH:7]=[CH:6][C:5]=12.[CH:22](=O)[CH2:23][CH2:24][CH3:25].N1CCCCC1>C(O)C>[CH:22](=[C:18]1[O:17][C:16](=[O:21])[N:15]([CH2:14][CH2:13][CH2:12][CH2:11][S:10][C:9]2[N:4]3[CH:3]=[CH:2][N:1]=[C:5]3[CH:6]=[CH:7][CH:8]=2)[C:19]1=[O:20])[CH2:23][CH2:24][CH3:25]
Reactant: CCCC=O
Reactant: O=C1COC(=O)N1CCCCSc1cccc2nccn12
Solvent: CCO
Solvent: C1CCNCC1
Product: CCCC=C1OC(=O)N(CCCCSc2cccc3nccn23)C1=O

Procedure:
To a solution of 3.66 g (12 mmol) of 3-[4-(imidazo[1,2-a]pyridin-5-ylthio)butyl]oxazolidine-2,4-dione and 1.08 ml (12 mmol) of n-butyraldehyde in 50 ml of ethanol, 0.12 ml (1.2 mmol) of piperidine was added, followed by refluxing for 16 hours. After the reaction mixture was cooled, the solvent was distilled off. The residue was dissolved in chloroform, washed with saturated aqueous sodium hydrogen carbonate and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, hexane/ethyl acetate=2/1→1/2) to yield 1.05 g (24.3%, light yellow oily substance) of the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:4]=1[C:5]([O:7]C)=[O:6].[OH-].[Na+].Cl>CO>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1cc(O)ccc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(O)cc1C(=O)O
Reaction time: 2 h

Procedure:
Combine methyl 2-methoxy-5-hydroxybenzoate (0.37 g, 2.0 mmol) and a 1 M aqueous sodium hydroxide solution (20 mL, 20 mmol) in methanol (20 mL). After 2 hours, adjust the pH to about 2 using a 1 M aqueous hydrochloric acid solution and extract with dichloromethane. Dry the organic layer over MgSO4, filter, and evaporate in vacuo to give the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([F:19])=[C:6]([CH:13]([O:17][CH3:18])[C:14]([OH:16])=O)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2].[NH2:20][CH2:21][C:22]1[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=1>>[C:21]([C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH:27][C:14](=[O:16])[CH:13]([C:6]2[CH:7]=[CH:8][C:9]([O:10][CH2:11][CH3:12])=[C:4]([O:3][CH2:1][CH3:2])[C:5]=2[F:19])[O:17][CH3:18])=[CH:24][CH:23]=1)#[N:20]
Reactant: CCOc1ccc(C(OC)C(=O)O)c(F)c1OCC
Reactant: N#Cc1ccc(CN)cc1
Product: CCOc1ccc(C(OC)C(=O)NCc2ccc(C#N)cc2)c(F)c1OCC

Procedure:
(RS)-(3,4-Diethoxy-2-fluoro-phenyl)-methoxy-acetic acid was coupled with 4-aminomethyl benzonitrile according to general procedure B to give (RS)-N-(4-cyano-benzyl)-2-(3,4-diethoxy-2-fluoro-phenyl)-2-methoxy-acetamide. Colorless solid. MS 387.3 ([M+H]+)
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[CH2:5][C@H:6](N)[C:7]([OH:9])=[O:8].S(=O)(=O)(O)O.[Br-:17].[K+].N([O-])=O.[Na+]>O>[CH3:2][O:3][C:4](=[O:11])[CH2:5][C@H:6]([Br:17])[C:7]([OH:9])=[O:8]
Reactant: [Br-]
Reactant: COC(=O)C[C@H](N)C(=O)O
Agent: Cl
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)C[C@H](Br)C(=O)O
Reaction time: 2 h
Yield: 101.9 %

Procedure:
To a mixture of (3S)-3-amino-3-carboxypropionic acid methyl ester hydrochloride (155 g), sulfuric acid (433 g), potassium bromide (402 g) and water (1900 ml) is added dropwise a solution of sodium nitrite (69.8 g) in water (150 ml) at a temperature from 10° C. to 12° C. over a period of 45 minutes. After the addition, the mixture is stirred at a temperature from 10° C. to 15° C. for two hours. The reaction solution is extracted with ethyl acetate, and the extract is washed, dried, and concentrated under reduced pressure at a temperature below 35° C. to give (3S)-3-bromo-3-carboxypropionic acid methyl ester (181.5 g) as an oily product.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][N:24]2[C:29]([CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[O:30])=[O:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:37]1[CH2:39][C@@H:38]1[CH2:40][O:41][C:42]1[CH:51]=[CH:50][CH:49]=[C:48]2[C:43]=1[CH:44]=[CH:45][CH:46]=[N:47]2>C(O)C>[C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][N:24]2[C:29]([CH:31]2[CH2:36][CH2:35][N:34]([CH2:39][C@@H:38]([OH:37])[CH2:40][O:41][C:42]3[CH:51]=[CH:50][CH:49]=[C:48]4[C:43]=3[CH:44]=[CH:45][CH:46]=[N:47]4)[CH2:33][CH2:32]2)=[O:30])=[O:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(NC(CCCc1ccccc1)CCCc1ccccc1)C1CCCCN1C(=O)C1CCNCC1
Reactant: c1cc(OC[C@H]2CO2)c2cccnc2c1
Solvent: CCO
Product: O=C(NC(CCCc1ccccc1)CCCc1ccccc1)C1CCCCN1C(=O)C1CCN(C[C@@H](O)COc2cccc3ncccc23)CC1
Temperature: 25 °C
Yield: 72.8 %

Procedure:
1-(Piperidine-4-carbonyl)-piperidine-2-carboxylic acid [4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (76) (243.4 mg; 0.497 mmol) is dissolved in ethanol (12 L) at ambient temperature. (R)-5-Oxiranylmethoxy-quinoline (2) (100.0 mg; 0.497 mmol) is added, then the mixture is refluxed for 17 hours. After cooling to ambient temperature, the solution is concentrated in vacuo at 40° C. The residue is purified via silica gel chromatography with gradient elution (50%→100% acetone in hexanes, then 5%→20% ethanol in acetone) affording the desired product (250 mg) as a white solid. ESMS: MH+ 691.6
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]2[CH2:11][CH2:12][CH2:13][C:3]=12.[NH:14]1[CH2:19][CH2:18][CH2:17][C@H:16]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:15]1.C(N(CC)CC)C>C(O)(C)C>[N+:8]([C:7]1[C:2]([N:14]2[CH2:19][CH2:18][CH2:17][C@H:16]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:25])([CH3:24])[CH3:26])[CH2:15]2)=[C:3]2[CH2:13][CH2:12][CH2:11][C:4]2=[N:5][CH:6]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cnc2c(c1Cl)CCC2
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCNC1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(c2c([N+](=O)[O-])cnc3c2CCC3)C1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 59.3 %

Procedure:
A mixture of 4-chloro-3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridine (40 mg, 0.20 mmol), tert-butyl (3S)-piperidin-3-ylcarbamate (81 mg, 0.40 mmol) and triethylamine (84 μL, 0.60 mmol) in isopropyl alcohol (0.46 mL) was stirred at 100° C. for 30 min. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (eluting with 0-40% EtOAc in hexanes) to give the sub-title compound as light yellow powder (43 mg, 59%). LCMS calc. for C18H27N4O4 (M+H)+: m/z=363.2. Found: 363.2.
Reaction SMILES: [NH:1]([C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[NH:10][C:11](=[O:21])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)=O)[NH2:2].[CH2:22]1[CH:24]([C:25](N)=[NH:26])[CH2:23]1.Cl.C[O-].[Na+]>C(O)C.[Cl-].[Na+].O>[CH:24]1([C:25]2[N:26]=[C:3]([C:5]3[S:6][CH:7]=[CH:8][C:9]=3[NH:10][C:11](=[O:21])[CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[NH:1][N:2]=2)[CH2:22][CH2:23]1
Reactant: COc1ccc(CC(=O)Nc2ccsc2C(=O)NN)cc1
Reactant: N=C(N)C1CC1
Agent: C[O-]
Agent: Cl
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: COc1ccc(CC(=O)Nc2ccsc2-c2nc(C3CC3)n[nH]2)cc1
Temperature: 120 °C
Reaction time: 17 h

Procedure:
A mixture of N-(2-(hydrazinecarbonyl)thiophen-3-yl)-2-(4-methoxyphenyl)acetamide (101 mg, 0.30 mmol), cyclopropylcarbamidine hydrochloride (47 mg, 0.39 mmol) and sodium methoxide (39 mg, 0.72 mmol) in ethanol (3 mL) was stirred at 120° C. for 17 h. The mixture was diluted with brine and extracted with ethyl acetate. The organic phase was separated, dried (Na2SO4), filtered, concentrated under vacuum and purified by preparative HPLC to give N-(2-(3-cyclopropyl-1H-1,2,4-triazol-5-yl)thiophen-3-yl)-2-(4-methoxyphenyl)acetamide. Retention time (min)=5.578, method [7], MS(ESI) 354.43 (M+H); 1H NMR (300 MHz, CDCl3) δ 10.48 (s, 1H), 8.11 (d, J=5.6 Hz, 1H), 7.25-7.32 (m, 3H), 6.94 (d, J=8.8 Hz, 2H), 3.83 (s, 3H), 3.74 (s, 2H), 1.98-2.03 (m, 1H), 1.07-1.17 (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:11]([CH2:21][N:22]([CH:38]3[C:47]4[N:46]=[CH:45][CH:44]=[CH:43][C:42]=4[CH2:41][CH2:40][CH2:39]3)[CH2:23][CH2:24][CH2:25][CH2:26][N:27]3C(=O)C4C(=CC=CC=4)C3=O)=[N:10][CH:9]=2)=[CH:4][CH:3]=1.O.NN>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:19])([CH3:20])[CH3:18])[C:11]([CH2:21][N:22]([CH:38]3[C:47]4[N:46]=[CH:45][CH:44]=[CH:43][C:42]=4[CH2:41][CH2:40][CH2:39]3)[CH2:23][CH2:24][CH2:25][CH2:26][NH2:27])=[N:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)CCOCn1c(-c2ccc(F)cc2)cnc1CN(CCCCN1C(=O)c2ccccc2C1=O)C1CCCc2cccnc21
Agent: NN
Solvent: O
Solvent: CCO
Product: C[Si](C)(C)CCOCn1c(-c2ccc(F)cc2)cnc1CN(CCCCN)C1CCCc2cccnc21
Temperature: 25 °C
Reaction time: 17 h
Yield: 73.1 %

Procedure:
To a solution of 2-{4-[[5-(4-Fluoro-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-ylmethyl]-(5,6,7,8-tetrahydro-quinolin-8yl)-amino]-butyl}-isoindole-1,3-dione (0.3125 g, 0.48 mmol) in ethanol (5 mL) was added hydrazine monohydrate (0.12 mL), and the reaction mixture was stirred at room temperature for 17 hours. The reaction mixture was concentrated, and purified via column chromatography on silica gel (20:1:1 CH2Cl2-MeOH—NH4OH) to yield 0.1838 g (73%) of N1-[5-(4-Fluoro-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-ylmethyl]-N1-(5,6,7,8-tetrahydro-quinolin-8-yl)-butane-1,4-diamine. 1H NMR (CDCl3) δ 0.85 (t, 2H, J=8.1 Hz), 1.25-1.34 (m, 7H), 1.61-1.72 (m, 1H), 1.89-2.05 (m, 4H), 2.54-2.82 (m, 8H), 3.35-3.47 (m, 3H), 3.93 (s, 2H), 4.06 (t, 1H, J=8.1 Hz), 5.53 (d, 2H, J=10.5 Hz), 5.78 (d, 2H, J=10.8 Hz), 6.99-7.04 (m, 3H), 7.15 (s, 1H), 7.31 (d, 1H, J=7.5 Hz), 7.66-7.70 (m, 2H), 8.47 (d, 1H, J=3.6 Hz).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:13][CH3:14])[CH2:4][S:5][C:6]1[CH:7]=[C:8]([OH:12])[CH:9]=[CH:10][CH:11]=1.[CH3:15][N:16]=[C:17]=[O:18].CCOCC>C1C=CC=CC=1.CN(C)C>[CH3:15][NH:16][C:17](=[O:18])[O:12][C:8]1[CH:9]=[CH:10][CH:11]=[C:6]([S:5][CH2:4][CH:3]([O:2][CH3:1])[O:13][CH3:14])[CH:7]=1
Reactant: CN=C=O
Reactant: COC(CSc1cccc(O)c1)OC
Agent: CN(C)C
Solvent: CCOCC
Solvent: c1ccccc1
Product: CNC(=O)Oc1cccc(SCC(OC)OC)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-(2,2-Dimethoxyethylthio)phenol (1.80 grams) dissolved in benzene (5 ml) was charged into a glass reaction vessel equipped with a mechanical stirrer. Methyl isocyanate (12 ml) and trimethylamine (2 drops) were then added, and the resulting mixture was stirred at room temperature for a period of about 51/2 hours. The mixture was then allowed to stand overnight and was then stripped of excess methyl isocyanate and a portion of the benzene. The concentrated solution was then added to ether and cooled to -60° C., resulting in a precipitate. The precipitate was recrystallized from ether to yield the desired product O-[3-(2,2-dimethoxyethylthio)phenyl]-0 N-methylcarbamate having a melt point of 46° to 48° C.
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4]([C:7]2[CH:12]=[C:11]([OH:13])[CH:10]=[CH:9][C:8]=2[C:14]2[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=2[F:22])[CH2:3][CH2:2]1>CO.[C].[Pd]>[F:22][C:15]1[CH:16]=[CH:17][C:18]([O:20][CH3:21])=[CH:19][C:14]=1[C:8]1[CH:9]=[CH:10][C:11]([OH:13])=[CH:12][C:7]=1[CH:4]1[CH2:3][CH2:2][O:1][CH2:6][CH2:5]1
Reactant: COc1ccc(F)c(-c2ccc(O)cc2C2=CCOCC2)c1
Agent: [Pd]
Solvent: CO
Product: COc1ccc(F)c(-c2ccc(O)cc2C2CCOCC2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-(3,6-dihydro-2H-pyran-4-yl)-2′-fluoro-5′-methoxybiphenyl-4-ol (138 mg) in methanol (3.0 mL) was added 10% palladium-carbon (55 mg), and the mixture was stirred under a hydrogen atmosphere at room temperature for 1 hr. The mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was directly used for the next step.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[C:15]1[CH:16]=[CH:17][C:18]2[N:19]([C:21]([C:24]([F:27])([F:26])[F:25])=[N:22][N:23]=2)[CH:20]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[F:27][C:24]([F:25])([F:26])[C:21]1[N:19]2[CH:20]=[C:15]([N:4]3[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]3)[CH:16]=[CH:17][C:18]2=[N:23][N:22]=1
Reactant: FC(F)(F)c1nnc2ccc(Br)cn12
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc3nnc(C(F)(F)F)n3c2)CC1
Temperature: 100 °C
Yield: 66.2 %

Procedure:
A solution of tert-butyl piperazine-1-carboxylate (1.30 g, 6.99 mmol)], 6-bromo-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine (0.93 g, 3.50 mmol), bis(dibenzylideneacetone)palladium (0.101 g, 0.17 mmol), rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.163 g, 0.26 mmol) and sodium tert-butoxide (0.84 g, 8.74 mmol) in xylenes (30 mL) was sealed into a microwave tube and degassed for 10 minutes. The reaction mixture was heated at 100° C. for 30 minutes and then cooled to ambient temperature. The reaction mixture was diluted with water (20 mL) and then extracted with ethyl acetate (2×40 mL). The organic phases were combined, dried over Na2SO4, filtered, and evaporated to give an involatile residue. The residue was purified by flash chromatography on silica-gel using an increasing gradient of ethyl acetate in isohexane as eluant to give tert-butyl 4-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)piperazine-1-carboxylate (0.86 g, 66.2%) as a yellow solid.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[F:12][C:13]1[C:26]2[C:25](=[O:27])[C:24]3[CH:23]=[N:22][CH:21]=[CH:20][C:19]=3[C:18](=[O:28])[C:17]=2[C:16]([O:29][S:30]([C:33]2[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=2)(=[O:32])=[O:31])=[CH:15][CH:14]=1>ClCCl>[F:12][C:13]1[C:26]2[C:25](=[O:27])[C:24]3[CH:23]=[N+:22]([O-:6])[CH:21]=[CH:20][C:19]=3[C:18](=[O:28])[C:17]=2[C:16]([O:29][S:30]([C:33]2[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=2)(=[O:32])=[O:31])=[CH:15][CH:14]=1
Reactant: Cc1ccc(S(=O)(=O)Oc2ccc(F)c3c2C(=O)c2ccncc2C3=O)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)Oc2ccc(F)c3c2C(=O)c2cc[n+]([O-])cc2C3=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.5 %

Procedure:
A solution of 3-chloroperoxybenzoic acid (3.92 g; 55% titre) in dichloromethane (50 mL) is dropped during 5 min into a mixture of 9-fluoro-6-(p-toluenesulfonyloxy)benzo[g]isoquinoline-5,10-dione (1.98 g) in dichloromethane (20 mL). Care is taken to avoid the addition of the aqueous layer that separates from the dichloromethane solution of 3-chloroperoxybenzoic acid. An exothermic reaction ensues, and at the end of the addition the mixture is refluxed overnight. After cooling to room temperature the reaction mixture is diluted with dichloromethane (50 mL) and the organic solution is washed with water (3×30 mL). After drying over sodium sulfate the organic solution is concentrated to a volume of about 20 mL, diluted with absolute ethanol (30 mL) and concentrated to a small volume. After stirring at 0° C. for 1 h a yellow solid separates which is filtered, to give 9-fluoro-6-(p-toluenesulfonyloxy)benzo[g]isoquinoline-5,10-dione-2-oxide (1.35 g).