Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.C(SCl)CCCCCCCCC.[C:20]1([CH3:47])[CH:25]=[CH:24][C:23]([N:26](SCCCCCCCCCC)[CH:27]=[N:28][C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=2)=[CH:22][CH:21]=1>C1C=CC=CC=1>[C:32]1([CH3:35])[CH:33]=[CH:34][C:29]([NH:28][CH:27]=[N:26][C:23]2[CH:22]=[CH:21][C:20]([CH3:47])=[CH:25][CH:24]=2)=[CH:30][CH:31]=1
Reactant: CCCCCCCCCCSN(C=Nc1ccc(C)cc1)c1ccc(C)cc1
Agent: CCCCCCCCCCSCl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: Cc1ccc(N=CNc2ccc(C)cc2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The N,N'-di-p-tolylformamidine which is prepared according to the above paragraph is then placed in a flask which is cooled to a temperature of about 0° C. by means of an ice bath. In addition, there was also present in the flask 100 grams of triethylamine and 200 cc. of benzene. When the mixture has reached the desired reduced temperature, decanesulfenyl chloride is slowly added dropwise accompanied by continuous stirring. Upon completion of the addition of the decanesulfenyl chloride, the mixture is stirred for an additional period of 1 hour and then allowed to warm to room temperature. Upon standing the desired product comprising N,N'-di-p-tolyl-N-decylthioformamidine crystallizes, is filtered, washed and recovered.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:21]([O-])=O)[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:12][CH2:11][C@@H:10]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]1>CCOC(C)=O.[Pd]>[NH2:21][C:4]1[CH:5]=[CH:6][C:7]([N:8]2[CH2:12][CH2:11][C@@H:10]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]2)=[C:2]([F:1])[CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(c2ccc([N+](=O)[O-])cc2F)C1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H]1CCN(c2ccc(N)cc2F)C1

Procedure:
3-Fluoro-4-((3R)-3-t-butoxycarbonylamino-1-pyrrolidinyl)nitrobenzene (32.7 g, 0.101 M) was dissolved in EtOAc (500 ml) treated with palladium catalyst (10% on carbon, 7.5 g) and hydrogenated at atmospheric pressure until the theoretical uptake of gas. After filtration through celite and evaporation. the required product was obtained as a red gum of sufficient quality for use without purification (29.85 g).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[C:7]([OH:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:13])[CH:3]=1.[CH3:14][N:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[C:20]#[N:21].CC1C=C(C2N(C)C=CN=2)C2C(=C(O)C=CC=2)N=1.[Li+].CC([N-]C(C)C)C>CCCCCCC.C1COCC1.C(C1C=CC=CC=1)C>[OH:12][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[N:5]=[C:4]([CH3:13])[CH:3]=[C:2]2[C:19]1[N:15]([CH3:14])[C:16]([C:20]#[N:21])=[CH:17][CH:18]=1
Reactant: Cc1cc(Br)c2cccc(O)c2n1
Reactant: Cn1cccc1C#N
Agent: CC(C)[N-]C(C)C
Agent: Cc1cc(-c2nccn2C)c2cccc(O)c2n1
Agent: [Li+]
Solvent: CCc1ccccc1
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: Cc1cc(-c2ccc(C#N)n2C)c2cccc(O)c2n1

Procedure:
Coupling of 4-bromo-2-methyl-quinolin-8-ol (75 mg. 0.32 mmol) with 1-methyl-1H-pyrrole-2-carbonitrile (84 mg. 0.79 mmol) according to the synthesis of of 2-methyl-4-(1-methyl-1H-imidazol-2-yl)-quinolin-8-ol using LDA as the base (1.8 M in Heptan/THF/Ethylbenzol. 0.44 mL. 0.79 mmol) yielded the title compound. MS (m/z): 264.2 [M+H+].
Reaction SMILES: [OH:1][C@H:2]([CH3:6])[C:3](N)=O.F[B-](F)(F)F.C([O+](CC)CC)C.[F:19][C:20]([F:41])([F:40])[CH2:21][NH:22][C@H:23]1[CH2:28][CH2:27][C@H:26]([NH:29][C:30]2[C:35]([NH2:36])=[CH:34][N:33]=[C:32]3[CH:37]=[CH:38][S:39][C:31]=23)[CH2:25][CH2:24]1>O1CCCC1.C(O)C>[F:41][C:20]([F:19])([F:40])[CH2:21][NH:22][C@H:23]1[CH2:24][CH2:25][C@H:26]([N:29]2[C:30]3=[C:31]4[S:39][CH:38]=[CH:37][C:32]4=[N:33][CH:34]=[C:35]3[N:36]=[C:3]2[C@H:2]([OH:1])[CH3:6])[CH2:27][CH2:28]1
Reactant: Nc1cnc2ccsc2c1N[C@H]1CC[C@H](NCC(F)(F)F)CC1
Reactant: C[C@@H](O)C(N)=O
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCO
Product: C[C@@H](O)c1nc2cnc3ccsc3c2n1[C@H]1CC[C@H](NCC(F)(F)F)CC1
Reaction time: 0.25 h

Procedure:
A mixture of (2R)-2-hydroxypropanamide (21 mg, 0.24 mmol) and triethyloxonium tetrafluoroborate (45 mg, 0.24 mmol) in tetrahydrofuran (0.3 mL) became a solution after stirring for 15 min. After another 45 min, this solution was added to a mixture of N7-{trans-4-[(2,2,2-trifluoroethyl)amino]cyclohexyl}thieno[3,2-b]pyridine-6,7-diamine (27 mg, 0.078 mmol) in ethanol (0.62 mL) and heated at reflux for 2 h. The resulting mixture was purified on RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product (3.2 mg, 10%). LCMS calculated for C18H22F3N4OS (M+H)+: m/z=399.1. Found: 399.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2CO[CH2:12][N:11](C)[C:10]2=[N:16][N+:17]([O-:19])=[O:18])=[CH:4][N:3]=1.[OH-].[Na+]>Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([NH:11][CH3:12])=[N:16][N+:17]([O-:19])=[O:18])=[CH:4][N:3]=1
Reactant: CN1COCN(Cc2ccc(Cl)nc2)C1=N[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CNC(=N[N+](=O)[O-])NCc1ccc(Cl)nc1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A mixture of 4.0 g of 5-(2-chloropyrid-5-ylmethyl)-3-methyl-4-nitroimino-perhydro-1,3,5-oxadiazine and 20 ml of concentrated hydrochloric acid is stirred for 2 hours at 80° C. The reaction mixture is cooled to 5° C., adjusted to a pH of about 5 with concentrated caustic soda solution and filtered. The filtering residue is mixed with diethyl ether/ethyl acetate 1:1 and filtered again. The title compound is thus obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][CH:30]=1)[CH2:5][NH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=2)=[CH:9][C:8]=1[N+:25]([O-])=O.CCN(C(C)C)C(C)C>C1COCC1.[Pt]>[Br:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][CH:30]=1)[CH2:5][NH:6][C:7]1[C:8]([NH2:25])=[CH:9][C:10]([O:13][CH2:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=2)=[CH:11][CH:12]=1
Reactant: O=[N+]([O-])c1cc(OCc2ccc3ccccc3n2)ccc1NCc1cccc(Br)c1
Agent: [Pt]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Nc1cc(OCc2ccc3ccccc3n2)ccc1NCc1cccc(Br)c1
Reaction time: 23 h
Yield: 58.4 %

Procedure:
To a solution of N-(3-bromobenzyl)-2-nitro-4-(quinolin-2-ylmethoxy)aniline (5.9 g, 13 mmol) in THF (200 mL) was added DIPEA (1.1 mL, 6.4 mmol) followed by 5% platinum on carbon (0.4 g, 1.9 mmol). The reaction vessel was evacuated and placed under 1 atmosphere of H2 atmosphere for 23 h. The mixture was then flushed with N2 and filtered through a pad of Celite. The Celite was then rinsed with additional THF and the filtrate was concentrated to dryness. The resulting residue was purified using FCC to provide 3.3 g of the title compound as a tan solid. MS (ESI): mass calcd. for C23H20BrN3O, 434.33; m/z found 435.0 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[C:16]([OH:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[CH3:28][O:29][C:30]([C:32]1[CH:37]=[CH:36][C:35]([CH2:38]Br)=[CH:34][CH:33]=1)=[O:31]>CC(=O)CC>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[C:16]([O:19][CH2:38][C:35]3[CH:34]=[CH:33][C:32]([C:30]([O:29][CH3:28])=[O:31])=[CH:37][CH:36]=3)[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(O)cc2CC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COC(=O)c1ccc(COc2ccc3c(c2)CCN(C(=O)OC(C)(C)C)CC3)cc1

Procedure:
7-Hydroxy-1,2,4,5-tetrahydro-benzo[d]azepine-3-carboxylic acid tert-butyl ester (WO 02/40471) (5.27 g, 20.0 mmol), potassium carbonate (8.30 g, 60.0 mmol) and catalytic potassium iodide were suspended in butanone (100 ml). Methyl 4-(bromomethyl) benzoate (5.5 g, 24.0 mmol) dissolved in butanone (50 ml) was added dropwise after which the reaction mixture was stirred at reflux for 24 hours. The reaction mixture was cooled, the solids were filtered and then washed with acetone. The filtrate was concentrated in vacuo and the crude mixture was purified by column chromatography eluting with a mixture of ethyl acetate:hexane (1:4) to afford the title compound (D3). MS (ES+) m/e 344 [(M+H)—CO2tBu]+.
Reaction SMILES: Cl[CH:2](P(=O)(OCC)OCC)[C:3]1[CH:12]=[CH:11][C:10]2[C:9]([CH3:14])([CH3:13])[CH2:8][CH2:7][C:6]([CH3:16])([CH3:15])[C:5]=2[CH:4]=1.[CH:25]([C:27]1[CH:37]=[CH:36][C:30]([CH:31]=[CH:32][C:33]([OH:35])=[O:34])=[CH:29][CH:28]=1)=O>C(O)C>[CH3:13][C:9]1([CH3:14])[CH2:8][CH2:7][C:6]([CH3:16])([CH3:15])[C:5]2[CH:4]=[C:3]([C:2]#[C:25][C:27]3[CH:37]=[CH:36][C:30](/[CH:31]=[CH:32]/[C:33]([OH:35])=[O:34])=[CH:29][CH:28]=3)[CH:12]=[CH:11][C:10]1=2
Reactant: CCOP(=O)(OCC)C(Cl)c1ccc2c(c1)C(C)(C)CCC2(C)C
Reactant: O=Cc1ccc(C=CC(=O)O)cc1
Solvent: CCO
Product: CC1(C)CCC(C)(C)c2cc(C#Cc3ccc(/C=C/C(=O)O)cc3)ccc21
Yield: 39.3 %

Procedure:
Using a procedure similar to that described in Example 6b, 16.5 g (44 millimoles) of diethyl 1-chloro-1-(5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphth-2-yl)-methylphosphonate (about 85% strength), 7.8 g (44 millimoles) of 4-formylcinnamic acid and 15.5 g (137 millimoles) of potassium tert.-butylate were converted to 6.2 g (39%) of the title compound of melting point 256°-258° C. (from ethanol).
Reaction SMILES: C[O-].[Na+].[Na].[N+:5]([CH:8]=[C:9](SC)[S:10]([CH3:12])=O)([O-:7])=[O:6].Br.[Br:16][CH2:17][CH2:18][NH2:19]>CO>[N+:5]([CH:8]=[C:9]([S:10][CH3:12])[NH:19][CH2:18][CH2:17][Br:16])([O-:7])=[O:6]
Reactant: NCCBr
Reactant: CSC(=C[N+](=O)[O-])S(C)=O
Agent: Br
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CSC(=C[N+](=O)[O-])NCCBr
Reaction time: 0.25 h
Yield: 6975.4 %

Procedure:
(i) A solution of sodium methoxide (sodium (0.3 g, 0.013 mol) in methanol (10 ml) was added dropwise, over a period of 10 minutes to a stirred mixture of 1-nitro2-methylthio-2-methylsulphinylethylene (2 g, 0.011 mol) and 2-bromoethylamine hydrobromide (2.7 g, 0.013 mol) in methanol (25 ml), cooled to 0°. The solution was stirred at 0° for a further 15 minutes, and then it was allowed to attain room temperature. After 1 hour, the solvent was removed in vacuo, and the semi-solid residue was extracted with hot chloroform (2×25 ml). The extracts were combined and concentrated in vacuo. The solid residue was recrystallised from propan-2-ol to give 1-nitro-2-methylthio-2-(2-bromoethylamino)ethylene (185 g, 71%) m.p. 123°-126°.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH3:27])[C:15]2[C:20]([NH:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:19][CH:18]=[C:17]([F:26])[N:16]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>C(O)C.[OH-].[OH-].[Pd+2]>[CH3:27][N:14]([CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)[C:15]1[C:20]([NH:21][C:22]([CH3:25])([CH3:23])[CH3:24])=[CH:19][CH:18]=[C:17]([F:26])[N:16]=1
Reactant: [H][H]
Reactant: CN(c1nc(F)ccc1NC(C)(C)C)C1CCN(Cc2ccccc2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CN(c1nc(F)ccc1NC(C)(C)C)C1CCNCC1

Procedure:
1-Benzyl-4-[N-methyl-N-(3-tert-butylamino-6-fluoro-2-pyridinyl)amino]piperidine (EXAMPLE 153, 900 mg, 2.43 mmol) and palladium hydroxide on carbon (350 mg) in 50 ml ethanol is hydrogenated at 40 p.s.i. hydrogen for 24 hrs. Filtration and removal of the solvent gives the title compound, which is used without further purification, NMR (300 MHz, CD3OD) 7.38, 6.61, 3.16-3.27, 2.71-2.79, 2.56, 1.84, 1.61-1.66 and 1.33δ.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:16]2[C:21]3[CH:22]=[C:23]4[CH2:28][CH2:27][CH2:26][C:24]4=[CH:25][C:20]=3[O:19][C:18](=[O:29])[C:17]=2[C:30]([O:32]CC)=[O:31])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].C(O)C.Cl>O>[C:12]([C:9]1[CH:8]=[C:7]([C:16]2[C:21]3[CH:22]=[C:23]4[CH2:28][CH2:27][CH2:26][C:24]4=[CH:25][C:20]=3[O:19][C:18](=[O:29])[C:17]=2[C:30]([OH:32])=[O:31])[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:10]=1[OH:11])([CH3:13])([CH3:14])[CH3:15]
Reactant: CCOC(=O)c1c(-c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c2cc3c(cc2oc1=O)CCC3
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(C)c1cc(-c2c(C(=O)O)c(=O)oc3cc4c(cc23)CCC4)cc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of ethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxo-2,6,7,8-tetrahydrocyclopenta[g][1]benzopyran-3-carboxylate (1.85 g), potassium hydroxide (1.12 g) and 80% ethanol (12 ml) was stirred at room temperature for 3 hours. The reaction mixture was then diluted with water, adjusted to pH4 with 6N HCl and extracted with ethyl acetate. The extract was washed with water and dried (MgSO4) and the solvent was distilled off to give crystals of 4-(3,5-di-tert-butyl-4-hydroxyphen-yl)-2-oxo-2,6,7,8-tetrahydrocyclopenta[g][1]benzopyran-3-carboxylic acid. The crystals were collected by filtration and washed with isopropyl ether (1.13 g, 64.9%). mp. 256°-260° C.
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:16]([OH:18])=O)[CH:13]([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[CH2:19]([O:21][C:22](=[O:30])[CH2:23][NH:24][CH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1)[CH3:20].C(OCC)(=O)C>C(Cl)Cl.CN(C)C1C=CN=CC=1.Cl>[CH2:19]([O:21][C:22](=[O:30])[CH2:23][N:24]([C:16](=[O:18])[C@H:12]([CH:13]([CH3:14])[CH3:15])[NH:11][C:1]([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2])[CH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1)[CH3:20]
Reactant: CCOC(=O)CNC1CCCC1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)CN(C(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)C1CCCC1
Temperature: 25 °C

Procedure:
CBZ-L-Valine (15.1 g, 0.06 mol) was dissolved in CH2Cl2 (250 mL) and the following reagents were added in equal molar amounts in the stated order; 4-Dimethylaminopyridine (DMAP), ethyl-N-(cyclopentyl)glycinate and WSCDI. The reaction mixture was allowed to stir at room temperature over night. Evaporation of the solvent yielded a viscous semisolid which was treated with ethyl acetate and then diluted with HCl (4:1) and separated. The organic extract was washed with 1N HCl followed by 5% aqueous Na2CO3 and saturated aqueous NaCl-solution. After drying over MgSO4, filtration and evaporation under reduced pressure yielded an oil (25.1 g) which was purified over silica gel using CH2Cl2 as eluent. The product was collected (6.6 g) as a semisolid. (Rf=0.3, silica gel, CH2Cl2 :CH3OH; 97:3).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]([CH2:21][CH2:22][NH2:23])[C:5](=[O:20])[C:6]1[C:14]([I:15])=[C:13]([NH:16][CH3:17])[C:12]([I:18])=[C:8]([C:9]([OH:11])=[O:10])[C:7]=1[I:19].[Br:24][CH2:25][C:26](Br)=[O:27]>CC(N(C)C)=O>[Br:24][CH2:25][C:26]([NH:1][CH2:2][CH2:3][N:4]([CH2:21][CH2:22][NH:23][C:26](=[O:27])[CH2:25][Br:24])[C:5](=[O:20])[C:6]1[C:14]([I:15])=[C:13]([NH:16][CH2:17][C:26](=[O:27])[CH2:25][Br:24])[C:12]([I:18])=[C:8]([C:9]([OH:11])=[O:10])[C:7]=1[I:19])=[O:27]
Reactant: CNc1c(I)c(C(=O)O)c(I)c(C(=O)N(CCN)CCN)c1I
Reactant: O=C(Br)CBr
Solvent: CC(=O)N(C)C
Product: O=C(CBr)CNc1c(I)c(C(=O)O)c(I)c(C(=O)N(CCNC(=O)CBr)CCNC(=O)CBr)c1I
Temperature: 40 °C
Reaction time: 20 h

Procedure:
50 g (76.1 mmol) of N,N-bis-(2-aminoethyl)-5-(methylamino)-2,4,6-triiodoisophthalic acid amide (title compound 1a) is dissolved in 500 ml of dimethylacetamide, and at 0° C., 70.6 g (350 mmol) of bromoacetyl bromide (Aldrich) is added in drops over 15 minutes. Then, it is stirred for 20 hours at 40° C. The reaction mixture is poured into 4000 ml of ice water, the accumulating solid is filtered off, dissolved in 800 ml of ethyl acetate and extracted three times with 250 ml each of water. The organic phase is dried on sodium sulfate, and the solvent is evaporated to the dry state. The crude product is recrystallized from methyl-tert-butyl ether.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][C@@H:8]1[CH2:13][CH2:12][C@H:11]([NH:14]C(OCC2C=CC=CC=2)=O)[C@H:10]([CH2:25][O:26][CH3:27])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2]>CO.[OH-].[OH-].[Pd+2]>[C:1]([O:5][C:6](=[O:28])[NH:7][C@@H:8]1[CH2:13][CH2:12][C@H:11]([NH2:14])[C@H:10]([CH2:25][O:26][CH3:27])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COC[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CC[C@@H]1NC(=O)OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: COC[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CC[C@@H]1N
Reaction time: 3 h
Yield: 99.8 %

Procedure:
A solution of (1R,3R,4S)-(4-benzyloxycarbonylamino-3-methoxymethylcyclohexyl)carbamic acid tert-butyl ester (1.24 g) was dissolved in MeOH (20 mL) and the resultant solution was charged with 20 wt % Pd(OH)2/C (300 mg) before being evacuated and purged with hydrogen. The reaction was stirred under 1 atm of H2 for 3 h and then filtered through celite with EtOAc washings. The filtrate was concentrated in vacuo to provide (1R,3R,4S)-(4-amino-3-methoxymethyl-cyclohexyl)-carbamic acid tert-butyl ester (815 mg). MS found: (M+H)+=259.2.
Reaction SMILES: [CH3:1][NH:2][C@H:3]([C:10]([OH:12])=[O:11])[CH2:4][C:5]1[N:9]=[CH:8][NH:7][CH:6]=1.[CH3:13]O>>[CH3:13][O:11][C:10](=[O:12])[C@H:3]([CH2:4][C:5]1[N:9]=[CH:8][NH:7][CH:6]=1)[NH:2][CH3:1]
Reactant: CO
Reactant: CN[C@@H](Cc1c[nH]cn1)C(=O)O
Product: CN[C@@H](Cc1c[nH]cn1)C(=O)OC

Procedure:
One gram of N-methyl-L-histidine was dissolved in methanol and HCl was bubbled in at 0° C. for a few minutes. The mixture was heated at reflux 1.5 hours (more hydrochloric acid was introduced on several occasions) and the cooled solution was concentrated at reduced pressure. HPLC indicated about 7% of unreacted starting material remaining. The product was not additionally purified.
Reaction SMILES: [NH:1]1[CH:7]([CH2:8][CH2:9][C:10]([OH:12])=O)[C:5](=[O:6])[NH:4][C:2]1=[O:3].Cl.Cl.[CH3:15][C:16]1[CH:25]=[C:24]([CH2:26][O:27][C:28]2[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=2)[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=1.N1CC(=O)NC1=O>>[O:3]=[C:2]1[NH:1][CH:7]([CH2:8][CH2:9][C:10]([NH:32][C:31]2[CH:30]=[CH:29][C:28]([O:27][CH2:26][C:24]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17]=[C:16]([CH3:15])[CH:25]=3)=[CH:34][CH:33]=2)=[O:12])[C:5](=[O:6])[NH:4]1
Reactant: Cc1cc(COc2ccc(N)cc2)c2ccccc2n1
Reactant: O=C(O)CCC1NC(=O)NC1=O
Agent: Cl
Agent: O=C1CNC(=O)N1
Product: Cc1cc(COc2ccc(NC(=O)CCC3NC(=O)NC3=O)cc2)c2ccccc2n1
Yield: 47.8 %

Procedure:
(+/−)-5-hydantoinpropionic acid (Dakin; Am. Chem. J. 1910, 44, 49) (50 mg, 0.29 mmol) was coupled with 4-[(2-methyl-4-quinolinyl)methoxy]-aniline bis-HCl salt (213 mg, 0.63 mmol) using general coupling method A to give 58 mg (44%) of the product hydantoin. MS found: (M+H)+=419.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[C:8](=[O:15])[NH:9][C:10](SC)=[N:11][CH:12]=2)=[CH:4][CH:3]=1.[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[C:8](=[O:15])[NH:9][C:10]([N:22]3[CH2:23][CH2:24][N:19]([CH3:18])[CH2:20][CH2:21]3)=[N:11][CH:12]=2)=[CH:4][CH:3]=1
Reactant: CSc1ncc(Oc2ccc(Cl)cc2)c(=O)[nH]1
Reactant: CN1CCNCC1
Product: CN1CCN(c2ncc(Oc3ccc(Cl)cc3)c(=O)[nH]2)CC1
Yield: 37.2 %

Procedure:
A solution of of 5-(4-chlorophenoxy)-2-(methylmercapto)pyrimidin-4(3H)-one (158 g, 5.87 mmoles) and 1-methylpiperazine (Aldrich) (6.1 mL, 55 mmoles) was heated at 135° C. for 18 hours. The dark brown mixture was spin evaporated in vacuo. The residue was dissolved in ethyl acetate and applied to a column (d=5 cm) of Silica Gel 80 that was equilibrated with ethyl acetate. The column was eluted with ethyl acetate by flash chromatography to remove unreacted starting material. Elution with 10% methanol-dichloromethane and spin evaporation in vacuo of the combined fractions gave a beige solid that was triturated with ethyl acetate to give 0.70 g (37% yield) of 5-(4-chlorophenoxy)-2-(4-methylpiperazino)pyrimidin-4(3H)-one. Recrystallization from ethyl acetate gave off-white flakes that had an NMR spectrum consistent with the assigned structure.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6](B(O)O)[CH:7]=1.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH:24]=[C:23](OS(C(F)(F)F)(=O)=O)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>[Cl-].[Na+].O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(OCC)(=O)C>[C:13]([O:17][C:18]([N:20]1[CH2:21][CH:22]=[C:23]([C:6]2[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[O:11][CH3:12])[CH2:24][CH2:25]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Reactant: COc1ccc(F)cc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: O
Product: COc1ccc(F)cc1C1=CCN(C(=O)OC(C)(C)C)CC1
Temperature: 90 °C
Reaction time: 2 h
Yield: 127.3 %

Procedure:
To a mixture of 5-fluoro-2-methoxyphenylboronic acid (1 g, 5.88 mmol), 4-trifluoromethanesulfonyloxy-3,6-dihydro-2H-pyridine-1-carboxylic acid t-butyl ester (4.22 g, 7.64 mmol) (David J. Wustrow, Lawrence D. Wise, Synthesis, 1991, 993) and 1,2-dimethoxyethane (30 mL) were added tetrakis(triphenylphosphine)palladium(0) (0.34 g, 0.29 mmol) and 2N aqueous solution of sodium carbonate (8.82 mL, 17.6 mmol), followed by stirring for 2 hours at an external temperature of 90° C. under a nitrogen atmosphere. Brine was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and the filtrate was concentrated to give a residue, which was purified by silica gel column chromatography (ethyl acetate/heptane) to give 2.3 g of the title compound as a yellow oil.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:8]([NH2:9])=[CH:7][S:6][CH:5]=1.C(N(CC)CC)C.Cl.[CH3:18][O:19][CH2:20][C:21](=N)OCC.C(=O)([O-])O.[Na+]>C(O)C>[CH3:18][O:19][CH2:20][C:21]1[NH:3][C:4]2=[CH:5][S:6][CH:7]=[C:8]2[N:9]=1
Reactant: Nc1cscc1N
Reactant: CCOC(=N)COC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCN(CC)CC
Product: COCc1nc2cscc2[nH]1
Temperature: 25 °C
Reaction time: 70 h
Yield: 58 %

Procedure:
[step 1] 3,4-Diaminothiophene dihydrochloride (300 mg, 1.60 mmol) was suspended in ethanol (12 mL), triethylamine (0.45 mL, 3.21 mmol) and ethyl 2-methoxyacetimidate monohydrochloride (Journal of Medicinal Chemistry, 1991, vol. 34, p 2468; 906 mg, 4.01 mmol) were added, and the mixture was stirred at room temperature for 70 hr. To the mixture was added saturated aqueous sodium hydrogen carbonate, and the mixture was extracted 3 times with chloroform. The combined organic layers were dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=100/0 v/v-0/100 v/v) to give 2-(methoxymethyl)-1H-thieno[3,4-d]imidazole (156 mg, 58%).
Reaction SMILES: [C:1](Cl)(=O)C.[Br:5][C:6]1[C:7]([C:14]([OH:16])=[O:15])=[N:8][C:9]([S:12][CH3:13])=[N:10][CH:11]=1.C(=O)([O-])O.[Na+]>CO>[CH3:1][O:15][C:14]([C:7]1[C:6]([Br:5])=[CH:11][N:10]=[C:9]([S:12][CH3:13])[N:8]=1)=[O:16]
Reactant: CC(=O)Cl
Reactant: CSc1ncc(Br)c(C(=O)O)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1nc(SC)ncc1Br
Temperature: 2.5 °C
Reaction time: 0.08 h
Yield: 58.3 %

Procedure:
Acetyl chloride (6.26 ml, 0.088 mol) was added dropwise at 0-5° C. to methanol (100 ml). The mixture was stirred at 0-5° C. for 5 min. 5-Bromo-2-methylsulfanylpyrimidine-4-carboxylic acid (20 g, 0.08 mol) was added in portions at 0-5° C. then the mixture was heated under reflux for 1 h, during which time the slurry dissolved, then it was cooled to ambient temperature and poured into saturated aqueous sodium hydrogencarbonate solution (100 ml). The product was extracted into dichloromethane (3×100 ml), the extracts were washed with water (100 ml), dried (MgSO4) and evaporated in vacuo. The residual solid was crystallised from hexane to give 5-bromo-2-methylsulfanylpyrimidine-4-carboxylic acid methyl ester (12.27 g) as an off white crystalline solid, m.pt. 67-70° C.; 250 MHz 1H-NMR (CDCl3) δ (ppm): 2.6 (s, 3H) (—SCH3), 4.05 (s, 3H) (—OCH3), 8.7 (s, 1H) (ArH); m/z (M+H)+. 249; HPLC purity 96%; HPLC retention time 1.58 min.