Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11](/[CH:14]=[C:15]3/[C:16](=[O:22])[N:17]=[C:18](SC)[S:19]/3)[CH:12]=2)[N:7]=[CH:6][C:5]=1[C:23]#[N:24])[CH3:2].[N:25]1[CH:30]=[CH:29][N:28]=[CH:27][C:26]=1[CH2:31][NH2:32].CCN(C(C)C)C(C)C>>[CH2:1]([O:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11](/[CH:14]=[C:15]3/[C:16](=[O:22])[N:17]=[C:18]([NH:32][CH2:31][C:26]4[CH:27]=[N:28][CH:29]=[CH:30][N:25]=4)[S:19]/3)[CH:12]=2)[N:7]=[CH:6][C:5]=1[C:23]#[N:24])[CH3:2]
Reactant: NCc1cnccn1
Reactant: CCOc1c(C#N)cnc2ccc(/C=C3\SC(SC)=NC3=O)cc12
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1c(C#N)cnc2ccc(/C=C3\SC(NCc4cnccn4)=NC3=O)cc12

Procedure:
Similar procedure as described in example 14h was used, starting from 4-ethoxy-6-[2-methylsulfanyl-4-oxo-4H-thiazol-(5Z)-ylidenemethyl]-quinoline-3-carbonitrile (example 14g), pyrazin-2-ylmethylamine and DIEA to give 4-ethoxy-6-[4-oxo-2-[(pyrazin-2-ylmethyl)-amino]-4H-thiazol-(5Z)-ylidenemethyl]-quinoline-3-carbonitrile. LC-MS m/e 417 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].C(OCC)(=O)C.Br[C:22]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:23]=1[C:24]([OH:26])=[O:25]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:22]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:23]=2[C:24]([OH:26])=[O:25])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: COc1ccc(Br)c(C(=O)O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1ccc(Oc2ccc(Br)cc2)c(C(=O)O)c1
Temperature: 110 °C

Procedure:
4-Bromophenol (8.7 g, 50 mmol), Cs2CO3 (16 g, 50 mmol), CuOTf toluene complex (2:1) (0.625 mmol, 5 mol % Cu, 150 mg), ethyl acetate (0.25 ml, 2.5 mmol) were added to a solution of 2-bromo-5-methoxybenzoic acid (11.6 g, 50 mmol) in toluene (40 mL) in a sealed tube. The reaction mixture was purged with N2, and was heated to 110° C. until the aryl halide was consumed as determined by LC-MS (48 h). After cooling to RT, the mixture was filtered through a Celite plug. The Celite plug was washed with EtOAc. The mixture was acidified by 1N HCl, and extracted w/EtOAc. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. This residue was purified via column chromatography on silica gel (gradient elution with 0-10% MeOH/DCM) to afford 2-(4-bromophenoxy)-5-methoxybenzoic acid. MS m/z=324.9 [M+H]+. Calc'd for C14H11BrO4: 323.1.
Reaction SMILES: [C:1]([O:4][CH2:5][C@@:6]12[C@@H:25]3[C@H:14]([C@H:15]4[C@:22]([CH3:26])([CH2:23][CH2:24]3)[C@@:18]([O:27][C:28](=[O:34])[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])([C:19](=[O:21])[CH3:20])[CH2:17][CH2:16]4)[CH2:13][CH2:12][C:11]1=[CH:10][C:9](=[O:35])[CH2:8][CH2:7]2)(=[O:3])[CH3:2].[CH3:36]OCOC.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>C(Cl)Cl>[C:1]([O:4][CH2:5][C@@:6]12[C@@H:25]3[C@H:14]([C@H:15]4[C@:22]([CH3:26])([CH2:23][CH2:24]3)[C@@:18]([O:27][C:28](=[O:34])[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])([C:19](=[O:21])[CH3:20])[CH2:17][CH2:16]4)[CH2:13][C:12](=[CH2:36])[C:11]1=[CH:10][C:9](=[O:35])[CH2:8][CH2:7]2)(=[O:3])[CH3:2]
Reactant: CCCCCC(=O)O[C@]1(C(C)=O)CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(COC(C)=O)[C@H]3CC[C@@]21C
Reactant: COCOC
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: ClCCl
Product: C=C1C[C@@H]2[C@H](CC[C@@]3(C)[C@H]2CC[C@]3(OC(=O)CCCCC)C(C)=O)[C@@]2(COC(C)=O)CCC(=O)C=C12

Procedure:
Analogously to Example 1, 1.0 g of 19-acetoxy-17-hexanoyloxy-4-pregnene-3,20-dione in 7 ml of methylene chloride is reacted with 4.9 ml of formaldehyde dimethylacetal and a mixture of 200 mg of phosphorus pentoxide and 1.5 g of kieselguhr W 20, and worked up. The crude product is purified on 110 g of silica gel with a hexane/acetone gradient (0-20% acetone), thus isolating 563 mg of 19-acetoxy-17-hexanoyloxy-6-methylene-4-pregnene-3,20-dione, mp 111°-112° C.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]=[CH:17][N:18]([C:19]3[S:23][C:22]([C:24]([O:26][CH3:27])=[O:25])=[C:21]([OH:28])[CH:20]=3)[C:12]=2[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[CH:36](O)[CH3:37].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>ClCCl>[Si:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]=[CH:17][N:18]([C:19]3[S:23][C:22]([C:24]([O:26][CH3:27])=[O:25])=[C:21]([O:28][CH:36]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=4[CH3:29])[CH3:37])[CH:20]=3)[C:12]=2[CH:11]=1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: Cc1ccccc1C(C)O
Reactant: COC(=O)c1sc(-n2cnc3cnc(CO[Si](C)(C)C(C)(C)C)cc32)cc1O
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1sc(-n2cnc3cnc(CO[Si](C)(C)C(C)(C)C)cc32)cc1OC(C)c1ccccc1C

Procedure:
In a similar manner as described for example B31, 1.50 g of methyl 5-[6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1H-imidazo[4,5-c]pyridin-1-yl]-3-hydroxythiophene-2-carboxylate, 0.63 g of 1-(2-methylphenyl)ethanol, 2.4 g of triphenylphosphine (polymer bound, ˜3 mmol/g) and 1.66 g of di-tert-butyl azodicarboxylate in 40 ml anhydrous dichloromethane yield the title compound.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:25][C:26]([F:41])([F:40])[C:27]1[C:35]2[CH2:34][CH2:33][CH2:32][CH2:31][C:30]=2[N:29]([CH2:36][C:37]([OH:39])=O)[N:28]=1.CCN(C(C)C)C(C)C.[F:51][C:52]1[CH:53]=[C:54]([CH2:59][CH:60]([C:62]2[N:63]=[CH:64][S:65][C:66]=2[C:67]2[CH:72]=[CH:71][CH:70]=[CH:69][C:68]=2[CH3:73])[NH2:61])[CH:55]=[C:56]([F:58])[CH:57]=1>CN(C=O)C>[F:51][C:52]1[CH:53]=[C:54]([CH2:59][CH:60]([NH:61][C:37](=[O:39])[CH2:36][N:29]2[C:30]3[CH2:31][CH2:32][CH2:33][CH2:34][C:35]=3[C:27]([C:26]([F:25])([F:41])[F:40])=[N:28]2)[C:62]2[N:63]=[CH:64][S:65][C:66]=2[C:67]2[CH:72]=[CH:71][CH:70]=[CH:69][C:68]=2[CH3:73])[CH:55]=[C:56]([F:58])[CH:57]=1
Reactant: Cc1ccccc1-c1scnc1C(N)Cc1cc(F)cc(F)c1
Reactant: O=C(O)Cn1nc(C(F)(F)F)c2c1CCCC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccccc1-c1scnc1C(Cc1cc(F)cc(F)c1)NC(=O)Cn1nc(C(F)(F)F)c2c1CCCC2
Reaction time: 0.17 h

Procedure:
HATU (40 mg, 0.105 mmol) was added to a solution of 2-(3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetic acid (25.0 mg, 0.1 mmol) and DIPEA (0.02 mL, 0.12 mmol) in DMF (0.3 mL). After 10 minutes, 13D (33.1 mg, 0.1 mmol) in 0.2 mL of DMF was added to the reaction. The reaction was stirred for 2 hours. LC/MS shows desired product with a small amount of acid. Purified reaction mixture on prep reverse phase HPLC using 20-80% B over 20 min. (A=0.1% TFA/H2O; B=0.1% TFA/Acetonitrile). Combined pure fractions as determined by LC/MS and lyophilized to provide the desired product. 1H NMR (400 MHz, DMSO) δ 9.23 (s, 1H), 8.89 (d, J=8.3 Hz, 1H), 7.35-7.16 (m, 2H), 7.11 (t, J=7.6 Hz, 1H), 6.99 (t, J=9.5 Hz, 1H), 6.79 (d, J=7.2 Hz, 1H), 6.51 (d, J=6.4 Hz, 2H), 4.83-4.77 (m, 1H), 4.72 (s, 2H), 3.05 (d, J=7.7 Hz, 2H), 2.46-2.21 (m, 4H), 1.87 (s, 3H), 1.61 (s, 4H). MS (m/z) 561 [M+H]+.
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:9][C:8]([CH2:32][C:33]#[N:34])([N:10]2[CH:14]=[C:13]([C:15]3[C:16]4[CH:23]=[CH:22][N:21](COCC[Si](C)(C)C)[C:17]=4[N:18]=[CH:19][N:20]=3)[CH:12]=[N:11]2)[CH2:7]1)(=[O:5])=[O:4])[CH3:2].[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38]>C(Cl)Cl>[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38].[CH2:1]([S:3]([N:6]1[CH2:9][C:8]([CH2:32][C:33]#[N:34])([N:10]2[CH:14]=[C:13]([C:15]3[C:16]4[CH:23]=[CH:22][NH:21][C:17]=4[N:18]=[CH:19][N:20]=3)[CH:12]=[N:11]2)[CH2:7]1)(=[O:4])=[O:5])[CH3:2]
Reactant: CCS(=O)(=O)N1CC(CC#N)(n2cc(-c3ncnc4c3ccn4COCC[Si](C)(C)C)cn2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCS(=O)(=O)N1CC(CC#N)(n2cc(-c3ncnc4[nH]ccc34)cn2)C1
Reaction time: 1.5 h
Yield: 47 %

Procedure:
To a solution of 1-(ethylsulfonyl)-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-ylacetonitrile (0.111 g, 0.22 mmol) in methylene chloride (3 mL) was added trifluoroacetic acid (2 mL) and the solution was stirred for 1.5 hours. The solvents were removed in vacuo and the residue was dissolved in methanol (3 mL) and ethylenediamine (0.1 mL) was added. After stirring for 3 hours, the volume was reduced in vacuo and the product was purified by preparative-HPLC/MS, (SunFire C18 column, eluting with a gradient of MeCN/H2O containing 0.1% TFA) to afford the product as the trifluoroacetic acid salt (50 mg, 47%).
Reaction SMILES: C(O)(C(F)(F)F)=O.C(Cl)(Cl)Cl.C(O[C:17]([N:19]1[CH2:24][CH2:23][CH:22]([C:25]2[C:34]3[C:29](=[CH:30][C:31]([O:35][CH2:36][CH2:37][CH2:38][NH:39][S:40]([CH2:43]C)(=[O:42])=[O:41])=[CH:32][CH:33]=3)[N:28]=[CH:27][N:26]=2)[CH2:21][CH2:20]1)=[O:18])(C)(C)C.[Al].CCN(C(C)C)C(C)C.[N+](C1C=CC(OC(=O)[NH:66][C:67]2[CH:72]=[CH:71][C:70]([O:73][CH:74]([CH3:76])[CH3:75])=[CH:69][CH:68]=2)=CC=1)([O-])=O>C(Cl)Cl.CC(C)=O.C(Cl)(Cl)Cl>[CH:74]([O:73][C:70]1[CH:71]=[CH:72][C:67]([NH:66][C:17]([N:19]2[CH2:20][CH2:21][CH:22]([C:25]3[C:34]4[C:29](=[CH:30][C:31]([O:35][CH2:36][CH2:37][CH2:38][NH:39][S:40]([CH3:43])(=[O:41])=[O:42])=[CH:32][CH:33]=4)[N:28]=[CH:27][N:26]=3)[CH2:23][CH2:24]2)=[O:18])=[CH:68][CH:69]=1)([CH3:76])[CH3:75]
Reactant: CC(C)Oc1ccc(NC(=O)Oc2ccc([N+](=O)[O-])cc2)cc1
Reactant: CCS(=O)(=O)NCCCOc1ccc2c(C3CCN(C(=O)OC(C)(C)C)CC3)ncnc2c1
Agent: [Al]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: CC(C)Oc1ccc(NC(=O)N2CCC(c3ncnc4cc(OCCCNS(C)(=O)=O)ccc34)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A premixed solution of 1:1 TFA/CHCl3 (80 μL, 539 μmol TFA) was added to 4-[7-(3-ethanesulfonylamino-propoxy)-quinazolin-4-yl]-piperidine-1-carboxylic acid tert-butyl ester (38.7 mg, 83.4 μmol), prepared as described in the previous step, and the tightly capped reaction was stirred under air at 100° C. (aluminum block) for 10 min. After cooling to rt, DIEA (117 μL, 709 μmol) was added dropwise, followed by CHCl3 (0.5 mL), and the resulting homogeneous solution was stirred at rt while (4-isopropoxy-phenyl)-carbamic acid 4-nitro-phenyl ester (32.9 mg, 104 μmol), as prepared in Example 1a, was added in one portion. The resulting homogeneous dark yellow solution was stirred at rt overnight, and then directly loaded onto a flash silica column (5:3 DCM/acetone eluent) to afford impure title compound. This material was taken up in EtOAc (2 mL) and washed with 1.0 M NaHCO3 (3×2 mL), 1.0 M NaH2PO4 (2×2 mL), and again 1.0 M NaHCO3 (2×2 mL). One contaminant was removed (apparently protonated DIEA), but another substantially remained (apparently nitrophenol), so the EtOAc layer was directly loaded onto a flash silica column (5:3 DCM/acetone eluent) to afford the title compound as a white foam (16.0 mg, 35%). 1H-NMR (400 MHz, CDCl3) δ 9.13 (s, 1H), 8.06 (d, 1H), 7.32 (d, 1H), 7.27-7.21 (m, 3H), 6.84 (m, 2H), 6.34 (br s, 1H), 4.69 (br t, 1H), 4.48 (heptet, 1H), 4.26 (m, 4H), 3.67 (tt, 1H), 3.42 (q, 2H), 3.13 (td, 2H), 2.97 (s, 3H), 2.21-2.05 (m, 4H), 2.00-1.91 (m, 2H), 1.32 (d, 6H). LC/MS (ESI): calcd mass 541.2, found 542.1 (MH)+. Anal. Calcd for C27H35N5O5S: C, 59.87; H, 6.51; N, 12.93. Found: C, 60.03; H, 6.51; N, 12.78.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][C:4]=1[F:12])#[N:2].[Cl:13][C:14]1[CH:19]=[C:18](Cl)[N:17]=[C:16]([NH2:21])[N:15]=1.C([O-])(O)=O.[Na+]>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.O1CCOCC1>[NH2:21][C:16]1[N:17]=[C:18]([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([F:12])[CH:5]=2)[CH:19]=[C:14]([Cl:13])[N:15]=1
Reactant: N#Cc1ccc(B(O)O)cc1F
Reactant: Nc1nc(Cl)cc(Cl)n1
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: [Na+]
Solvent: C1COCCO1
Product: N#Cc1ccc(-c2cc(Cl)nc(N)n2)cc1F
Temperature: 95 °C
Reaction time: 16 h
Yield: 35.4 %

Procedure:
In a 25 mL sealable tube under argon were combined (4-cyano-3-fluorophenyl)boronic acid (0.50 g, 3.03 mmol), 4,6-dichloro-2-pyrimidinamine (0.497 g, 3.03 mmol), saturated aqueous NaHCO3 (4.04 mL), and 1,4-dioxane (16.2 mL), and the mixture was degassed with argon for 5 minutes. Pd(Ph3P)4 (0.175 g, 0.152 mmol) was added, the vial was sealed, and the reaction mixture was stirred for 16 hours at 95° C. The reaction was cooled to room temperature, filtered through a plug of celite503, and concentrated. The resulting orange tar was partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried (MgSO4), filtered and concentrated. The resulting orange solid was sonicated in CHCl3 (50 mL) for 2 minutes. The mixture was filtrated, the solid was washed with CHCl3, and the filtrate was concentrated. Flash chromatography on SiO2 (40 g) of the resulting residue (gradient: 100% CHCl3 to 5% EtOAc/CHCl3) afforded the title compound (267 mg, 32%) as a yellow solid. LC-MS (ES) m/z=249 [M+H]+.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([OH:10])[N:7]2[C:11]([SH:14])=[N:12][N:13]=[C:6]2[N:5]=1)([OH:3])=[O:2].C(O[CH2:19][C:20]1[CH2:27][S:26][C@H:25]2[N:22]([C:23](=[O:41])[C@H:24]2[NH:28][C:29](=[O:40])/[C:30](/[C:34]2[N:35]=[C:36]([NH2:39])[S:37][CH:38]=2)=[N:31]\[O:32][CH3:33])[C:21]=1[C:42]([OH:44])=[O:43])(=O)C.C(=O)(O)[O-].[Na+]>P([O-])([O-])([O-])=O>[NH2:39][C:36]1[S:37][CH:38]=[C:34](/[C:30](=[N:31]/[O:32][CH3:33])/[C:29]([NH:28][C@@H:24]2[C:23](=[O:41])[N:22]3[C@@H:25]2[S:26][CH2:27][C:20]([CH2:19][S:14][C:11]2[N:7]4[C:8]([OH:10])=[CH:9][C:4]([C:1]([OH:3])=[O:2])=[N:5][C:6]4=[N:13][N:12]=2)=[C:21]3[C:42]([OH:44])=[O:43])=[O:40])[N:35]=1
Reactant: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(COC(C)=O)CS[C@H]12)c1csc(N)n1
Reactant: O=C(O)c1cc(O)n2c(S)nnc2n1
Agent: O=C([O-])O
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(CSc3nnc4nc(C(=O)O)cc(O)n34)CS[C@H]12)c1csc(N)n1
Yield: 15.6 %

Procedure:
Starting from the product obtained in Step 2 (6.7 g) and the product obtained in Step 2 of Example 7 (15 g) and using 240 ml of 0.1M phosphate buffer (pH 6.4) and 8.0 g of sodium bicarbonate, 3 g of the objective compound was obtained in a manner similar to Step 4 of Example 37.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[C:9]2[C:18]3[C:17](=[O:19])[N:16]([CH2:20][CH2:21][CH2:22][O:23][CH:24]4CCCC[O:25]4)[C:15](=[O:30])[N:14]([CH3:31])[C:13]=3[N:12]=[CH:11][C:10]=2[O:32][C:33]2[CH:34]=[N:35][CH:36]=[C:37]([F:39])[CH:38]=2)=[CH:4][CH:3]=1>C(O)=O.[Zn]>[CH:24]([O:23][CH2:22][CH2:21][CH2:20][N:16]1[C:17](=[O:19])[C:18]2[C:9]([CH2:8][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)=[C:10]([O:32][C:33]3[CH:34]=[N:35][CH:36]=[C:37]([F:39])[CH:38]=3)[CH:11]=[N:12][C:13]=2[N:14]([CH3:31])[C:15]1=[O:30])=[O:25]
Reactant: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c(C(O)c3ccc(Cl)cc3)c(Oc3cncc(F)c3)cnc21
Agent: [Zn]
Solvent: O=CO
Product: Cn1c(=O)n(CCCOC=O)c(=O)c2c(Cc3ccc(Cl)cc3)c(Oc3cncc(F)c3)cnc21
Temperature: 70 °C
Yield: 69.7 %

Procedure:
To a solution of 5-((4-chlorophenyl)(hydroxy)methyl)-6-((5-fluoropyridin-3-yl)oxy)-1-methyl-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (45 mg, 0.092 mmol) in HCOOH (5 mL) was added Zn dust (30.2 mg, 0.462 mmol). The reaction was heated at 70° C. for 1.5 h, cooled to RT and filtered. The filtrate was concentrated and dried to a residue which was purified by chromatography eluted with PE/EA (10:1 to 1:1) to give 3-(5-(4-chlorobenzyl)-6-((5-fluoropyridin-3-yl)oxy)-1-methyl-2,4-dioxo-1,2-dihydropyrido[2,3-d]pyrimidin-3(4H)-yl)propyl formate (32 mg, 69.4% yield) as an oil. LCMS: MH+ 499 and TR=1.513 min.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:7]([C:32](OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=[O:33])[C@H:8]([C:29]([OH:31])=[O:30])[CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14](=[C:19]1[C:27](=[O:28])[CH2:26][C:23]([CH3:25])([CH3:24])[CH2:22][C:20]1=[O:21])[CH2:15][CH:16]([CH3:18])[CH3:17]>CN(C=O)C>[NH:1]([C:20]([CH3:19])=[O:21])[C@H:6]([C:32]([NH:7][C@H:8]([C:29]([OH:31])=[O:30])[CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14](=[C:19]1[C:27](=[O:28])[CH2:26][C:23]([CH3:24])([CH3:25])[CH2:22][C:20]1=[O:21])[CH2:15][CH:16]([CH3:17])[CH3:18])=[O:33])[CH2:5][C:4]1[CH:29]=[CH:8][CH:9]=[CH:2][CH:3]=1
Reactant: CC(C)CC(NCCCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)=C1C(=O)CC(C)(C)CC1=O
Reactant: C1CCNCC1
Solvent: CN(C)C=O
Product: CC(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CCCCNC(CC(C)C)=C1C(=O)CC(C)(C)CC1=O)C(=O)O
Reaction time: 0.02 h

Procedure:
In a separate control experiment, regular piperidine deprotection was used. To the Fmoc-Lys(ivDde)-resin (10 mg, ˜8 μmol) was added piperidine in DMF (20%, 2 mL). The mixture was shaken for 1 min and drained. Another 2 mL of 20% piperidine was added and the mixture was shaken for 15 min. The resin was then washed, coupled with Fmoc-Phe as described above to give Ac-Phe-Lys(ivDde)-resin.
Reaction SMILES: [C:1]([N:3]=[C:4]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)OC(C)C)#[N:2].[F:15][C:16]([F:26])([F:25])[C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH2:22])=[CH:19][CH:18]=1>CO>[C:1]([NH:3][C:4]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)=[N:22][CH2:21][C:20]1[CH:19]=[CH:18][C:17]([C:16]([F:15])([F:25])[F:26])=[CH:24][CH:23]=1)#[N:2]
Reactant: NCc1ccc(C(F)(F)F)cc1
Reactant: CC(C)OC(=NC#N)c1cccnc1
Solvent: CO
Product: N#CNC(=NCc1ccc(C(F)(F)F)cc1)c1cccnc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.4 %

Procedure:
Isopropyl N-cyano-3-pyridinecarboximidate (0.50 g, 2.6 mmol) was dissolved in methanol (10 ml), and 4-(trifluoromethyl)benzylamine (0.51 g, 2.9 mmol) was added. The mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the concentrated residue thus obtained was crystallized from diethyl ether to give the title compound (0.53 g, 1.7 mmol, yield: 66%) as colorless crystals.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@H:3]([OH:9])[CH2:2]2.C[O:11][C:12]([C:14]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=O.[H-].[Na+].C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1.CCOC(C)=O>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@H:3]([O:9][C:12]([C:14]1([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1)=[O:11])[CH2:2]2
Reactant: COC(=O)C1(c2ccccc2)CCCCCC1
Reactant: O[C@@H]1CN2CCC1CC2
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C(O[C@@H]1CN2CCC1CC2)C1(c2ccccc2)CCCCCC1
Temperature: 25 °C
Yield: 59.9 %

Procedure:
A solution of (S)-(+)-3-quinuclidinol (299 mg) and 1-phenyl-cycloheptanecarboxylic acid methyl ester (Example 14d) (455 mg) in 6.5 mL dry toluene under nitrogen was treated with a 60% dispersion of sodium hydride (94 mg) and the mixture was heated to reflux for 24 h then cooled to room temperature and allowed to stand over the weekend. EtOAc and sat. NaHCO3 (aq) were added and the phases separated. The aqueous phase was extracted with EtOAc (×3) and the combined organic layer was washed with brine, dried (MgSO4) and evaporated to afford the crude product. Purification was achieved by silica gel chromatography eluting with 0-10% MeOH/dichloromethane to give the sub-titled compound (384 mg) as a yellow oil.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:31]1([C:37]([C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[N:38]2[CH:42]=[C:41]([CH2:43][CH2:44][CH2:45]O)[N:40]=[CH:39]2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[C:53]1([C:37]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)([C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=2)[N:38]2[CH:42]=[C:41]([CH2:43][CH2:44][CH2:45][O:9][C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:10])([F:11])[F:1])=[CH:8][CH:7]=3)[N:40]=[CH:39]2)[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1
Reactant: Oc1ccc(C(F)(F)F)cc1
Reactant: OCCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: FC(F)(F)c1ccc(OCCCc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1
Reaction time: 0.08 h

Procedure:
5 ml of tetrahydrofuran, 129 mg (0.8 mmol) of 4-trifluoromethylphenol and 209 mg (0.8mmol) of triphenylphosphine are added, under nitrogen, to 280 mg (0.76 mmol) of 1-triphenylmethyl-4-(3-hydroxypropyl)-1H-imidazole. The resulting mixture is stirred for 5 min. 139 mg (0.8 mmol) of diethyl azodicarboxylate in 5 ml of tetrahydrofuran are then slowly added. Stirring is continued at room temperature for 3 hours under nitrogen. The solvent is then evaporated and the residue is then chromatographed on a column of silica gel (first eluent petroleum ether containing increasing amounts of diethyl ether up to 100%) to give the monohydrate of 1-triphenylmethyl-4-[3-(4-trifluoromethylphenoxy)propyl]-1H-imidazole which is crystallized from ethanol, M.p.: 150°-151° C.
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([OH:3])=[O:2].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[CH:15][CH:14]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[N:22][S:19]([C:16]2[CH:15]=[CH:14][C:13]([Cl:12])=[CH:18][CH:17]=2)(=[O:21])=[O:20])=[CH:6][CH:5]=1)([OH:3])=[O:2]
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: NS(=O)(=O)c1ccc(Cl)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(O)c1ccc(C=NS(=O)(=O)c2ccc(Cl)cc2)cc1
Temperature: 25 °C

Procedure:
A well-stirred slurry consisting of 4.64g (31 mmol) of 4-carboxybenzaldehyde and 5.92 g (31 mmol) of 4-chlorobenzenesulfonamide and 20 mg of p-toluenesulfonic acid (TsOH) in 130 mL of toluene was heated to reflux for a total of 5 hours. The water formed from the reaction was removed by a Soxhlet extractor packed with 3A molecular sieves as described above. The mixture was allowed to cool to room temperature and was filtered to provide 9.76 g (98%) of SULF-1 as a white powder: mp >245° C.; IR (Nujol) 3300-2300 (br), 3090, 1689, 1616, 1168, 1013 cm-1 ; 1H NMR (DSMO-d6, TMS ext standard, 60 MHz) δ9.15 (s, 1), 8.01 (s, 4), 7.79 (AB, 4, JAB =11, Δν=16).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([C@H:9]([NH:16][C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[CH2:10][C@H:11]([CH3:15])[NH:12]2)=[CH:7][C:6]=1[O:27][CH3:28])=[O:4].N1C=CC=CC=1.Cl[C:36]([O:38][CH2:39][CH3:40])=[O:37].ClC(OC)=O>ClCCl>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([C@H:9]([NH:16][C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[CH2:10][C@H:11]([CH3:15])[N:12]2[C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:7][C:6]=1[O:27][CH3:28])=[O:4]
Reactant: CCOC(=O)Cl
Reactant: COC(=O)c1cc2c(cc1OC)[C@H](NC(=O)OCc1ccccc1)C[C@H](C)N2
Agent: COC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)N1c2cc(C(=O)OC)c(OC)cc2[C@H](NC(=O)OCc2ccccc2)C[C@@H]1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89.3 %

Procedure:
To a solution of cis-4-benzyloxycarbonylamino-6-methoxy-2-methyl-1,2,3,4-tetrahydro-quinoline-7-carboxylic acid methyl ester (0.99 g, 2.6 mmol) in anhydrous dichloromethane (30 mL) was added pyridine (0.27 mL, 3.35 mmol). The mixture was cooled to 0° C., and ethyl chloroformate (0.29 mL, 3.1 mmol) was slowly added. The reaction was stirred at 0° C. for 30 min, then at room temperature for 2.5 h. Additional aliquots of pyridine and methyl chloroformate were added to drive the reaction to completion. The reaction mixture was evaporated to dryness, and the residue was partitioned between ethyl acetate (75 ml) and water (25 ml). The organic layer was washed with water (25 mL), dried over magnesium sulfate, filtered and concentrated in vacuo to give the crude product. Purification by silica gel chromatography using 25% ethyl acetate/hexanes as eluent afforded the title product (1.06 g). MS m/z 457 (M++1); 1H NMR (DMSO-d6) δ 1.45 (d, 3H), 6.68 (s, 1H).