Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([CH2:24][C:25]1[S:29][CH:28]=[N:27][CH:26]=1)[CH2:3][C@H:4]([OH:23])[C@@H:5]([NH:13][C:14]([O:16][CH2:17][C:18]1[S:22][CH:21]=[N:20][CH:19]=1)=[O:15])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH:30]([C:33]1[S:34][CH:35]=[C:36]([CH2:38][O:39][C:40]([NH:42][C@H:43]([C:47](O)=[O:48])[CH:44]([CH3:46])[CH3:45])=[O:41])[N:37]=1)([CH3:32])[CH3:31].CO>ClCCl>[CH:30]([C:33]1[S:34][CH:35]=[C:36]([CH2:38][O:39][C:40]([NH:42][C@H:43]([C:47]([NH:1][C@H:2]([CH2:24][C:25]2[S:29][CH:28]=[N:27][CH:26]=2)[CH2:3][C@H:4]([OH:23])[C@@H:5]([NH:13][C:14]([O:16][CH2:17][C:18]2[S:22][CH:21]=[N:20][CH:19]=2)=[O:15])[CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:48])[CH:44]([CH3:46])[CH3:45])=[O:41])[N:37]=1)([CH3:32])[CH3:31]
Reactant: CC(C)c1nc(COC(=O)N[C@H](C(=O)O)C(C)C)cs1
Reactant: N[C@H](Cc1cncs1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OCc1cncs1
Solvent: ClCCl
Solvent: CO
Product: CC(C)c1nc(COC(=O)N[C@H](C(=O)N[C@H](Cc2cncs2)C[C@H](O)[C@H](Cc2ccccc2)NC(=O)OCc2cncs2)C(C)C)cs1

Procedure:
Using the procedure of Example 1U but replacing (2S,3S,5S)-5-amino-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane with (2S,3S,5S)-5-amino-1-phenyl-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-6-(5-thiazolyl)-3-hydroxyhexane and replacing N-((N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valine with N-((2-isopropyl-4-thiazolyl)methoxycarbonyl)valine provided, after silica gel chromatography using 10% methanol in dichloromethane, 25 mg (76%) of the desired compound (Rf 0.47, 10% methanol in dichloromethane). Mass spectrum: (M+H)+ =715.
Reaction SMILES: Cl[C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([Cl:14])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(=O)([O-])[O-].[K+].[K+].[NH2:21][CH2:22][CH2:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=1.Cl>CO>[Cl:14][C:8]1[CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:2]([NH:21][CH2:22][CH2:23][C:24]2[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=2)=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5]
Reactant: NCCc1ccc(C(=O)O)cc1
Reactant: O=C(O)c1cc(Cl)cc([N+](=O)[O-])c1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: O=C(O)c1ccc(CCNc2c(C(=O)O)cc(Cl)cc2[N+](=O)[O-])cc1
Yield: 55.2 %

Procedure:
A mixture of 2,5-dichloro-3-nitrobenzoic acid (23.6 g, 100 mmol), powdered potassium carbonate (41.1 g, 300 mmol), and 4-(aminoethyl)benzoic acid (60.04 g, 400 mmol) in 250 ml of methanol was refluxed under argon for 18 hours. The reaction mixture was poured into 650 ml of 10% aqueous hydrochloric acid solution. The solid was collected and triturated with ethyl acetate. The ethyl acetate extract was decanted, dried with magnesium sulfate and concentrated in vacuo to give 20.15 g (57.5%) of the title compound; mp 255°-257° C.
Reaction SMILES: [CH:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([CH:10]=O)[N:9]=1)([CH3:3])[CH3:2].[S:12]1[CH2:18][C:16](=[O:17])[N:15]([CH2:19][C:20]([OH:22])=[O:21])[C:13]1=[S:14].[Cl-].[NH4+].N>C(O)C>[CH:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([CH:10]=[C:18]2[S:12][C:13](=[S:14])[N:15]([CH2:19][C:20]([OH:22])=[O:21])[C:16]2=[O:17])[N:9]=1)([CH3:2])[CH3:3]
Reactant: O=C(O)CN1C(=O)CSC1=S
Reactant: CC(C)Nc1nc(C=O)cs1
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CC(C)Nc1nc(C=C2SC(=S)N(CC(=O)O)C2=O)cs1

Procedure:
The reaction described in Example 1 was repeated, but using 2.7 g of 2-isopropylaminothiazole-4-carbaldehyde, 2.3 g of rhodanine-3-acetic acid, 1.7 g of ammonium chloride, 1.7 ml of 28% v/v aqueous ammonia and 50 ml of ethanol, giving the title compound as dark red needles.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:20])[F:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:26][S:27]([N:30]1[CH2:35][CH2:34][CH:33]([C:36](Cl)=[O:37])[CH2:32][CH2:31]1)(=[O:29])=[O:28].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:22]([N:11]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]([F:21])([F:19])[F:20])[S:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:36]([CH:33]2[CH2:34][CH2:35][N:30]([S:27]([CH3:26])(=[O:29])=[O:28])[CH2:31][CH2:32]2)=[O:37])=[CH:3][CH:4]=1)(=[O:10])=[O:9])[CH:23]([CH3:25])[CH3:24]
Reactant: CC(C)CN(c1ccccc1C(F)(F)F)S(=O)(=O)c1ccc(N)cc1
Reactant: CS(=O)(=O)N1CCC(C(=O)Cl)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)CN(c1ccccc1C(F)(F)F)S(=O)(=O)c1ccc(NC(=O)C2CCN(S(C)(=O)=O)CC2)cc1
Yield: 65.1 %

Procedure:
A solution of 4-amino-N-isobutyl-N-(2-trifluoromethyl-phenyl)-benzenesulfonamide (100 mg, 0.268 mmol), 1-(methylsulfonyl)-4-piperidinecarbonyl chloride (108 mg, 0.48 mmol) and DIPEA (138 μL, 0.804 mmol) in DCM (8 mL) was stirred at room temperature for 3 hours. The mixture was diluted with DCM, washed with 1 N aqueous HCl, saturated aqueous NaHCO3, water and brine, dried over Na2SO4 and concentrated under vacuum. Purification by silica gel column chromatography (0-100% EtOAc in cyclohexane) and triturating with Et2O/pentane gave the title compound (98 mg, 65%). 1H NMR (400 MHz, DMSO δ 10.42 (s, 1H), 7.85 (d, J=8.8 Hz, 2H), 7.82 (dd, J=7.7, 1.9 Hz, 1H), 7.62-7.63 (m, 1H), 7.58 (d, J=8.8 Hz, 2H), 6.99 (d, J=7.8 Hz, 1H), 3.63 (d, J=11.8 Hz, 2H), 3.38-3.39 (m, 1H), 3.11 (dd, J=13.4, 4.7 Hz, 1H), 2.90 (s, 3H), 2.76-2.78 (m, 2H), 1.95 (d, J=13.5 Hz, 2H), 1.63-1.68 (m, 2H), 1.44-1.48 (m, 1H), 1.09 (t, J=7.0 Hz, 1H), 0.88 (d, J=6.5 Hz, 3H), 0.71 (d, J=6.7 Hz, 3H). LCMS (m/z, Method B) ES+ 562.0 [M+1]+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][Si:5]([O:12][CH2:13][CH3:14])([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8].NC(N)=[S:17].[I-].[Na+].N>>[SH:17][CH2:2][CH2:3][CH2:4][Si:5]([O:12][CH2:13][CH3:14])([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8]
Reactant: NC(N)=S
Reactant: CCO[Si](CCCCl)(OCC)OCC
Agent: N
Agent: [I-]
Agent: [Na+]
Product: CCO[Si](CCCS)(OCC)OCC

Procedure:
A suitable method for the preparation of bis-[γ-(trialkoxysilyl)-propyl]-disulfides is disclosed in copending application Ser. No. 529,203 filed Dec. 3, 1974 entitled "Bis-[γ-(Trialkoxysilyl)-Propyl]-Disulfides of High Purity", the disclosure of which is hereby incorporated specifically herein by reference. According to the process therein disclosed such a disulfide can be prepared by reacting a γ-chloropropyl-triethoxy silane with thiourea and sodium iodide in alcohol for 24 hours at ebullition. After the reaction mixture is cooled to room temperature and over a period of 4 hours a strong current of ammonia is passed through the solution. This causes ammonium chloride to precipitate. The filtrate and precipitate are separated and the filtrate can be concentrated whereby to obtain γ-mercaptopropyl-triethoxy silane. This latter material can be reacted with sulfuryl chloride in a solvent such as anhydrous benzene at a temperature of +8 - + 12°C. The SO2Cl2 is added to the γ-mercapto-propyl-triethoxy silane dropwise over a period of about 55 minutes. Sulfur dioxide and hydrogen chloride gas which are formed are removed by a nitrogen gas purge. After a period of about 6 hours at room temperature with stirring triethylamine can be added whereby to precipitate the amine hydrochloride. The filtrate is then fractionally distilled whereby there is recovered a bis-[γ-(triethoxysilyl)-propyl]-disulfide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][O:8][C:9]2=[O:10])=[CH:5][CH:4]=1.C1C(=O)N(Br)C(=[O:16])C1.CC(N=NC(C#N)(C)C)(C#N)C>ClC1C=CC=CC=1>[CH:7]([C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:12][C:11]=1[C:9]([OH:8])=[O:10])=[O:16]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc2c(c1)C(=O)OC2
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: Clc1ccccc1
Product: COc1ccc(C=O)c(C(=O)O)c1
Temperature: 85 °C

Procedure:
10 g (61 mmol) of 6-methoxyphthalide, 11.4 g (64.0 mmol) of NBS and 200 ml of chlorobenzene are mixed, while stirring, the suspension is heated to 85° C. and 2 ml of a solution of 100 mg of AIBN in 10 ml of chlorobenzene are added. In the course of a few minutes, the temperature rises to 110° C. and a red solution forms. After the rise in-temperature has subsided, the remaining 8 ml are added and the mixture is stirred at 85° C. for 40 min. After cooling to 0° C., the succinimide which has precipitated out is filtered off and rinsed with chlorobenzene. The filtrate is concentrated until an oily residue forms, which is taken up in 10% strength NaOH solution, and the mixture is washed three times with 300 ml of methylene chloride each time. After acidification of the aqueous phase with concentrated HCl, the mixture is stirred at 0° C. for 1 hour. The acid thereby precipitates out in the form of a white precipitate, which is filtered off.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)(OC(C)(C)C)=O.[H-].[Na+].[CH3:17][C:18]1[CH:27]=[C:26]([CH2:28]OC2C=CC(CCl)=CC=2)[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=1>C1COCC1>[CH3:17][C:18]1[CH:27]=[C:26]([CH2:28][O:14][CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Cc1cc(COc2ccc(CCl)cc2)c2ccccc2n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(COC2CCNCC2)c2ccccc2n1
Reaction time: 0.42 h
Yield: 15.6 %

Procedure:
To commercially available N-Boc-4-piperidinol (1.00 g, 5.0 mmol) in THF (50 mL) was added NaH (238 mg 60% oil dispersion) and after 25 min, 4-[(2-methyl-4-quinolinyl)methoxy]benzyl chloride (950 mg, 5.00 mmol). After 18 h, the reaction was quenched with water, the THF was removed by rotary evaporator, and the residue was extracted from water with 3×EtOAc. The combined organic extracts were dried over MgSO4, filtered, concentrated, and chromatographed on SiO2 using 40% EtOAc in hexane. Obtained 200 mg (11% yield) of desired product which was treated with TFA (2 mL) in DCM (5 mL) for 1 h. The solvents were removed by rotary evaporator and the product was obtained pure as a free base by extraction from aqueous NaHCO3 with EtOAc after drying over MgSO4, filtering, and concentrating in vacuo. MS found: (M+H)+=257.
Reaction SMILES: C([O:4][CH2:5][C@@H:6]1[CH2:11][CH2:10][CH2:9][C@H:8]([C:12]#[N:13])[O:7]1)(=O)C.CCN(CC)CC>CO>[OH:4][CH2:5][C@H:6]1[O:7][C@@H:8]([C:12]#[N:13])[CH2:9][CH2:10][CH2:11]1
Reactant: CC(=O)OC[C@@H]1CCC[C@H](C#N)O1
Solvent: CO
Solvent: CCN(CC)CC
Product: N#C[C@H]1CCC[C@@H](CO)O1
Temperature: 23 °C
Reaction time: 18 h
Yield: 73.2 %

Procedure:
To ((2S,6R)-6-cyanotetrahydro-2H-pyran-2-yl)methyl acetate (3.90 g, 21.29 mmol) in methanol (300 mL) was added Et3N (30 mL). The reaction mixture was stirred at 23° C. for 18 h. The solvents were evaporated in vacuo. The residue was redissolved in methanol the solvent removed in vacuo (2×20 mL). The crude material was then purified on a silica gel column (Biotage flash chromatography system) eluting with a gradient mixture ethyl acetate (100%) to ethyl acetate:methanol (8:2) to afford 2.20 g (73% yield) of the title compound. 1H NMR (400 MHz, CDCl3) δ ppm 4.31 (1 H, dd, J=11.6, 2.5 Hz), 3.58-3.63 (2 H, m), 3.51-3.57 (1 H, m), 2.06 (1 H, s), 1.94-2.03 (2 H, m), 1.79-1.90 (1 H, m), 1.53-1.65 (2 H, m), 1.36-1.47 (1 H, m).
Reaction SMILES: [Na].Cl.[C:3]([NH2:9])(=[NH:8])[CH2:4][CH2:5][CH2:6][CH3:7].[C:10]1([CH3:19])[CH:15]=[CH:14][C:13]([N:16]=[C:17]=[O:18])=[CH:12][CH:11]=1>CC(C)=O>[C:10]1([CH3:19])[CH:15]=[CH:14][C:13]([NH:16][C:17]([NH:8][C:3](=[NH:9])[CH2:4][CH2:5][CH2:6][CH3:7])=[O:18])=[CH:12][CH:11]=1
Reactant: Cc1ccc(N=C=O)cc1
Reactant: CCCCC(=N)N
Agent: Cl
Agent: [Na]
Solvent: CC(C)=O
Product: CCCCC(=N)NC(=O)Nc1ccc(C)cc1

Procedure:
Following a procedure similar to that described in Example 23 but using 2.3 g. sodium in 300 ml. dry acetone, 13.6 g. valeramidine hydrochloride and 13.3 g. 4-tolyl isocyanate in 100 ml. dry acetone, there was obtained after recrystallization from acetonitrile 10.6 g. 1-(4-tolyl)-3-(pentanimidoyl)urea hydrochloride; m.p. 159°-160°C.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8](=[O:12])[N:9]([CH3:11])[N:10]=2)[N:7]=1.[C:13]1([CH:19]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[O:20][CH:21]2[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][CH2:29][NH2:30])[CH2:23][CH2:22]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])O.[Na+]>CN(C)C=O>[C:31]1([CH:19]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:20][CH:21]2[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][CH2:29][NH:30][C:2]3[CH:3]=[CH:4][C:5]4[N:6]([C:8](=[O:12])[N:9]([CH3:11])[N:10]=4)[N:7]=3)[CH2:23][CH2:22]2)[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: Cn1nc2ccc(Cl)nn2c1=O
Reactant: NCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1nc2ccc(NCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)nn2c1=O
Temperature: 145 °C
Reaction time: 1 h
Yield: 26.8 %

Procedure:
0.277 g of 6-chloro-2-methyl[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one was dissolved in 2 ml of N,N-dimethylformamide; 0.487 g of 4-(diphenylmethoxy)-1-piperidinepropanamine was added, followed by stirring in an oil bath (bath temperature 140-150° C.) for 1 hour. After cooling, ice water and an aqueous solution of sodium hydrogen carbonate were added; the reaction mixture was extracted with ethyl acetate; the extract was washed with saturated saline and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography and eluted with ethyl acetate-methanol-triethylamine (90:10:1). The desired fraction was collected and concentrated; the crystal obtained was filtered, washed with diethyl ether, and dried, to yield 0.19 g of the title compound.
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][C:13]2([CH:16]3[O:20][CH2:19][CH2:18][O:17]3)[O:15][CH:10]([C:11]3[CH:24]=[CH:23][CH:22]=[CH:21][C:12]=32)[CH2:9]1)[C:2]1C=CC=CC=1.C(O)(=[O:27])C>C(O)C.[Pd]>[C:1]([N:8]1[CH2:14][C:13]2([CH:16]3[O:20][CH2:19][CH2:18][O:17]3)[O:15][CH:10]([C:11]3[CH:24]=[CH:23][CH:22]=[CH:21][C:12]=32)[CH2:9]1)(=[O:27])[CH3:2]
Reactant: c1ccc(CN2CC3OC(C4OCCO4)(C2)c2ccccc23)cc1
Reactant: CC(=O)O
Agent: [Pd]
Solvent: CCO
Product: CC(=O)N1CC2OC(C3OCCO3)(C1)c1ccccc12
Reaction time: 6 h
Yield: 88 %

Procedure:
A suspension of 10% Pd-C (1.42 g) in a solution of the product from Example 29 (9.75 g, 0.0302M) and glacial acetic acid (12 ml) in absolute ethanol (130 ml) was hydrogenated in a Parr apparatus at an initial pressure of 32 psi. After six hours, the catalyst was removed by filtration through Celite and the solvents removed in vacuo. The residue was taken up in CH2Cl2 (50 ml) and treated with acetic anhydride (6.0 ml). After 15 minutes, the mixture was evaporated to dryness and the residue crystallized from Et2O to give the titled compound (7.34 g, 88% yield) as white crystals, mp 122°-123° C. NMR (CDCl3) δ 1.73 ppm (s, 3H, COCH3), 3.0-4.60 (m, 8H, ##STR49## 5.17 (m, 2H, ##STR50## 7.25 (m, 4H, aromatic H). IR (KBr): 1635 cm-1 (C=O). MS: 275 (M+).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[C:17]([CH2:21][OH:22])[CH:18]=[CH:19][CH:20]=1.O[C:24]1[CH:25]=[N:26][CH:27]=[C:28]([CH:33]=1)[C:29]([O:31][CH3:32])=[O:30].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[C:17]([CH:18]=[CH:19][CH:20]=1)[CH2:21][O:22][C:24]1[CH:25]=[N:26][CH:27]=[C:28]([CH:33]=1)[C:29]([O:31][CH3:32])=[O:30]
Reactant: Cc1oc(-c2ccccc2)nc1COc1cccc(CO)c1
Reactant: COC(=O)c1cncc(O)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: COC(=O)c1cncc(OCc2cccc(OCc3nc(-c4ccccc4)oc3C)c2)c1
Reaction time: 15 h
Yield: 79 %

Procedure:
To a mixture of [3-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]phenyl]methanol (1.92 g), methyl 5-hydroxynicotinate (1.0 g), tributylphosphine (1.98 g) and tetrahydrofuran (100 mL) was added 1,1′-(azodicarbonyl)dipiperidine (2.47 g) at room temperature and the mixture was stirred for 15 hrs. The precipitated crystals were removed by filtration. The filtrate was concentrated and the residue was subjected to silica gel column chromatography to give crystals (2.21 g, 79%) of methyl 5-[3-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]nicotinate from a fraction eluted with ethyl acetate-hexane (1:3, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 96-97° C.
Reaction SMILES: [N:1]1[C:10]2[C:9](=O)[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[NH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21].[BH4-].[Na+]>C(O)C.C(O)(=O)C>[N:1]1[C:10]2[CH:9]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:21])[CH3:23])[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)NCCCCN
Reactant: O=C1CCCc2cccnc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NCCCCNC1CCCc2cccnc21
Temperature: 150 °C

Procedure:
To a solution of 6,7-dihydroquinolin-8(5H)-one (2.0 g, 13.6 mmol) in ethanol (15 mL) was added concentrated acetic acid (5 drops), tert-butyl 4-aminobutylcarbamate (2.7 g, 14.3 mmol) and 4 Å molecular sieves. The reaction mixture was heated at 150° C. in microwave reactor for 10 min. The mixture was cooled to room temperature and NaBH4 (0.8 g, 20.4 mmol) was added all at once. The crude reaction mixture was absorbed onto silica gel and the product purified by silica gel chromatography (0% to 10% methanol/CH2Cl2) to afford the desired product: ESI+ MS: m/z (rel intensity) 320.2 (100, [M+H]+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH:9]2[C:13](=[O:14])[CH2:12][CH2:11][C:10]2=[O:15])=[C:4]([CH3:16])[CH:3]=1.[C:17](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH3:16])[C:5]([C:9]2[C:13](=[O:14])[CH2:12][CH2:11][C:10]=2[O:15][CH3:17])=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc(Br)cc(C)c1C1C(=O)CCC1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COC1=C(c2c(C)cc(Br)cc2C)C(=O)CC1
Temperature: 27.5 °C
Reaction time: 16 h

Procedure:
To a solution of 2-(4-bromo-2,6-dimethylphenyl)cyclopentane-1,3-dione (40 g, 0.143 mol) in acetone (2000 ml) is added anhydrous potassium carbonate (98.5 g, 0.714 mol) and iodomethane (45 ml, 0.72 mol). The resulting mixture is stirred at 25-30°C. for 16 hours, then volatile solvents are removed in vacuo, and the residue is diluted with distilled water (200 ml) and extracted with ethyl acetate (3×500 ml). Organic fractions are combined, washed with distilled water, brine, then dried over sodium sulphate, filtered and the filtrate concentrated in vacuo. The crude product is purified by flash column chromatography to afford 2-(4-bromo-2,6-dimethylphenyl)-3-methoxycyclopent-2-enone.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:12]3([CH2:17][NH2:18])[CH2:16][CH2:15][CH2:14][CH2:13]3)[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:19][C:20]([F:36])([F:35])[C:21]1[O:25][N:24]=[C:23]([C:26]2[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=2)[C:29](O)=[O:30])[N:22]=1>>[C:1]1([C:7]2[N:8]=[C:9]([C:12]3([CH2:17][NH:18][C:29](=[O:30])[C:28]4[CH:32]=[CH:33][CH:34]=[C:26]([C:23]5[N:22]=[C:21]([C:20]([F:36])([F:35])[F:19])[O:25][N:24]=5)[CH:27]=4)[CH2:16][CH2:15][CH2:14][CH2:13]3)[S:10][CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Reactant: NCC1(c2nc(-c3ccccc3)cs2)CCCC1
Product: O=C(NCC1(c2nc(-c3ccccc3)cs2)CCCC1)c1cccc(-c2noc(C(F)(F)F)n2)c1
Yield: 34 %

Procedure:
This compound was synthesized from (1-(4-phenylthiazol-2-yl)cyclopentyl)methanamine and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in example 8 step 6 (65 mg, yield 34%). 1H NMR (400 MHz, DMSO-d6) 8.78 (m, 1H), 8.44 (s, 1H), 8.19 (d, J=7.6 Hz, 1H), 8.06 (d, J=7.9 Hz, 1H), 7.98 (s, 1H), 7.93 (d, J=7.3 Hz, 2H), 7.71 (t, J=7.9 Hz, 1H), 7.39 (m, 2H), 7.30 (m, 1H), 3.69 (d, J=6.2 Hz, 2H), 2.19 (m, 2H), 2.07 (m, 2H), 1.76 (m, 2H), 1.64 (m, 2H). MS (ESI) m/z: Calculated for C25H21F3N4O2S: 498.13. found: 499.2 (M+H)+.
Reaction SMILES: CS(O[CH2:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([Cl:24])[N:22]=3)[N:17]=[CH:16][C:15]=2[C:25](=[O:27])[CH3:26])[CH2:9][CH2:8]1)(=O)=O.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>>[Cl:24][C:21]1[N:22]=[C:23]2[C:18](=[CH:19][CH:20]=1)[N:17]=[CH:16][C:15]([C:25](=[O:27])[CH3:26])=[C:14]2[NH:13][C@H:10]1[CH2:11][CH2:12][C@H:7]([CH2:6][N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[CH2:8][CH2:9]1
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1N[C@H]1CC[C@H](COS(C)(=O)=O)CC1
Reactant: C1COCCN1
Product: CC(=O)c1cnc2ccc(Cl)nc2c1N[C@H]1CC[C@H](CN2CCOCC2)CC1

Procedure:
Following general procedure V, {trans-4-[(3-acetyl-6-chloro-1,5-naphthyridin-4-yl)-amino]cyclohexyl}methyl methanesulfonate (230 mg, 0.56 mmol) was reacted with morpholine (72 mg, 0.84 mmol) to afford the desired product (85 mg, 38%) as a yellow solid: 1H NMR (300 MHz, CDCl3) δ 10.90 (br s, 1H), 8.94 (s, 1H), 8.08 (d, J=8.7 Hz, 1H), 7.52 (d, J=8.7 Hz, 1H), 5.11-4.88 (m, 1H), 3.77-3.65 (m, 4H), 2.68 (s, 3H), 2.46-2.38 (m, 4H), 2.36-2.21 (m, 2H), 2.21-2.15 (m, 2H), 2.01-1.89 (m, 2H), 1.64-1.50 (m, 1H), 1.46-1.07 (m, 4H); ESI MS m/z 403 [M+H]+
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[CH3:12].[CH:13](O)=O.Cl.[OH-].[NH4+]>O>[CH3:12][C:3]1[C:2]2[NH:1][CH:13]=[N:8][C:7]=2[CH:6]=[CH:5][C:4]=1[N+:9]([O-:11])=[O:10]
Reactant: O=CO
Reactant: Cc1c([N+](=O)[O-])ccc(N)c1N
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: Cc1c([N+](=O)[O-])ccc2nc[nH]c12
Temperature: 25 °C

Procedure:
A mixture of 2,3-diamino-6-nitrotoluene (11.81 g), formic acid (88%, 390 mL) and 12N HCl (38 mL) is heated to reflux for 1 hour. The resulting mixture is cooled to room temperature and rotary evaporated. The residue is diluted with water (200 mL), then basified with ammonium hydroxide (28-30%). The suspension is extracted with ethyl acetate (3×200 mL). The combined extracts are dried over magnesium sulfate (MgSO4) and evaporated to afford 4-methyl-5-nitrobenzimidazole as an orange solid.
Reaction SMILES: C1(S(O[CH2:11][C:12]([O:14]CCCC)=[O:13])(=O)=O)C=CC=CC=1.[OH-].[Na+].[C:21]1([CH3:29])[CH:26]=[C:25]([CH3:27])[CH:24]=[C:23]([CH3:28])[CH:22]=1>O.CO>[C:21]1([CH3:29])[CH:26]=[C:25]([CH3:27])[CH:24]=[C:23]([CH3:28])[C:22]=1[CH2:11][C:12]([OH:14])=[O:13]
Reactant: Cc1cc(C)cc(C)c1
Reactant: CCCCOC(=O)COS(=O)(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cc(C)c(CC(=O)O)c(C)c1
Yield: 85 %

Procedure:
8.0 g (0.06 tool) and 5.4 g (0.0198 mol) of n-butyl phenylsulfonyloxyacetate are reacted in 60 ml of mesitylene by the method of Example 7, and the reaction mixture is hydrolyzed with 5 g of NaOH in 15 ml of water and 50 ml of methanol to give the acid. 3.0 g (85% of theory) of mesitylacetic acid are isolated.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([NH:14][CH2:15][C:16]([N:18]([CH2:22][CH2:23][CH3:24])[CH2:19][CH2:20][CH3:21])=[O:17])[C:11]([N+:25]([O-])=O)=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[CH2:28]([OH:30])C>[Pt](=O)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]3[C:11]([NH:25][C:28](=[O:30])[N:14]3[CH2:15][C:16]([N:18]([CH2:22][CH2:23][CH3:24])[CH2:19][CH2:20][CH3:21])=[O:17])=[CH:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: CCO
Reactant: CCCN(CCC)C(=O)CNc1nc(-c2ccc(Cl)cc2)ncc1[N+](=O)[O-]
Agent: O=[Pt]=O
Product: CCCN(CCC)C(=O)Cn1c(=O)[nH]c2cnc(-c3ccc(Cl)cc3)nc21
Reaction time: 4 h

Procedure:
A mixture of 2-[2-(4-chlorophenyl)-5-nitro-4-pyrimidinylamino]-N,N-dipropylacetamide (9 g), platinum (IV) oxide (1 g) and ethanol (150 ml) is stirred under hydrogen atmosphere for four hours, and the reaction mixture is filtered. The filtrate is concentrated under reduced pressure, and to the resulting residue is added urea (2.1 g). The mixture is stirred at 200° C. for two hours. After cooling, water is added to the reaction mixture, and the precipitates are collected by filtration, washed with water, and recrystallized from ethanol to give the desired compound (7 g).