Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[Cl:29])=[N:4][C:5]([NH:8][CH2:9][CH2:10][NH:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[C:14]([NH2:21])[N:13]=2)=[N:6][CH:7]=1.[CH3:30][N:31]([CH2:36][C:37](O)=[O:38])[CH2:32][C:33](O)=[O:34].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>>[NH2:21][C:14]1[N:13]=[C:12]([NH:11][CH2:10][CH2:9][NH:8][C:5]2[N:4]=[C:3]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[Cl:29])[C:2]([N:1]3[C:37](=[O:38])[CH2:36][N:31]([CH3:30])[CH2:32][C:33]3=[O:34])=[CH:7][N:6]=2)[CH:17]=[CH:16][C:15]=1[N+:18]([O-:20])=[O:19]
Reactant: Nc1cnc(NCCNc2ccc([N+](=O)[O-])c(N)n2)nc1-c1ccc(Cl)cc1Cl
Reactant: CN(CC(=O)O)CC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CN1CC(=O)N(c2cnc(NCCNc3ccc([N+](=O)[O-])c(N)n3)nc2-c2ccc(Cl)cc2Cl)C(=O)C1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
1 mmol of [5-amino-4-(2,4-dichlorophenyl)pyrimidin-2-yl]{2-[(6-amino-5-nitro(2-pyridyl))amino]ethyl}amine, and 2 mmol of methyliminodiacetic acid, 4 mmol of HBTU, and 5 mmol of N,N-diisopropylethylamine were added to solution and stirred for six hours at room temperature. The reaction mixture was concentrated in vacuo and diluted with water and ethyl acetate. The solution was extracted three times with ethyl acetate, dried over sodium sulfate, and purified by column chromatography eluting with 5-10% methanol/methylene chloride to obtain 1-[2-({2-[(6-amino-5-nitro(2-pyridyl))amino]ethyl}amino)-4-(2,4-dichlorophenyl)pyrimidin-5-yl]-4-methylpiperazine-2,6-dione.
Reaction SMILES: [CH2:1]([S:13]([CH2:16][CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27](=[O:32])[C:28]([F:31])([F:30])[F:29])=[CH:21][CH:20]=1)(=[O:15])=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(N(CC)CC)C.[C:40](OC(=O)C)(=[O:42])[CH3:41]>ClCCl.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[CH2:1]([S:13]([CH2:16][CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25]/[CH:26]=[C:27](\[O:32][C:40](=[O:42])[CH3:41])/[C:28]([F:29])([F:30])[F:31])=[CH:21][CH:20]=1)(=[O:14])=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCS(=O)(=O)CCOc1ccc(CCC(=O)C(F)(F)F)cc1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCS(=O)(=O)CCOc1ccc(C/C=C(\OC(C)=O)C(F)(F)F)cc1
Temperature: -25 °C
Reaction time: 2.5 h
Yield: 78.5 %

Procedure:
A solution of 4-[4-[2-(dodecylsulfonyl)ethoxy]phenyl]-1,1,1-trifluoro-2-butanone (1.10 g, 2.30 mmol) in dichloromethane (15 ml) was cooled to −25° C. and treated with triethylamine (0.5 ml) and 4-dimethylaminopyridine (0.560 g, 4.58 mmol). Then acetic anhydride (0.65 ml, 6.9 mmol) was added and the resulting mixture was stirred at −25° C. for 2.5 h. The solution was then diluted with ethyl acetate, washed with saturated sodium bicarbonate, dried (magnesium sulfate) and evaporated in vacuo. The residue was chromatographed on silica gel (elution toluene-ethyl acetate, 9:1) to give 0.94 g (78%) of a solid which was recrystallized from hexane to give white crystals: mp 48-49° C.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[N:9]=[C:10]3[C:15]([NH:16][C@H:17]4[C@@H:21]([CH2:22][CH3:23])[CH2:20][NH:19][CH2:18]4)=[C:14]([C:24]([NH2:26])=[O:25])[CH:13]=[N:12][N:11]3[CH:27]=2)[CH:5]=[N:4]1)[CH3:2].C(O)(C(F)(F)F)=O.[C:35](C1(C(O)=O)CC1)#[N:36].CN(C(ON1N=N[C:53]2[CH:54]=[CH:55][CH:56]=[N:57][C:52]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:35]([C:53]1[CH:54]=[CH:55][C:56]([N:19]2[CH2:20][C@H:21]([CH2:22][CH3:23])[C@H:17]([NH:16][C:15]3[C:10]4[N:11]([CH:27]=[C:8]([C:6]5[CH:5]=[N:4][N:3]([CH2:1][CH3:2])[CH:7]=5)[N:9]=4)[N:12]=[CH:13][C:14]=3[C:24]([NH2:26])=[O:25])[CH2:18]2)=[N:57][CH:52]=1)#[N:36]
Reactant: CC[C@H]1CNC[C@H]1Nc1c(C(N)=O)cnn2cc(-c3cnn(CC)c3)nc12
Reactant: N#CC1(C(=O)O)CC1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC[C@H]1CN(c2ccc(C#N)cn2)C[C@H]1Nc1c(C(N)=O)cnn2cc(-c3cnn(CC)c3)nc12
Yield: 76 %

Procedure:
A solution of 2-(1-ethyl-1H-pyrazol-4-yl)-8-(((3S,4S)-4-ethylpyrrolidin-3-yl)amino)imidazo[1,2-b]pyridazine-7-carboxamide, TFA (11 mg, 0.023 mmol), 1-cyanocyclopropanecarboxylic acid (5.07 mg, 0.046 mmol), HATU (13.00 mg, 0.034 mmol) and DIPEA (0.020 ml, 0.114 mmol) in DMF (0.4 ml) was stirred at room temperature for 45 min. The crude material was purified via preparative LC/MS (preparative LC/MS Method A). Fractions containing the desired product were combined and dried via centrifugal evaporation to afford the title compound of Example 36 (8 mg, 0.017 mmol, 76% yield). 1H NMR (500 MHz, methanol-d4, 2 rotamers) δ 8.52 (d, J=7.4 Hz, 2H), 8.17 (s, 1H), 8.12 (d, J=2.5 Hz, 2H), 8.10 (s, 1H), 8.05 (d, J=5.0 Hz, 2H), 6.20 (t, J=4.2 Hz, 1H), 6.19-6.16 (m, 1H), 4.57 (dd, J=11.4, 5.0 Hz, 1H), 4.51-4.46 (m, 1H), 4.45-4.38 (m, 6H), 4.07-4.02 (m, 2H), 3.97 (t, J=10.9 Hz, 1H), 3.59 (t, J=11.4 Hz, 1H), 2.84-2.75 (m, 1H), 2.73-2.65 (m, 1H), 2.03-1.98 (m, 1H), 1.96-1.81 (m, 4H), 1.81-1.73 (m, 4H), 1.73-1.63 (m, 8H), 1.62-1.58 (m, 1H), 1.21 (t, J=7.4 Hz, 3H), 1.18 (t, J=7.4 Hz, 3H). HPLC/LCMS (Method F): m/z 461.20 ([M+H]+), Rt. 1.30 min.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:17]([I:18])=[CH:16][NH:15][C:4]=2[N:5]=[C:6]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[N:7]=1.Cl[CH2:20][C:21]1[C:26]([CH3:27])=[C:25]([O:28][CH3:29])[C:24]([CH3:30])=[CH:23][N+:22]=1[O-:31].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[Cl:1][C:2]1[C:3]2[C:17]([I:18])=[CH:16][N:15]([CH2:20][C:21]3[C:26]([CH3:27])=[C:25]([O:28][CH3:29])[C:24]([CH3:30])=[CH:23][N+:22]=3[O-:31])[C:4]=2[N:5]=[C:6]([NH:8][C:9](=[O:14])[C:10]([CH3:11])([CH3:12])[CH3:13])[N:7]=1
Reactant: CC(C)(C)C(=O)Nc1nc(Cl)c2c(I)c[nH]c2n1
Reactant: COc1c(C)c[n+]([O-])c(CCl)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1c(C)c[n+]([O-])c(Cn2cc(I)c3c(Cl)nc(NC(=O)C(C)(C)C)nc32)c1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 36.7 %

Procedure:
A mixture of N-(4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-2-yl)pivalamide (235 mg), 2-(chloromethyl)-4-methoxy-3,5-dimethylpyridine 1-oxide (129 mg), and K2CO3 (413 mg) in DMF (6.0 mL) was stirred at rt for 3 days, and diluted with water. The precipitate was collected by filtration and washed with IPA to give 2-((4-chloro-5-iodo-2-pivalamido-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-4-methoxy-3,5-dimethylpyridine 1-oxide (124 mg).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:15]1(B(O)O)[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]=1>>[C:15]1([C:12]2[CH:13]=[C:8]([CH2:7][N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)[CH:9]=[CH:10][C:11]=2[NH2:14])[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]=1
Reactant: Nc1ccc(CN2CCOCC2)cc1
Reactant: OB(O)C1=CCCCC1
Product: Nc1ccc(CN2CCOCC2)cc1C1=CCCCC1

Procedure:
This compound was prepared from 4-morpholin-4-ylmethyl-phenylamine by brominating according to the procedure in Example 33, step (b), followed by Suzuki coupling to 1-cyclohexen-1-yl-boronic acid according to the procedure in Example 1, step (e). Mass spectrum (ESI, m/z): Calcd. for C17H24N2O, 273.2 (M+H). found 272.7
Reaction SMILES: C(O[C:4]([C:6]1[NH:7][CH:8]=[CH:9][C:10]=1[NH:11][CH2:12][CH2:13][O:14][CH:15]([CH3:17])[CH3:16])=[O:5])C.C(OC([N:23]=[C:24]=[S:25])=O)C>>[CH:15]([O:14][CH2:13][CH2:12][N:11]1[C:10]2[CH:9]=[CH:8][NH:7][C:6]=2[C:4](=[O:5])[NH:23][C:24]1=[S:25])([CH3:16])[CH3:17]
Reactant: CCOC(=O)c1[nH]ccc1NCCOC(C)C
Reactant: CCOC(=O)N=C=S
Product: CC(C)OCCn1c(=S)[nH]c(=O)c2[nH]ccc21
Yield: 23.1 %

Procedure:
The title compound (0.17 g, 23%) was prepared in accordance with the general method B using 3-[(2-isopropoxyethyl)amino]-1H-pyrrole-2-carboxylic acid ethyl ester (0.7 g, 2.91 mmol) and ethoxycarbonyl isothiocyanate (0.40 mL, 3.50 mmol).
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)=[O:4].[O:12]=[C:13]([O:31][C@@H:32]1[CH:37]2[CH2:38][CH2:39][N:34]([CH2:35][CH2:36]2)[CH2:33]1)[CH:14]([NH:21][C:22]1[CH:26]=[CH:25][S:24][C:23]=1[C:27]([O:29][CH3:30])=[O:28])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CCOCC>C(#N)C>[Br-:1].[OH:11][C:8]1[CH:9]=[CH:10][C:5]([C:3](=[O:4])[CH2:2][N+:34]23[CH2:39][CH2:38][CH:37]([CH2:36][CH2:35]2)[C@@H:32]([O:31][C:13](=[O:12])[CH:14]([NH:21][C:22]2[CH:26]=[CH:25][S:24][C:23]=2[C:27]([O:29][CH3:30])=[O:28])[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:33]3)=[CH:6][CH:7]=1
Reactant: O=C(CBr)c1ccc(O)cc1
Reactant: COC(=O)c1sccc1NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Solvent: CC#N
Solvent: CCOCC
Product: COC(=O)c1sccc1NC(C(=O)O[C@H]1C[N+]2(CC(=O)c3ccc(O)cc3)CCC1CC2)c1ccccc1
Product: [Br-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.2 %

Procedure:
2-Bromo-1-(4-hydroxyphenyl)ethanone (19.9 mg, 0.09 mmol) was added to a solution of methyl 3-(2-oxo-1-phenyl-2-((R)-quinuclidin-3-yloxy)ethylamino)thiophene-2-carboxylate (C11) (37 mg, 0.09 mmol) in acetonitrile (2 ml). The reaction mixture was stirred at room temperature overnight, and then Et2O (1 ml) was added and the product was collected by suction filtration to obtain (3R)-1-(2-(4-hydroxyphenyl)-2-oxoethyl)-3-(2-(2-(methoxycarbonyl)thiophen-3-ylamino)-2-phenylacetoxy)-1-azoniabicyclo[2.2.2]octane bromide (36.7 mg, 64.5% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH3:12])[N:8]=[CH:7][N:6](/[CH:13]=[CH:14]/[C:15]([OH:17])=O)[C:5]2=[O:18].S(Cl)(Cl)=O.[N:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][CH2:30][CH2:31][CH2:32][NH2:33])[CH:24]=1>>[CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH3:12])[N:8]=[CH:7][N:6](/[CH:13]=[CH:14]/[C:15]([NH:33][CH2:32][CH2:31][CH2:30][CH2:29][C:25]1[CH:24]=[N:23][CH:28]=[CH:27][CH:26]=1)=[O:17])[C:5]2=[O:18]
Reactant: Cc1cc2ncn(/C=C/C(=O)O)c(=O)c2cc1C
Reactant: NCCCCc1cccnc1
Solvent: O=S(Cl)Cl
Product: Cc1cc2ncn(/C=C/C(=O)NCCCCc3cccnc3)c(=O)c2cc1C

Procedure:
The acid chloride is prepared from (E)-3-(6,7-dimethyl-4-oxo-4H-quinazolin-3-yl]-2-propenoic acid and thionyl chloride as previously described. When this acid chloride is allowed to react with 3-pyridine butanamine under the usual conditions, (E)-3-(6,7-dimethyl-4-oxo-4H-quinazolin-3-yl)-N-[4-(3-pyridinyl)butyl]-2-propenamide is obtained.
Reaction SMILES: [C:1]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][C:4]([NH:7][C:8](=[O:13])[CH2:9][C:10]([OH:12])=O)=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[Br:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=1[S:59][CH:60]1[CH2:65][CH2:64][NH:63][CH2:62][CH2:61]1>CN(C=O)C.O>[C:1]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:2]=[CH:3][C:4]([NH:7][C:8](=[O:13])[CH2:9][C:10]([N:63]2[CH2:62][CH2:61][CH:60]([S:59][C:54]3[CH:55]=[CH:56][CH:57]=[CH:58][C:53]=3[Br:52])[CH2:65][CH2:64]2)=[O:12])=[CH:5][CH:6]=1
Reactant: Brc1ccccc1SC1CCNCC1
Reactant: O=C(O)CC(=O)Nc1ccc(-c2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CC(=O)N1CCC(Sc2ccccc2Br)CC1)Nc1ccc(-c2ccccc2)cc1
Reaction time: 8 h
Yield: 50.9 %

Procedure:
To a stirred solution of N-biphenyl-4-yl-malonamic acid (0.15 g, 0.00059 mole) in DMF (4 mL) was added DIPEA (0.226 g, 0.00176 mole), HOBt (0.095 g, 0.00071 mole) and EDCI.HCl (0.134 g, 0.00071 mole). After 2 minutes 4-(2-bromo-phenylsulfanyl)-piperidine hydrochloride (0.21 g, 0.00071 mole) was added and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water and the resulting precipitate was isolated by filtration. Purification by column chromatography using silica gel 60-120 mesh (60% ethyl acetate in hexane) afforded 0.153 g (51%) of N-biphenyl-4-yl-3-[4-(2-bromo-phenylsulfanyl)-piperidin-1-yl]-3-oxo-propionamide. LC-MS purity: 509.08 (M+1)+, 87.3%, 1H NMR (DMSO-d6): δ 10.2 (s, 1H), 7.82-7.6 (m, 6H), 7.48-7.36 (m, 3H), 7.36-7.28 (m, 1H), 7.22-7.12 (m, 1H), 5.6-5.2 (d, 1H), 4.25 (d, 1H), 3.7 (m, 1H), 3.55 (s, 2H), 2.95 (m, 1H), 2.0 (m, 2H), 1.7-1.5 (m, 1H), 1.5-1.35 (m, 1H).
Reaction SMILES: C(N(CC)CC)C.Cl.[NH:9]1[CH2:16][CH2:15][CH2:14][C@H:10]1[C:11]([NH2:13])=[O:12].[C:17](Cl)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(Cl)(Cl)Cl.ClCCl>[C:17]([N:9]1[CH2:16][CH2:15][CH2:14][C@@H:10]1[C:11]([NH2:13])=[O:12])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: NC(=O)[C@@H]1CCCN1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: NC(=O)[C@H]1CCCN1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 92.9 %

Procedure:
Under cold conditions (ice bath) and under an inert atmosphere, 10 ml of triethylamine (69.7 mmol) are added to 5 g (33.2 mmol) of prolinamide hydrochloride suspended in chloroform (50 ml), and 9.7 g (34.9 mmol) of trityl chloride are then added portionwise. The reaction mixture is stirred at room temperature for 2 days. The reaction mixture is dissolved in dichloromethane (200 ml) and washed successively twice with HCl solution (1N) (150 ml), with water (150 ml), with saturated NaHCO3 solution (150 ml) and with saturated NaCl solution (150 ml). The organic phase is dried (Na2SO4), filtered and evaporated under reduced pressure. The residue is recrystallized from 20 ml of hot ethanol, to give 11 g of compound in the form of white crystals. Yield=93%. Melting point: 162° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O>N1C=CC=CC=1>[Br:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]#[N:6]
Reactant: NC(=O)c1ccc(F)cc1Br
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Product: N#Cc1ccc(F)cc1Br
Reaction time: 2 h

Procedure:
A solution of 10.9 g. (0.05 mole) of 2-bromo-4-fluorobenzamide in 50 ml. of dry pyridine is stirred and cooled in an ice-bath while 11.2 g. (0.0525 mole) of trifluoroacetic anhydride is added dropwise. After 2 hours at room temperature, the bulk of the solvent is evaporated under reduced pressure and the residue is dissolved in ether. Evaporation of the washed and dried ethereal extract under reduced pressure leaves the product as the residual solid. Sublimation at 55° C. and 0.05 mm. yields white crystals, m.p. 75°-76.5° C. A sample from a previous experiment was resublimed for analysis, m.p. 77°-78° C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[S:35])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[C:22](=[O:26])[N:21]([C@@H:27]([CH:32]([CH3:34])[CH3:33])[C:28]([O:30][CH3:31])=[O:29])[CH2:20]3)=[CH:13][CH:12]=1.[NH2:36][C:37]1C=CC(C2C=C3C(=CC=2)C(=O)N([C@@H](C(C)C)C(OC)=O)C3)=CC=1.C(C1C=CC(N=C=S)=CC=1)#N>>[C:37]([C:6]1[CH:5]=[CH:4][C:3]([NH:8][C:9](=[S:35])[NH:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[C:22](=[O:26])[N:21]([C@@H:27]([CH:32]([CH3:33])[CH3:34])[C:28]([O:30][CH3:31])=[O:29])[CH2:20]4)=[CH:15][CH:16]=2)=[CH:2][CH:7]=1)#[N:36]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(NC(=S)Nc4ccccc4F)cc3)ccc2C1=O
Reactant: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(N)cc3)ccc2C1=O
Agent: N#Cc1ccc(N=C=S)cc1
Product: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(NC(=S)Nc4ccc(C#N)cc4)cc3)ccc2C1=O

Procedure:
The compound of example 268 was prepared analogous to compound of example 256 by reaction of compound of example 223 with 4-cyanophenyl isothiocyanate. The compound of example 268 was used directly without isolation for the preparation of compound of example 269.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[C:3]1[CH:4]=[C:5]([NH:9][C:10]2[CH:15]=[C:14]([NH:16][CH3:17])[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1.[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=1[N:27]=[C:28]=[O:29]>CN(C)C=O>[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=1[NH:27][C:28](=[O:29])[N:16]([C:14]1[CH:15]=[C:10]([NH:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([N:2]([CH3:1])[CH3:18])[CH:4]=2)[N:11]=[CH:12][N:13]=1)[CH3:17]
Reactant: O=C=Nc1c(Cl)cccc1Cl
Reactant: CNc1cc(Nc2cccc(N(C)C)c2)ncn1
Solvent: CN(C)C=O
Product: CN(C)c1cccc(Nc2cc(N(C)C(=O)Nc3c(Cl)cccc3Cl)ncn2)c1
Temperature: 90 °C
Reaction time: 14 h

Procedure:
A mixture of N-(3-dimethylamino-phenyl)-N′-methyl-pyrimidine-4,6-diamine (243.3 mg, 1 mmol), 2,6-dichlorophenyl isocyanate (188 mg, 1 mmol) in dry dimethylformamide (2.5 mL) is shaken for 14 h at 90° C. Two additional portions (188 mg, 1 mmol each) of 2,6-dichlorophenyl isocyanate are added after 14 h and 26 h. After 38 h the reaction mixture is evaporated in vacuo and the residue is distributed between ethyl acetate and half-saturated K2CO3 solution. The organic layer is dried over Na2SO4, evaporated, and the residue purified by flash chromatography (hexane/ethyl acetate). The combined pure fractions are evaporated, the residue triturated with CH2Cl2 and the solid filtered off and dried in vacuo to afford the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:11][C:10]=1[C:19]([CH3:23])([CH3:22])[CH:20]=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].Cl>CO>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([CH3:18])([CH3:16])[CH3:17])=[CH:11][C:10]=1[C:19]([CH3:23])([CH3:22])[CH2:20][OH:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)c1ccc(OCc2ccccc2)c(C(C)(C)C=O)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)c1ccc(OCc2ccccc2)c(C(C)(C)CO)c1
Temperature: 20 °C
Reaction time: 3 h

Procedure:
To a stirred solution of compound 8 (9.21 g, 0.030 mol) in MeOH (150 mL) was added slowly NaBH4 (2.3 g, 0.061 mol) at 0° C. After the mixture was stirred at 20° C. for 3 hours, 12 mL of 6N HCl was added, and the mixture was stirred for an additional 30 minutes. The solution was then concentrated to about one-quarter of the original volume and extracted with EtOAc. The organic layer was separated and washed with water and brine, dried with Na2SO4, filtered, and then concentrated in vacuo to afford compound 9 as a white solid. 1H NMR (DMSO-d6; 400 MHz) δ 7.47 (m), δ 7.42 (m), δ 7.34 (m), δ 7.28 (m), δ 7.16 (m), δ 6.94 (m), δ 5.08 (s), δ 4.45 (t), δ 3.64 (d), δ 1.28 (s), δ 1.25 (s).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[C:14]=1[CH2:22][C:23]([O-])=[O:24].Cl>C1(C)C=CC=CC=1.O1CCCC1>[CH3:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[C:14]=1[CH2:22][CH2:23][OH:24]
Reactant: COc1cccc([N+](=O)[O-])c1CC(=O)[O-]
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COc1cccc([N+](=O)[O-])c1CCO
Temperature: 0 °C
Reaction time: 1 h
Yield: 94.6 %

Procedure:
Diisobutylaluminium hydride (20 wt %; 2.38 g, 16.8 mmol) in toluene was added to a solution of 2-(2-methoxy-6-nitro-phenyl)acetate (1.0 g, 4.18 mmol) in tetrahydrofuran (8 mL) at −5° C. The reaction mixture was stirred at 0° C. for 1 h and then poured into 1N hydrochloric acid. The mixture was extracted with ethyl acetate (30 mL) and the separated organic phase was washed with water (2×30 mL), brine (25 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to afford 2-(2-methoxy-6-nitro-phenyl)ethanol (780 mg, 94%).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH3:10][O:11][CH2:12]Cl.[Si:14]([O:31][CH2:32][CH2:33][C@@H:34]([OH:55])[C@H:35]([C:46]1[CH:51]=[C:50]([F:52])[C:49]([F:53])=[C:48]([F:54])[CH:47]=1)[C:36]([O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:37])([C:27]([CH3:30])([CH3:29])[CH3:28])([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>ClCCCl>[Si:14]([O:31][CH2:32][CH2:33][C@@H:34]([O:55][CH2:10][O:11][CH3:12])[C@H:35]([C:46]1[CH:51]=[C:50]([F:52])[C:49]([F:53])=[C:48]([F:54])[CH:47]=1)[C:36]([O:38][CH2:39][C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)=[O:37])([C:27]([CH3:30])([CH3:29])[CH3:28])([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COCCl
Reactant: CC(C)(C)[Si](OCC[C@@H](O)[C@@H](C(=O)OCc1ccccc1)c1cc(F)c(F)c(F)c1)(c1ccccc1)c1ccccc1
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCO[C@H](CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)[C@@H](C(=O)OCc1ccccc1)c1cc(F)c(F)c(F)c1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
IPEA (0.742 mL) and chloromethyl methyl ether (0.324 mL) were added to a solution of benzyl (2S,3R)-5-(tert-butyldiphenylsilanyloxy)-3-hydroxy-2-(3,4,5-trifluorophenyl)pentanoate (840 mg) in 1,2-dichloroethane (20 mL) at 0° C. The reaction solution was stirred at 60° C. for 4 hours and then left to cool to room temperature and concentrated under reduced pressure. Ethyl acetate and a saturated ammonium chloride solution were added to the residue, and the organic layer was separated. The resulting organic layer was washed with brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain 875 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [CH2:1]([C:8]1[C:13](I)=[CH:12][CH:11]=[C:10]([N:15]2[CH2:19][C@@H:18]([O:20][CH3:21])[C@H:17]([OH:22])[CH2:16]2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]([C@:25]1([OH:33])[CH:30]2[CH2:31][CH2:32][N:27]([CH2:28][CH2:29]2)[CH2:26]1)#[CH:24].C(N(CC)CC)C>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.CN(C)C=O>[CH2:1]([C:8]1[C:13]([C:24]#[C:23][C@:25]2([OH:33])[CH:30]3[CH2:31][CH2:32][N:27]([CH2:28][CH2:29]3)[CH2:26]2)=[CH:12][CH:11]=[C:10]([N:15]2[CH2:19][C@@H:18]([O:20][CH3:21])[C@H:17]([OH:22])[CH2:16]2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C#C[C@@]1(O)CN2CCC1CC2
Reactant: CO[C@@H]1CN(c2ccc(I)c(Cc3ccccc3)n2)C[C@H]1O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CO[C@@H]1CN(c2ccc(C#C[C@@]3(O)CN4CCC3CC4)c(Cc3ccccc3)n2)C[C@H]1O
Reaction time: 3 h
Yield: 34.8 %

Procedure:
A mixture of 4.19 g of 2-benzyl-3-iodo-6-[(3R,4R)-3-hydroxy-4-methoxypyrrolidine-1-yl]pyridine, 1.7 g of (3R)-3-ethynyl-3-quinuclidinol, 500 mg of tetrakis(triphenylphosphine)palladium(0), 10 mg of cuprous iodide, 4.2 ml of triethylamine and 13 ml of N,N-dimethylformamide was heated under stirring in an oil bath kept at 70° C. for 3 hours in a nitrogen atmosphere. After cooling as it was, the mixture was extracted with ethyl acetate-dilute aqueous ammonia. The organic phase was washed with water and brine, dried over anhydrous magnesium sulfate and evaporated. The residue was subjected to NH-silica gel column chromatography and eluted with 20-100% ethyl acetate/hexane and then with 5% methanol/ethyl acetate, to give 1.54 g of the target compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]1[C:17]2[CH2:16][CH:15]([C:18]([O:20]CC)=[O:19])[N:14]([C:23](=[O:37])[CH:24]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:13][C:12]=2[N:11]=[CH:10]1.[OH-].[Na+]>C1COCC1.CO.Cl.CO.O>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]1[C:17]2[CH2:16][CH:15]([C:18]([OH:20])=[O:19])[N:14]([C:23](=[O:37])[CH:24]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:13][C:12]=2[N:11]=[CH:10]1
Reactant: CCOC(=O)C1Cc2c(ncn2Cc2ccccc2O)CN1C(=O)C(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)C1Cc2c(ncn2Cc2ccccc2O)CN1C(=O)C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of the product from Example 16 (2.35 g) in 25 mL THF-methanol (2:1) is treated with 10 mL 1N NaOH, stirring 90 min at 25° C. After treatment with 10 mL 1N HCl, the mixture is diluted with 60 mL methanol-water (2:1) and concentrated in vacuo until a thick slurry forms. The slurry is diluted with water and the desired carboxylic acid is collected by filtration. MS (FAB) 468 (M+1); mp 187°-190° C.