Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[N:8]=[C:7]([N:9]([CH3:19])[CH2:10][CH:11]2[CH2:18][CH2:17][C:14]3([CH2:16][CH2:15]3)[CH2:13][CH2:12]2)[C:6]([C:20](O)=[O:21])=[CH:5][N:4]=1)#[N:2].[C:23]1([CH2:29][C@@H:30]([NH2:37])[CH2:31][N:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CCN=C=NCCCN(C)C.Cl.C1C=NC2N(O)N=NC=2C=1>CN(C=O)C>[C:23]1([CH2:29][C@@H:30]([NH:37][C:20]([C:6]2[C:7]([N:9]([CH3:19])[CH2:10][CH:11]3[CH2:18][CH2:17][C:14]4([CH2:15][CH2:16]4)[CH2:13][CH2:12]3)=[N:8][C:3]([C:1]#[N:2])=[N:4][CH:5]=2)=[O:21])[CH2:31][N:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CN(CC1CCC2(CC1)CC2)c1nc(C#N)ncc1C(=O)O
Reactant: N[C@H](Cc1ccccc1)CN1CCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Product: CN(CC1CCC2(CC1)CC2)c1nc(C#N)ncc1C(=O)N[C@H](Cc1ccccc1)CN1CCCC1
Reaction time: 24 h

Procedure:
To a solution of the crude 2-cyano-4-(methylspiro[2.5]oct-6-ylmethylamino)pyrimidine-5-carboxylic acid (82 mg, step 73.4) in DMF (1.5 mL) are added (R)-2-phenyl-1-pyrrolidin-1-ylmethylethylamine (0.3 mmol), EDCI-HCl (0.4 mmol), and HOAt (0.4 mmol) at room temperature. The reaction mixture is stirred for 24 h and the reaction is quenched by the addition of water. The mixture is extracted with AcOEt and the organic extracts are dried over Na2SO4, filtered, concentrated in vacuo. The resulting residue is purified by RP-HPLC to give the title compound; MS (M+1)+ 488, Rf (solvent) 0.13 (CH2Cl2:MeOH=10:1).
Reaction SMILES: [OH:1][C:2]1[C:3]([O:12][CH3:13])=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].C(=O)([O-])[O-].[K+].[K+].[CH:20]1(Br)[CH2:24][CH2:23][CH2:22][CH2:21]1>CN(C)C=O.O>[CH:20]1([O:1][C:2]2[C:3]([O:12][CH3:13])=[N:4][CH:5]=[C:6]([CH:11]=2)[C:7]([O:9][CH3:10])=[O:8])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: COC(=O)c1cnc(OC)c(O)c1
Reactant: BrC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cnc(OC)c(OC2CCCC2)c1
Temperature: 60 °C

Procedure:
A mixture of methyl 5-hydroxy-6-methoxynicotinoate (250 mg), anhydrous potassium carbonate (600 mg) and cyclopentyl bromide (0.26 mL) in dry dimethylformamide (5 mL) is stirred and heated at 60±5° C. for 24 hours. The mixture is cooled to room temperature, diluted with water and extracted with ethyl acetate. The extracts are washed with water and dried (MgSO4). Concentration gave methyl 5-cyclopentyloxy-6-methoxynicotinoate (290 mg) as an oil.
Reaction SMILES: CC(O)C.[CH2:5]([O:12][C:13]1[CH:14]=[C:15]([C:21]2[N:22]=[C:23]([CH:31]3[CH2:34][CH2:33][CH2:32]3)[N:24]3[CH:29]=[CH:28][N:27]=[C:26](Cl)[C:25]=23)[CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[NH3:35]>C(Cl)Cl>[CH2:5]([O:12][C:13]1[CH:14]=[C:15]([C:21]2[N:22]=[C:23]([CH:31]3[CH2:34][CH2:33][CH2:32]3)[N:24]3[CH:29]=[CH:28][N:27]=[C:26]([NH2:35])[C:25]=23)[CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: N
Reactant: COc1ccc(-c2nc(C3CCC3)n3ccnc(Cl)c23)cc1OCc1ccccc1
Solvent: CC(C)O
Solvent: ClCCl
Product: COc1ccc(-c2nc(C3CCC3)n3ccnc(N)c23)cc1OCc1ccccc1
Temperature: 110 °C

Procedure:
An iPrOH (5 ml)/DCM (4 ml) solution of 1-(3-benzyloxy-4-methoxyphenyl)-8-chloro-3-cyclobutylimidazo[1,5-a]pyrazine (290 mg, 87%, 0.601 mmol), cooled to −78° C. in a dry ice/acetone bath, was charged with liquid NH3 for 15 min. The sealed tube was equipped with a Teflon washer, sealed and heated 110° C. for 14 h. After that time, the excess NH3 and the solvent were evaporated. The remaining material was purified by chromatography on silica gel to obtain the title compound as a brown oil. The impurities that could not be removed by conventional methods (eg. TLC, HPLC etc.), were removed by SCX column (washed with 7 ml of DCM, 7 ml of MeOH and 7 ml of 2 N NH3 in MeOH); 1H NMR (CDCl3, 400 MHz) δ 2.00-2.24 (m, 2H), 2.42-2.66 (m, 4H), 3.78 (quintet, 1H, J=8.4 Hz), 3.95 (s, 3H), 4.95 (brs, 2H), 5.23 (s, 2H), 6.98-7.02 (m, 2H), 7.07 (d, 1H, J=5.2 Hz), 7.17 (d, 1H, J=2.0 Hz), 7.23 (dd, 1H, J=2.0 and 8.0 Hz), 7.29-7.45 (m, 5H); MS (ES): 401.1 (M+1).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH2:10][C:11](=O)[C:12]([F:15])([F:14])[F:13])=[CH:5][CH:4]=1.[NH2:20][C:21]1[C:25]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)=[CH:24][NH:23][N:22]=1>>[F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([C:12]([F:15])([F:14])[F:13])[N:22]3[N:23]=[CH:24][C:25]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=4)=[C:21]3[N:20]=2)=[CH:5][CH:4]=1
Reactant: Nc1n[nH]cc1-c1ccccn1
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(C(F)(F)F)cc1
Product: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)n3ncc(-c4ccccn4)c3n2)cc1
Yield: 71 %

Procedure:
Reaction of 1-(4-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (142 mg, 0.5 mmol), prepared from commercially available 3,4-dichloro-acetophenone according to general procedure A, and 3-amino-4-(2-pyridinyl)-pyrazole [CAS No. 493038-87-2; prepared from 2-cyanomethyl-pyridine as described in Bioorg. Med. Chem. Lett. 12 (2002) 3537-3541] (80 mg, 0.5 mmol) according to general procedure B yielded the title compound as a yellow solid (145 mg, 71%). MS (ISP) 409.2 [(M+H)+]; mp 202° C.
Reaction SMILES: CO.O=[C:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH:5]1[C:10]([O:12][CH2:13][CH3:14])=[O:11].[C:15]1([C@@H:21]([NH2:23])[CH3:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>CCCCCCC>[C:15]1([C@@H:21]([NH:23][C:4]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH3:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)C1CCCCC1=O
Reactant: C[C@H](N)c1ccccc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CCCCCCC
Solvent: CO
Product: CCOC(=O)C1=C(N[C@@H](C)c2ccccc2)CCCC1

Procedure:
In an additional embodiment, (1S,2S)-2-[(S)-1-phenylethyl amino]cyclohexyl)methanol (11) is produced from a starting material comprising ethyl 2-oxocyclohexane carboxylate (6). This embodiment comprises reacting ethyl 2-oxocyclohexane carboxylate (6) with (S)-(−)-1-phenylethylamine (7) in the presence of a catalyst, ytterbium trifluoromethanesulfonate, and heptane to produce (S)-Ethyl 2-(1-phenylethylamino)cyclohex-1-enecarboxylate (8). The next step is reduction of the amine (8) with sodium acetoxyborohydride in the presence of a acetonitrile produce (1R,2S)-Ethyl 2-((S)-1-phenylethylamino)cyclohexanecarboxylate (9), as illustrated in FIG. 1. The production of the cis-cyclohexane derivative (9) is followed by epimerization of the chiral center adjacent to the ethyl ester functionality using sodium t-butoxide to afford trans-cyclohexane derivative (10) as a major diastereomer. Reduction of the ester functionality in compound (10), using lithium borohydride yields (1S,2S)-2-[(S)-1-phenylethyl amino]cyclohexyl)methanol (11) in good overall yield, which is subsequently purified by chromatography.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([N:15]3[CH2:20][CH2:19][CH2:18][C@H:17]([NH:21][C:22](=[O:31])[O:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:16]3=[O:32])[CH2:11][CH2:10]2)=[N:7][CH:8]=1)[CH3:2].[H-].[Na+].I[CH3:36]>CN(C=O)C>[CH2:1]([C:3]1[CH:8]=[N:7][C:6]([N:9]2[CH2:10][CH2:11][CH:12]([N:15]3[CH2:20][CH2:19][CH2:18][C@H:17]([N:21]([CH3:36])[C:22](=[O:31])[O:23][CH2:24][C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[C:16]3=[O:32])[CH2:13][CH2:14]2)=[N:5][CH:4]=1)[CH3:2]
Reactant: CI
Reactant: CCc1cnc(N2CCC(N3CCC[C@H](NC(=O)OCc4ccccc4)C3=O)CC2)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1cnc(N2CCC(N3CCC[C@H](N(C)C(=O)OCc4ccccc4)C3=O)CC2)nc1
Reaction time: 0.08 h
Yield: 38.5 %

Procedure:
(S)-benzyl 1′-(5-ethylpyrimidin-2-yl)-2-oxo-1,4′-bipiperidin-3-ylcarbamate (Example 58, Steps A-B; 0.250 g, 0.571 mmol) was dissolved in DMF (5 mL). 60% NaH (0.0274 g, 0.686 mmol) was added and stirred for 5 minutes. Iodomethane (0.071 mL, 1.1 mmol) was added and stirred at ambient temperature overnight. The reaction was concentrated and purified over silica gel (25-100% EtOAc in hexanes) to afford (S)-benzyl 1′-(5-ethylpyrimidin-2-yl)-2-oxo-1,4′-bipiperidin-3-yl(methyl)carbamate (100 mg, 0.22 mmol, 39% yield).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4](=[O:9])[C:5]([CH3:8])([CH3:7])[CH3:6].C(N(CC)C(C)C)(C)C.Cl[C:20](=[O:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22]>C(Cl)Cl>[CH2:24]([O:23][C:21](=[O:22])[C:20]([NH:2][CH2:3][C:4](=[O:9])[C:5]([CH3:8])([CH3:7])[CH3:6])=[O:26])[CH3:25]
Reactant: CCOC(=O)C(=O)Cl
Reactant: CC(C)(C)C(=O)CN
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(=O)NCC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.4 %

Procedure:
To a mixture of 1-amino-3,3-dimethylbutan-2-one hydrochloride salt (35 g, 231 mmol) in CH2Cl2 (500 mL) at 0° C. are added N,N-diisopropylethylamine (74 g, 577 mmol) and ethyl chloro(oxo)acetate (31.5 g, 231 mmol) slowly over a period of 15 min. The reaction mixture is stirred at room temperature for 2 h and is filtered through Celite. The filtrate is concentrated to afford the title compound (40 g, 81%).
Reaction SMILES: Cl[CH2:2][CH2:3][NH2:4].[CH2:5]([C:7]1[CH:12]=[CH:11][C:10]([N:13]=[C:14]=[O:15])=[CH:9][CH:8]=1)[CH3:6].[H-].[Na+]>C(OCC)C.O1CCCC1>[CH2:5]([C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:2][CH2:3][NH:4][C:14]2=[O:15])=[CH:9][CH:8]=1)[CH3:6]
Reactant: NCCCl
Reactant: CCc1ccc(N=C=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCc1ccc(N2CCNC2=O)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 76.5 %

Procedure:
To a solution of 3.98 g of 2-chloroethylamine in 30 ml of diethyl ether, a solution of 3.68 g of 4-ethylphenyl isocyanate in 15 ml of tetrahydrofuran was added dropwise under ice cooling. After the resultant mixture was stirred at room temperature for 30 minutes, diethyl ether was added, followed by the collection of precipitated crystals by filtration. The crystals so obtained were added under ice cooling to a suspension of 10.8 g of 60%-sodium hydride in 35 ml of tetrahydrofuran, followed by stirring at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure, to which 1N hydrochloric acid was added. Resulting crystals were collected by filtration and washed with n-hexane, whereby 3.64 g of the title compound were obtained (yield: 89%).
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[CH3:12].[CH:13]([C:16]1[CH:17]=[C:18]([OH:24])[CH:19]=[CH:20][C:21]=1[O:22][CH3:23])([CH3:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CS(C)=O>[CH3:12][C:3]1[CH:4]=[C:5]([N+:9]([O-:11])=[O:10])[CH:6]=[C:7]([CH3:8])[C:2]=1[O:24][C:18]1[CH:19]=[CH:20][C:21]([O:22][CH3:23])=[C:16]([CH:13]([CH3:15])[CH3:14])[CH:17]=1
Reactant: COc1ccc(O)cc1C(C)C
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COc1ccc(Oc2c(C)cc([N+](=O)[O-])cc2C)cc1C(C)C

Procedure:
4-Chloro-3,5-dimethylnitrobenzene (2.12 g), 1.9 g of 3-isopropyl-4-methoxyphenol, and 1.74 g of potassium carbonate are heated 18 hrs at 125° in 25 ml dimethylsulfoxide. The mixture is poured into ethyl acetate and extracted once with water and five times with brine. The ethyl acetate is dried, filtered, and stripped to yield an oil which is chromatographed on silica gel with 97:3 hexane:ethyl acetate to afford 3,5-dimethyl-4-(3'-isopropyl-4'-methoxyphenoxy)-nitro benzene NMR (CDCl3): δ1.1 (6H,d), 2.2 (6H,s), 3.3 (1H,m), 3.7 (3H, s) 6.3 (1H,d of d), 6.6 (1H,d), 6.7 (1H, d), 8.0 (2H, s).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]([CH3:9])[C:4](=[O:10])[C:3]=1[C:11](=[O:25])[CH:12]=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][C:22]([NH2:24])=[O:23])[CH:15]=1.S(OC)(O[CH3:30])(=O)=O>>[CH3:30][O:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]([CH3:9])[C:4](=[O:10])[C:3]=1[C:11](=[O:25])[CH:12]=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][C:22]([NH2:24])=[O:23])[CH:15]=1
Reactant: COS(=O)(=O)OC
Reactant: Cc1cc(O)c(C(=O)C=Cc2cccc(OCC(N)=O)c2)c(=O)n1C
Product: COc1cc(C)n(C)c(=O)c1C(=O)C=Cc1cccc(OCC(N)=O)c1

Procedure:
According to the same manner as that of Example a-25 except that 0.78 g of 4-hydroxy-3-[3-[3-(aminocarbonylmethoxy)phenyl]-1-oxo-2-propenyl]-1,6-dimethyl-2(1H)-pyridinone was used in place of 4-hydroxy-3-[3-[3-(2-hydroxyethoxy)phenyl]-1-oxo-2-propenyl]-1,6-dimethyl-2(1H)-pyridinone, and 0.5 ml of dimethyl sulfate was used in place of iodomethane, 0.18 g of 4-methoxy-3-[3-[3-(aminocarbonylmethoxy)phenyl]-1-oxo-2-propenyl]-1,6-dimethyl-2(1H)-pyridinone [Compound No. (68a)] was obtained as a yellow crystal.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C@@H:11]([NH:23][C:24]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:12][NH:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH3:22])=[CH:2]1.C(N(CC)CC)C.[C:50](OC(=O)C)(=[O:52])[CH3:51]>O1CCCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C@@H:11]([NH:23][C:24]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:12][N:13]([C:50](=[O:52])[CH3:51])[CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH3:22])=[CH:2]1
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccccc1CNC[C@@H](Cc1c[nH]c2ccccc12)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccccc1CN(C[C@@H](Cc1c[nH]c2ccccc12)NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(C)=O
Reaction time: 4 h

Procedure:
To a stirring solution of (R)-3-(1H-indol-3-yl)-1-[N-(2-methoxybenzyl)amino]-2-(N-triphenylmethylamino)propane (0.404 mol) in anhydrous tetrahydrofuran (1.2 L) under a nitrogen atmosphere at 0° C. was added triethylamine (66.5 ml, 0.477 mol) and acetic anhydride (45.0 ml, 0.477 mol). After 4 hours, the mixture was concentrated on a rotary evaporator, redissolved in methylene chloride and ethyl acetate, washed with water (2×) and brine (2×), dried over anhydrous sodium sulfate, filtered, and concentrated to a solid on a rotary evaporator. The resulting solid was dissolved in chloroform and loaded onto silica gel 60 (230-400 mesh) and eluted with a 1:1 mixture of ethyl acetate and hexanes. The product was then crystallized from an ethyl acetate/hexanes mixture. The resulting product of (R)-3-(1H-indol-3-yl)-1-[N-(2-methoxybenzyl)acetylamino]-2-(N-triphenylmethylamino)propane was crystallized and isolated over three crops giving 203.97 grams (87% yield) of analytically pure material.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([OH:30])=O)=[CH:24][CH:23]=2)[CH:5]=[C:6]([Cl:21])[C:7]=1[CH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:10]1=[O:20].Cl.[F:32][C:33]([F:41])([F:40])[CH:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.CCN=C=NCCCN(C)C.Cl>ClCCl>[Cl:21][C:6]1[CH:5]=[C:4]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([N:37]3[CH2:38][CH2:39][CH:34]([C:33]([F:41])([F:40])[F:32])[CH2:35][CH2:36]3)=[O:30])=[CH:24][CH:23]=2)[CH:3]=[C:2]([Cl:1])[C:7]=1[CH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([CH:14]2[CH2:15][CH2:16][O:17][CH2:18][CH2:19]2)[C:10]1=[O:20]
Reactant: O=C(O)c1ccc(-c2cc(Cl)c(C[C@@H]3CCN(C4CCOCC4)C3=O)c(Cl)c2)cc1
Reactant: FC(F)(F)C1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: O=C(c1ccc(-c2cc(Cl)c(C[C@@H]3CCN(C4CCOCC4)C3=O)c(Cl)c2)cc1)N1CCC(C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 70.4 %

Procedure:
Treat a solution of 3′,5′-dichloro-4′-[(R)-2-oxo-1-(tetrahydro-pyran-4-yl)-pyrrolidin-3-ylmethyl]-biphenyl-4-carboxylic acid (0.25 g, 0.56 mmol), 4-(trifluoromethyl)piperidine hydrochloride (0.13 g, 0.67 mmol), 1-hydroxybenzotriazole (0.23 g, 0.67 mmol), and 4-methylmorpholine (0.18 mL, 1.67 mmol) in dichloromethane (10 mL) with N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (0.13 g, 0.67 mmol) and stir at room temperature for 6 hr. Quench the reaction with 1N hydrochloric acid and extract with ethyl acetate. Wash the organic layer with brine, dry over magnesium sulfate, and filter. Purify the crude material by silica gel column chromatography using hexanes:ethyl acetate to afford 0.23 g (72%) of desired product: MS (m/z): 583 (M+).
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[C:5](=[C:7]([C:19]#[N:20])[C:8]([CH3:18])=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:10]=2[F:11])[N:6]=1.[CH:21]([N:24](CC)C(C)C)(C)C.CN>ClCCl>[F:11][C:10]1[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:8]([CH3:18])[C:7]([C:19]#[N:20])=[C:5]2[C:4]=1[O:3][C:2]([NH:24][CH3:21])=[N:6]2
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(Cl)nc2c1C#N
Agent: CN
Solvent: ClCCl
Product: CNc1nc2c(C#N)c(C)c(-c3ccccc3)c(F)c2o1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
2-Chloro-7-fluoro-5-methyl-6-phenyl-1,3-benzoxazole-4-cabonitrile (I-130) (0.20 g, 0.70 mmol) was dissolved in dichloromethane (10 ml), then N,N-diisopropylethylamine (0.15 ml, 0.88 mmol), methylamine (2 M tetrahydrofuran solution, 0.50 ml, 1.00 mmol) were added. After stirring in a sealed tube at an external temperature of about 60° C. for 3 hours, this was diluted with dichloromethane.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[NH2:10])=[O:4].[CH2:11]([O:18][C:19]([N:21]1[CH2:26][CH2:25][C:24](=O)[CH2:23][CH2:22]1)=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Sn](CCCC)(CCCC)(Cl)Cl.C1([SiH3])C=CC=CC=1>C1COCC1>[CH2:11]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH:24]([NH:10][C:9]2[CH:8]=[CH:7][S:6][C:5]=2[C:3]([O:2][CH3:1])=[O:4])[CH2:23][CH2:22]1)=[O:20])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COC(=O)c1sccc1N
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Agent: CCCC[Sn](Cl)(Cl)CCCC
Agent: [SiH3]c1ccccc1
Solvent: C1CCOC1
Product: COC(=O)c1sccc1NC1CCN(C(=O)OCc2ccccc2)CC1
Yield: 101.4 %

Procedure:
Reductive amination of 3-amino-thiophene-2-carboxylic acid methyl ester (3.0 g, 19.1 mmol) and 4-oxo-piperidine-1-carboxylic acid benzyl ester (4.46 g, 19.1 mmol)in THF (4.6 mL) employing Bu2SnCl2 (0.598 g, 1.92 mmol) and PhSiH3 (2.58 mL, 21.6 mmol) was carried out as described for example 19, step I gave 4-(2-methoxycarbonyl-thiophen-3-ylamino)-piperidine-1-carboxylic acid benzyl ester (7.25 g, quantitative). NMR 1H (CDCl3, 400 MHz): 7.4-7.3 (m, 6H), 6.9-6.78 (m, 1H), 6.7-6.6 (m, 1H), 5.14 (s, 2H), 4.15-4.0 (m, 2H), 3.81 (s, 3H), 3.6-3.45 (m), 3.1 (brt, 2H), 2.1-1.9 (m, 2H), 1.6-1.45 (m, 2H).
Reaction SMILES: [CH3:1][C:2](C)([O-])[CH3:3].[K+].[Br:7][C:8]1[NH:9][C:10]([Br:16])=[C:11]([Br:15])[C:12]=1[C:13]#[N:14].C(I)C=C>>[CH2:3]([N:9]1[C:10]([Br:16])=[C:11]([Br:15])[C:12]([C:13]#[N:14])=[C:8]1[Br:7])[CH:2]=[CH2:1]
Reactant: N#Cc1c(Br)[nH]c(Br)c1Br
Reactant: CC(C)(C)[O-]
Agent: C=CCI
Agent: [K+]
Product: C=CCn1c(Br)c(Br)c(C#N)c1Br
Yield: 93.3 %

Procedure:
Potassium t-butoxide (0.75 g, 6.7 mmol) is added portionwise at room temperature to a solution of 2,4,5-tribromopyrrole-3-carbonitrile (2.0 g, 6.1 mmol) in anhydrous tetrafuran (20 mL). After 30 minutes allyl iodide (1.12 g, 6.7 mmol) is added dropwise and then refluxed for 2 hours. Work-up as described in Example 15 gives the product as a pale pink liquid (2.1 g).
Reaction SMILES: Br[C:2]1[C:3](=[O:19])[C:4]([CH3:18])([CH3:17])[O:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=1.[S:20]1[C:24](B(O)O)=[CH:23][C:22]2[CH:28]=[CH:29][CH:30]=[CH:31][C:21]1=2>>[S:20]1[C:24]([C:2]2[C:3](=[O:19])[C:4]([CH3:18])([CH3:17])[O:5][C:6]=2[C:7]2[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=2)=[CH:23][C:22]2[CH:28]=[CH:29][CH:30]=[CH:31][C:21]1=2
Reactant: CC1(C)OC(c2ccc(S(C)(=O)=O)cc2)=C(Br)C1=O
Reactant: OB(O)c1cc2ccccc2s1
Product: CC1(C)OC(c2ccc(S(C)(=O)=O)cc2)=C(c2cc3ccccc3s2)C1=O
Yield: 26 %

Procedure:
200 mg of 4-bromo-2,2-dimethyl-5-{4-(methylsulfonyl)phenyl}-3(2H)-furanone was coupled with 125 mg of (2-benzo[b]thienyl)boronic acid according to a procedure similar to the procedure in Example 2 to afford 60 mg of 4-(2-benzo[b]thienyl)-2,2-dimethyl-5-{4-(methylsulfonyl)phenyl}-3(2H)-furanone as a solid. mp: 204-206° C. NMR: δ1.61 (s, 6H), 3.11 (s, 3H), 7.32˜7.43 (m, 4H), 7.51˜7.53 (m, 1H), 7.74˜7.84 (m, 2H), 8.01 (s, 2H). IR (cm−1): 1702, 1620, 1382, 1147, 957, 750.
Reaction SMILES: [Na].[C:2]([C:4]([C:11]#[N:12])=[C:5]([NH:8][C:9]#[N:10])[S:6][CH3:7])#[N:3].[ClH:13]>C(OCC)C>[NH2:10][C:9]1[N:3]=[C:2]([Cl:13])[C:4]([C:11]#[N:12])=[C:5]([S:6][CH3:7])[N:8]=1
Reactant: CSC(NC#N)=C(C#N)C#N
Reactant: Cl
Agent: [Na]
Solvent: CCOCC
Product: CSc1nc(N)nc(Cl)c1C#N
Temperature: 25 °C

Procedure:
The compound of formula (56), the sodium salt of 2,2-dicyano-1-methylsulfanyl-vinyl-cyanamide, is reacted by addition to a large excess of anhydrous hydrogen chloride in an ethereal solvent, preferably diethyl ether, at 0° C. and the mixture is allowed to warm slowly to room temperature for over 1-36 hours, preferably 18 hours. The product of formula (57), 2-amino-4-chloro-6-methylsulfanyl-pyrimidine-5-carbonitrile, is isolated by conventional means, and preferably purified by means of recrystallisation or chromatography. Alternatively, the compound of formula (56), the sodium salt of 2,2-dicyano-1-methylsulfanyl-vinyl-cyanamide, is reacted with hydrogen bromide in a protic solvent, preferably acetic acid, at 5° C. and the mixture is allowed to warm slowly to room temperature for over 1-36 hours, preferably 1 hour. The product of formula (57), 2-amino-4-bromo-6-methylsulfanyl-pyrimidine-5-carbonitrile, is isolated by conventional means, and preferably purified by means of recrystallisation or chromatography.
Reaction SMILES: COC(C1C=C(OC2C=CC(S(C)(=O)=O)=CC=2)C=C2OC(C)CC=12)=O.[C:26]([O:30][C:31]([C:33]1[CH:44]=[C:43]([OH:45])[C:36]2[CH2:37][C:38]([CH2:41][OH:42])([CH3:40])[O:39][C:35]=2[CH:34]=1)=[O:32])([CH3:29])([CH3:28])[CH3:27].[CH:46]1([S:49]([C:52]2[CH:57]=[CH:56][C:55](F)=[CH:54][CH:53]=2)(=[O:51])=[O:50])[CH2:48][CH2:47]1>>[C:26]([O:30][C:31]([C:33]1[CH:44]=[C:43]([O:45][C:55]2[CH:56]=[CH:57][C:52]([S:49]([CH:46]3[CH2:48][CH2:47]3)(=[O:50])=[O:51])=[CH:53][CH:54]=2)[C:36]2[CH2:37][C:38]([CH2:41][OH:42])([CH3:40])[O:39][C:35]=2[CH:34]=1)=[O:32])([CH3:27])([CH3:28])[CH3:29]
Reactant: CC(C)(C)OC(=O)c1cc(O)c2c(c1)OC(C)(CO)C2
Reactant: O=S(=O)(c1ccc(F)cc1)C1CC1
Agent: COC(=O)c1cc(Oc2ccc(S(C)(=O)=O)cc2)cc2c1CC(C)O2
Product: CC(C)(C)OC(=O)c1cc(Oc2ccc(S(=O)(=O)C3CC3)cc2)c2c(c1)OC(C)(CO)C2

Procedure:
The title compound was prepared in a similar manner as described for Intermediate 1f, from 4-hydroxy-2-hydroxymethyl-2-methyl-2,3-dihydro-benzofuran-6-carboxylic acid tert-butyl ester (227c) and 1-cyclopropanesulfonyl-4-fluoro-benzene. 1H NMR (400 MHz, CDCl3) δ 7.86 (d, J=8.59 Hz, 2 H) 7.23 (s, 1H) 7.07 (d, J=8.59 Hz, 2 H) 3.73 (dd, J=11.87, 5.81 Hz, 1 H) 3.62 (d, J=7.58 Hz, 1 H) 3.16 (d, J=16.67 Hz, 1 H) 2.78 (d, J=16.67 Hz, 1 H) 2.48 (td, J=8.02, 4.67 Hz, 1 H) 1.55-1.58 (m, 12H) 1.45 (s, 2 H) 1.36 (dd, J=4.67, 1.89 Hz, 2 H) 0.97-1.13 (m, 2 H); LCMS for C24H27O7S m/z 460.80 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([O:23][CH3:24])=[CH:11][C:12]([C:17]2[N:21]=[C:20]([CH3:22])[O:19][N:18]=2)=[C:13]([CH:16]=1)[CH:14]=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25]1([Mg]Br)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[Cl-].[NH4+].Cl>C(OCC)(=O)C.O1CCCC1>[CH2:1]([O:8][C:9]1[C:10]([O:23][CH3:24])=[CH:11][C:12]([C:17]2[N:21]=[C:20]([CH3:22])[O:19][N:18]=2)=[C:13]([CH:14]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[OH:15])[CH:16]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Br[Mg]c1ccccc1
Reactant: COc1cc(-c2noc(C)n2)c(C=O)cc1OCc1ccccc1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(-c2noc(C)n2)c(C(O)c2ccccc2)cc1OCc1ccccc1
Reaction time: 0.5 h

Procedure:
To a mixture of 5-benzyloxy-4-methoxy-2-(5-methyl-[1,2,4]oxadiazol-3-yl)benzaldehyde (reference example 15-1) (450 mg) and tetrahydrofuran (5.6 mL) was added dropwise phenylmagnesium bromide (1.08 mol/L tetrahydrofuran solution, 1.4 mL) in an ice salt bath. After stirring at the same temperature for 30 minutes, an aqueous solution of ammonium chloride, 2 mol/L hydrochloric acid and ethyl acetate were added to the mixture. The separated organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (564 mg).