Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13](B2OC(C)(C)C(C)(C)O2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:25])[CH:11]=2)[CH:6]=1.Br[C:28]1[CH:33]=[CH:32][C:31]([S:34][C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][C:36]=2[Cl:42])=[CH:30][CH:29]=1.C(=O)(O)[O-].[Na+].O>C(COC)OC.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>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:28]2[CH:29]=[CH:30][C:31]([S:34][C:35]3[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][C:36]=3[Cl:42])=[CH:32][CH:33]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:25])[CH:11]=2)[CH:6]=1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(B2OC(C)(C)C(C)(C)O2)c1C
Reactant: Clc1ccc(Sc2ccc(Br)cc2)c(Cl)c1
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: COCCOC
Solvent: O
Product: COC(=O)Cc1cc2ccc(F)cc2c(-c2ccc(Sc3ccc(Cl)cc3Cl)cc2)c1C
Yield: 28.8 %

Procedure:
A stirred solution of [6-fluoro-3-methyl-4-(4,4,5,5-tetra methyl-[1,3,2]-dioxaborolan-2-yl)-naphthalen-2-yl]-acetic acid methyl ester (0.2 g, 0.55 mmol) in dimethoxyethane (5 mL) was purged with argon for 5 minutes at room temperature. Tetrakis(triphenylphosphine)palladium(0) (0.032 g, 0.028 mmol), impure 1-(4-bromo-phenylsulfanyl)-2,4-dichlorobenzene (0.2 g, 0.61 mmol) and 1.0 M aqueous sodium bicarbonate (5 mL, 5 mmol) were added simultaneously to the reaction mixture under argon. The reaction mixture was refluxed for 2 hours and then brought to room temperature. Water was added and the resulting mixture was extracted twice with ethyl acetate. The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product, which was finally purified using flash chromatography (0-3% ethyl acetate in hexanes) to give {4-[4-(2,4-dichloro-phenylsulfanyl)-phenyl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (0.077 g, 29%) as a solid.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].Br[CH2:13][CH2:14][O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[H-].[Na+]>CN(C)C=O>[CH2:16]([O:15][CH2:14][CH2:13][N:3]1[CH:4]=[CH:5][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:2]1[CH3:1])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCOC(=O)c1cc[nH]c1C
Reactant: BrCCOCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccn(CCOCc2ccccc2)c1C
Temperature: 0 °C
Reaction time: 15 h

Procedure:
Ethyl 2-methyl-1H-pyrrole-3-carboxylate (10 g, 65.3 mmol) is dissolved in 100 mL of dimethylformamide under argon cooled to 0° C., and then 2-bromoethoxymethylbenzene (28.1 g, 130.6 mmol) is added all at once. The reaction mixture is placed under stirring. There is then added thereto, at 0° C., in three portions, NaH (1.72 g, 71.83 mmol) over a period of 15 minutes. The reaction mixture is stirred for 15 minutes at 0° C., and then for 15 hours at ambient temperature. It is then poured into an ice bath and then extracted 3 times with ethyl acetate. The organic phase is washed 3 times with saturated aqueous lithium chloride solution, dried over MgSO4, filtered and then evaporated to dryness. The residue thereby obtained is purified by chromatography over silica gel using petroleum ether and ethyl acetate as eluants. The expected compound is obtained in the form of an oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[N:4][N:3]=1.[NH:19]1[CH2:24][CH2:23][NH:22][CH2:21][C@@H:20]1[CH2:25][OH:26].C(N(C(C)C)CC)(C)C>CS(C)=O>[F:18][C:15]1[CH:16]=[CH:17][C:12]([C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:2]([N:22]3[CH2:23][CH2:24][NH:19][C@@H:20]([CH2:25][OH:26])[CH2:21]3)=[N:3][N:4]=2)=[CH:13][CH:14]=1
Reactant: OC[C@H]1CNCCN1
Reactant: Fc1ccc(-c2nnc(Cl)c3ccccc23)cc1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: OC[C@H]1CN(c2nnc(-c3ccc(F)cc3)c3ccccc23)CCN1
Yield: 83.4 %

Procedure:
Dissolve 1-chloro-4-(4-fluorophenyl)phthalazine (0.1 g, 0.39 mmol), (R)-piperazin-2-ylmethanol (0.07 g, 0.58 mmol) and diisopropylethylamine (0.34 mL, 1.93 mmol) in DMSO (1 mL). Stir the reaction at 120° C. for 64 h. Purify the reaction mixture by flash silica gel chromatography (0-10% 2 M ammonia/MeOH in CH2Cl2) to yield the title compound as a brown solid (0.11 g, 84%). ES/MS m/z 339.0 (M+1).
Reaction SMILES: CN1CCOCC1.[CH:8]1([N:11]([C@H:19]2[C:28]3[CH:27]=[C:26]([F:29])[CH:25]=[CH:24][C:23]=3[N:22]([C:30](=[O:42])[C:31]3[CH:36]=[CH:35][C:34]([O:37][C:38]([F:41])([F:40])[F:39])=[CH:33][CH:32]=3)[C@H:21]3[CH2:43][CH2:44][CH2:45][C@@H:20]23)[C:12](=[O:18])[CH2:13][CH2:14][C:15]([OH:17])=[O:16])[CH2:10][CH2:9]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[OH:70][CH:71]1[CH:76]([OH:77])[CH:75]([OH:78])[CH:74](O)[O:73][CH:72]1[C:80]([O:82][CH2:83][C:84]1[CH:89]=[CH:88][CH:87]=[CH:86][CH:85]=1)=[O:81]>C(#N)C.C(Cl)Cl.CO>[CH:8]1([N:11]([C@H:19]2[C:28]3[CH:27]=[C:26]([F:29])[CH:25]=[CH:24][C:23]=3[N:22]([C:30](=[O:42])[C:31]3[CH:32]=[CH:33][C:34]([O:37][C:38]([F:39])([F:41])[F:40])=[CH:35][CH:36]=3)[C@H:21]3[CH2:43][CH2:44][CH2:45][C@@H:20]23)[C:12](=[O:18])[CH2:13][CH2:14][C:15]([O:17][CH:74]2[O:73][CH:72]([C:80]([O:82][CH2:83][C:84]3[CH:89]=[CH:88][CH:87]=[CH:86][CH:85]=3)=[O:81])[CH:71]([OH:70])[CH:76]([OH:77])[CH:75]2[OH:78])=[O:16])[CH2:10][CH2:9]1
Reactant: O=C(OCc1ccccc1)C1OC(O)C(O)C(O)C1O
Reactant: O=C(O)CCC(=O)N(C1CC1)[C@H]1c2cc(F)ccc2N(C(=O)c2ccc(OC(F)(F)F)cc2)[C@H]2CCC[C@H]21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CO
Solvent: ClCCl
Product: O=C(CCC(=O)N(C1CC1)[C@H]1c2cc(F)ccc2N(C(=O)c2ccc(OC(F)(F)F)cc2)[C@H]2CCC[C@H]21)OC1OC(C(=O)OCc2ccccc2)C(O)C(O)C1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 102.2 %

Procedure:
N-methylmorpholine (0.077 mL, 0.702 mmol) was added to a stirred mixture of 4-(cyclopropyl((3aS,9R,9aR)-7-fluoro-4-(4-(trifluoromethoxy)benzoyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]quinolin-9-yl)amino)-4-oxobutanoic acid (150 mg, 0.281 mmol), HATU (133 mg, 0.351 mmol) and benzyl 3,4,5,6-tetrahydroxytetrahydro-2H-pyran-2-carboxylate (100 mg, 0.351 mmol) in acetonitrile (3 mL) and the mixture was stirred at room temperature for 3 h. TLC showed clean reaction (MeOH in DCM 10%). Solvent was removed and the residue was purified by column chromatography on silica gel (24 g prepacked column) eluting with DCM/MeOH gradient up to 20% MeOH to give benzyl 6-((4-(cyclopropyl((3aS,9R,9aR)-7-fluoro-4-(4-(trifluoromethoxy)benzoyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]quinolin-9-yl)amino)-4-oxobutanoyl)oxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate 174A (0.23 g).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:7]([CH2:30][CH:31]2[CH2:35][CH2:34][O:33][CH2:32]2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl>C(OCC)(=O)C>[C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([CH2:30][CH:31]2[CH2:35][CH2:34][O:33][CH2:32]2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n(CC2CCOC2)n1
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cc(N)n(CC2CCOC2)n1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
In a 200 mL round-bottomed flask, to a solution of Example 85C (6.24 g, 13.4 mmol) in ethyl acetate (20 mL) was added hydrogen chloride (4 N in dioxane, 20 mL) and stirred at 20° C. for 2 hours. The reaction was concentrated and triturated with ethyl acetate. The solid was collected and dried to provide the title compound as the hydrogen chloride salt (2.12 g, 61%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.28 (s, 9H) 1.61-1.69 (m, 1H) 1.81-1.89 (m, 1H) 2.73-2.81 (m, 1H) 3.45 (dd, J=8.85, 5.80 Hz, 1H) 3.61-3.67 (m, 3H) 3.78-3.84 (m, 1H) 4.17-4.26 (m, 2H) 5.53 (s, 1H) 7.07 (s, 2H); MS (DCI/NH3) m/z 224 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[Cl:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1/[CH:27]=[CH:28]/[C:29](O)=[O:30]>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:29](=[O:30])/[CH:28]=[CH:27]/[C:21]3[CH:22]=[CH:23][C:24]([F:26])=[CH:25][C:20]=3[Cl:19])=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: O=C(O)/C=C/c1ccc(F)cc1Cl
Reactant: CC1(c2ccc(Cn3ccc(N)n3)o2)OCCO1
Product: CC(=O)c1ccc(Cn2ccc(NC(=O)/C=C/c3ccc(F)cc3Cl)n2)o1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and (E)-3-(2-chloro-4-fluoro-phenyl)-acrylic acid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:14])[CH2:9][S:10]([NH2:13])(=[O:12])=[O:11])=[CH:4][CH:3]=1.Br[C:16]1[C:17]2[C:18]3[CH:32]=[CH:31][S:30][C:19]=3[C:20](=[O:29])[NH:21][C:22]=2[C:23]([CH3:28])=[CH:24][C:25]=1[O:26][CH3:27]>>[CH3:27][O:26][C:25]1[CH:24]=[C:23]([CH3:28])[C:22]2[NH:21][C:20](=[O:29])[C:19]3[S:30][CH:31]=[CH:32][C:18]=3[C:17]=2[C:16]=1[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:14])[CH2:9][S:10]([NH2:13])(=[O:12])=[O:11])=[CH:4][CH:3]=1
Reactant: COc1cc(C)c2[nH]c(=O)c3sccc3c2c1Br
Reactant: CC(CS(N)(=O)=O)c1ccc(Br)cc1
Product: COc1cc(C)c2[nH]c(=O)c3sccc3c2c1-c1ccc(C(C)CS(N)(=O)=O)cc1
Yield: 8.4 %

Procedure:
Following General Procedure E, 2-(4-bromophenyl)propane-1-sulfonamide (0.12 g, 0.43 mmol) was reacted with 9-bromo-8-methoxy-6-methylthieno[2,3-c]quinolin-4(5H)-one (0.14 g, 0.44 mmol) to afford the desired product (16 mg, 8%) as a brown solid: ESI MS m/z 443 [C22H22N2O4S2+H]+.
Reaction SMILES: S(C1C=CC(C)=CC=1)([O:4][CH2:5][CH2:6][C:7]1[N:8]=[C:9]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)[O:10][C:11]=1[CH3:12])(=O)=O.C([O:27][C:28](=[O:48])[C:29]([CH3:47])([O:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[CH2:30][C:31]1[CH:36]=[CH:35][C:34](O)=[C:33]([O:38][CH3:39])[CH:32]=1)C>>[CH3:39][O:38][C:33]1[CH:32]=[C:31]([CH2:30][C:29]([CH3:47])([O:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:28]([OH:48])=[O:27])[CH:36]=[CH:35][C:34]=1[O:4][CH2:5][CH2:6][C:7]1[N:8]=[C:9]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)[O:10][C:11]=1[CH3:12]
Reactant: CCOC(=O)C(C)(Cc1ccc(O)c(OC)c1)Oc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3cccs3)oc2C)cc1
Product: COc1cc(CC(C)(Oc2ccccc2)C(=O)O)ccc1OCCc1nc(-c2cccs2)oc1C

Procedure:
The title compound was prepared from 2-(5-methyl-2-thiophen-2-yloxazol-4-yl)ethyl tosylate and 3-(4-hydroxy-3-methoxyphenyl)-2-methyl-2-phenoxypropionic acid ethyl ester according to the parallel synthesis procedure (A). MS (EI) 494.4 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([N:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[N+:20]([O-])=O)[CH3:12])=[N:9][CH:8]=[CH:7][N:6]=1)=[O:4]>[Ni].C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[C:10]([N:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[NH2:20])[CH3:12])=[N:9][CH:8]=[CH:7][N:6]=1)=[O:4]
Reactant: COC(=O)c1nccnc1N(C)c1ccc(Cl)cc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CCOC(C)=O
Product: COC(=O)c1nccnc1N(C)c1ccc(Cl)cc1N

Procedure:
A mixture of 4.0 g 3-(4-chloro-N-methyl-2-nitrophenylamino)-pyrazine-2-carboxylic acid methyl ester, 200 ml ethyl acetate and 4 g Raney Nickel are hydrogenated at room temperature under normal pressure. The catalyst is removed by filtration and the filtrate is evaporated to afford the heading compound. It is used without further purification.
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].CC([Si](C)(C)[O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH2:33][O:34][CH3:35])[C:27]=1[CH:36]([OH:39])[CH2:37][CH3:38])(C)C>O1CCCC1>[OH:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH2:33][O:34][CH3:35])[C:27]=1[CH:36]([OH:39])[CH2:37][CH3:38]
Reactant: CCC(O)c1c(CO[Si](C)(C)C(C)(C)C)cccc1OCOC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCC(O)c1c(CO)cccc1OCOC
Temperature: 25 °C

Procedure:
In a 50 ml round-bottomed flask 1-(2-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)-6-{[(methyloxy)methyl]oxy}phenyl)-1-propanol (Intermediate 104, 132.1 mg) was dissolved in Tetrahydrofuran (2 ml) to give a pale yellow solution. 1M/THF sol of TBAF (0.388 ml, 0.388 mmol) was added. The reaction mixture was stirred at room temperature. After over night stirring, the reaction was completed. The reaction mixture was evaporated under vacuum to give the crude product as a pale yellow oil which was purified via Biotage SP1 (with Cyclohexane/EtOAc as eluents from 3:1 to 2:1 in 10 CV; then 2:1 for 5 CV; then from 2:1 to 2:1 in 5 CV; then 1:1 for 5 CV; 25 g SNAP Silica column). The collected fractions afforded a residue which was purified again in the same conditions to afford the title compound as a pale yellow oil.
Reaction SMILES: Cl[CH2:2][N:3]1[C:13](=[O:14])[C:12]2[CH:11]([CH:15]([CH3:17])[CH3:16])[CH2:10][CH:9]([O:18][CH3:19])[CH2:8][C:7]=2[S:4]1(=[O:6])=[O:5].[CH3:20][C:21]1[C:26]([C:27]([OH:29])=[O:28])=[C:25]([CH3:30])[CH:24]=[CH:23][N:22]=1>>[CH3:20][C:21]1[C:26]([C:27]([O:29][CH2:2][N:3]2[C:13](=[O:14])[C:12]3[CH:11]([CH:15]([CH3:17])[CH3:16])[CH2:10][CH:9]([O:18][CH3:19])[CH2:8][C:7]=3[S:4]2(=[O:6])=[O:5])=[O:28])=[C:25]([CH3:30])[CH:24]=[CH:23][N:22]=1
Reactant: COC1CC2=C(C(=O)N(CCl)S2(=O)=O)C(C(C)C)C1
Reactant: Cc1ccnc(C)c1C(=O)O
Product: COC1CC2=C(C(=O)N(COC(=O)c3c(C)ccnc3C)S2(=O)=O)C(C(C)C)C1

Procedure:
It is contemplated that following the procedure of Example 17, 2-chloromethyl-4-isopropyl-6-methoxy-4,5,6,7-tetrahydrosaccharin of preparation 23BJ can be coupled with 2,4-dimethyl-3-pyridinecarboxylic acid to provide 4-isopropyl-6-methoxy-4,5,6,7-tetrahydro-2-saccharinylmethyl 2,4-dimethylpyridine-3-carboxylate.
Reaction SMILES: C[O:2][C:3](=[O:34])[C@@H:4]([O:31][CH2:32][CH3:33])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[N:15]=[C:16]([C:20]3[CH:25]=[CH:24][C:23]([CH:26]([CH3:28])[CH3:27])=[CH:22][CH:21]=3)[O:17][C:18]=2[CH3:19])=[CH:8][C:7]=1[O:29][CH3:30].[Li+].[OH-]>>[CH2:32]([O:31][C@@H:4]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[N:15]=[C:16]([C:20]3[CH:25]=[CH:24][C:23]([CH:26]([CH3:27])[CH3:28])=[CH:22][CH:21]=3)[O:17][C:18]=2[CH3:19])=[CH:8][C:7]=1[O:29][CH3:30])[C:3]([OH:34])=[O:2])[CH3:33]
Reactant: CCO[C@@H](Cc1ccc(OCc2nc(-c3ccc(C(C)C)cc3)oc2C)cc1OC)C(=O)OC
Agent: [Li+]
Agent: [OH-]
Product: CCO[C@@H](Cc1ccc(OCc2nc(-c3ccc(C(C)C)cc3)oc2C)cc1OC)C(=O)O

Procedure:
In analogy to the procedure described in example 1 g], (S)-2-ethoxy-3-{4-[2-(4-isopropyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methoxy-phenyl}-propionic acid methyl ester was treated with LiOH to obtain (S)-2-ethoxy-3-{4-[2-(4-isopropyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methoxy-phenyl}-propionic acid as colorless solid.
Reaction SMILES: C([O:8][C@@H:9]1[C@@H:14]([O:15]CC2C=CC=CC=2)[C@H:13]([O:23]CC2C=CC=CC=2)[C@@H:12]([CH2:31][O:32]CC2C=CC=CC=2)[O:11][C@:10]21[C:48]1[C:43](=[CH:44][C:45]([Cl:58])=[C:46]([CH2:49][C:50]3[CH:55]=[CH:54][C:53]([CH2:56][CH3:57])=[CH:52][CH:51]=3)[CH:47]=1)[O:42][CH:41]([OH:59])[CH2:40]2)C1C=CC=CC=1.[H][H]>CO.C1COCC1.[OH-].[OH-].[Pd+2]>[Cl:58][C:45]1[CH:44]=[C:43]2[O:42][CH:41]([OH:59])[CH2:40][C@@:10]3([C@H:9]([OH:8])[C@@H:14]([OH:15])[C@H:13]([OH:23])[C@@H:12]([CH2:31][OH:32])[O:11]3)[C:48]2=[CH:47][C:46]=1[CH2:49][C:50]1[CH:51]=[CH:52][C:53]([CH2:56][CH3:57])=[CH:54][CH:55]=1
Reactant: [H][H]
Reactant: CCc1ccc(Cc2cc3c(cc2Cl)OC(O)C[C@]32O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCc1ccc(Cc2cc3c(cc2Cl)OC(O)C[C@]32O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1
Yield: 88.7 %

Procedure:
To a solution of 41 (20 mg, 25 μmol) in a mixture of MeOH (1.5 mL) and THF (0.5 mL) was added Pd(OH)2 on carbon (15 mg). A balloon of hydrogen gas was attached for 0.5 h with vigorous stirring. LC/MS indicated that de-protection was complete. The reaction mixture was filtered through Celite, concentrated to a residue, and purified by preparatory HPLC to give 44 (10 mg, 90%) as a mixture of two diastereomers. LCMS m/z 433 (M−OH).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1C1C=NN(C)C=1)=[O:11].CC1C=CC([N:35]2[N:39]=[CH:38][CH:37]=[N:36]2)=C(C=1)C(O)=O>>[NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[N:35]1[N:39]=[CH:38][CH:37]=[N:36]1)=[O:11]
Reactant: Cc1ccc(-n2nccn2)c(C(=O)O)c1
Reactant: Cc1ccc(-c2cnn(C)c2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Product: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1

Procedure:
The title compound was prepared following the same general protocol as described for ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(1-methyl-1H-pyrazol-4-yl)phenyl)methanone in Example A1 using 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid. MS (ESI) 314 (M+H).
Reaction SMILES: Cl.Cl.[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17]N)=[CH:13][CH:12]=1.[CH2:19]([O:21][C:22](=[O:35])[C:23]([CH3:34])([CH3:33])[CH2:24][C:25](=O)[CH2:26][S:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH3:20].CC([O-])=O.[Na+].C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CC(O)=O.O>[CH2:19]([O:21][C:22](=[O:35])[C:23]([CH3:34])([CH3:33])[CH2:24][C:25]1[NH:17][C:14]2[C:15]([C:26]=1[S:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:16][C:11]([O:10][CH2:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][N:3]=1)=[CH:12][CH:13]=2)[CH3:20]
Reactant: NNc1ccc(OCc2ccccn2)cc1
Reactant: CCOC(=O)C(C)(C)CC(=O)CSC(C)(C)C
Agent: CC(=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)C(C)(C)Cc1[nH]c2ccc(OCc3ccccn3)cc2c1SC(C)(C)C
Yield: 62.8 %

Procedure:
[4-(Pyridin-2-ylmethoxy)-phenyl]-hydrazine dihydrochloride (75 g), 5-tert-butylsulfanyl-2,2-dimethyl-4-oxo-pentanoic acid ethyl ester (64 g), NaOAc (40 g) in toluene (800 mL) and HOAc (400 mL) was stirred at room temperature for 3 days. In one aspect, 5-tert-butylsulfanyl-2,2-dimethyl-4-oxo-pentanoic acid ethyl ester was prepared according to the procedures described in U.S. Pat. No. 5,288,743 issued Feb. 22, 1994. In another aspect, 5-tert-butylsulfanyl-2,2-dimethyl-4-oxo-pentanoic acid ethyl ester was prepared as outlined herein. The mixture was poured into water and made basic with solid Na2CO3. The mixture was extracted with EtOAc (×3), then washed with water (×2), brine, dried (MgSO4), filtered and concentrated to give a dark red-black oil. Column chromatography of the mother liquor (silica gel packed in hexanes; eluting with hexane then hexane-EtOAc 9:1 rising to 4:1) afforded 68 g of the title compound, as a yellow solid.
Reaction SMILES: C1([C@H]2C[C@H]2C(OCC)=O)C=CC=CC=1.C[O:16][C:17]([CH:19]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:20]1)=O>>[C:24]1([CH:21]2[CH2:22][CH2:23][CH:19]([CH2:17][OH:16])[CH2:20]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COC(=O)C1CCC(c2ccccc2)C1
Agent: CCOC(=O)[C@@H]1C[C@@H]1c1ccccc1
Product: OCC1CCC(c2ccccc2)C1
Yield: 86.3 %

Procedure:
Instead of ethyl cis-2-phenylcyclopropanecarboxylate, 3-phenyl-cyclopentanecarboxylic acid methyl ester (1.76 g) was used and treated by the same technique as in Reference Example 23-1(2) to give (3-phenylcyclopentyl)methanol as a colorless oil (1.31 g).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4](Cl)=[O:5].[F:12][C:13]1([F:30])[O:17][C:16]2[CH:18]=[C:19]([CH3:29])[C:20]([C:22]3[N:23]=[CH:24][C:25]([NH2:28])=[N:26][CH:27]=3)=[CH:21][C:15]=2[O:14]1.CCN(C(C)C)C(C)C>ClCCl.O1CCCC1.CO.[OH-].[Na+]>[F:30][C:13]1([F:12])[O:17][C:16]2[CH:18]=[C:19]([CH3:29])[C:20]([C:22]3[N:23]=[CH:24][C:25]([NH:28][C:4](=[O:5])[C:3]4[C:2]([F:1])=[CH:10][CH:9]=[CH:8][C:7]=4[F:11])=[N:26][CH:27]=3)=[CH:21][C:15]=2[O:14]1
Reactant: O=C(Cl)c1c(F)cccc1F
Reactant: Cc1cc2c(cc1-c1cnc(N)cn1)OC(F)(F)O2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc2c(cc1-c1cnc(NC(=O)c3c(F)cccc3F)cn1)OC(F)(F)O2
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 65.1 %

Procedure:
Under an atmosphere of argon, 2,6-difluorobenzoyl chloride (40 mg, 0.2 mmol) was added to a stirred solution of 9 (30 mg, 0.1 mmol) and Hünig's base (120 μL, 88 mg, 0.7 mmol) in dichloromethane (1.0 mL) at room temperature. The reaction was stirred for 0.5 h. The solution was diluted with tetrahydrofuran (0.9 mL), methanol (0.6 mL) and 2 M sodium hydroxide solution (0.2 mL). The mixture was stirred and heated to 60° C. for 10 min then cooled to room temperature, extracted with dichloromethane (3×5 mL), dried with sodium sulfate and concentrated under reduced pressure. Flash chromatography (ISCO system, silica, 0-20% ethyl acetate in hexane) provided 10 (26.4 mg, 58%) as a crystalline solid: LRESIMS m/z 406.1 [M+H]+, calcd. for C19H12F4N3O3 406.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([CH2:11][CH:12]=O)[CH:8]=[CH:7][C:4]=1[C:5]#[N:6].[N:14]1([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C([BH3-])#N.[Na+].CC(O)=O>CO>[C:5]([C:4]1[CH:7]=[CH:8][C:9]([CH2:11][CH2:12][N:17]2[CH2:16][CH2:15][N:14]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19][CH2:18]2)=[CH:10][C:3]=1[O:2][CH3:1])#[N:6]
Reactant: COc1cc(CC=O)ccc1C#N
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COc1cc(CCN2CCN(C(=O)OC(C)(C)C)CC2)ccc1C#N
Reaction time: 0.17 h

Procedure:
2-(Methyloxy)-4-(2-oxoethyl)benzonitrile (200 mg, 1.142 mmol), tert-butyl piperazine-1-carboxylate (532 mg, 2.85 mmol), and SODIUM CYANOBOROHYDRIDE (717 mg, 11.4 mmol) were combined in a 50 mL Flask and dissolved in MeOH. The resulting mixture was then stirred for 10 minutes followed by addition of few drops of AcOH. The mixture was stirred for overnight. The reaction mixture was concentrated to dryness, re-dissolved in EtOAc and washed with saturated NaHCO3 solution, brine, and the organic layer was dried over Na2SO4, filtered and concentrated to dryness. The residue purified by MPLC to yield the title compound. LC-MS (IE, m/z): 346 [M+1]+;
Reaction SMILES: Br.[C:2]([NH:5][CH2:6][C:7](=[NH:21])[S:8][CH2:9][C:10]([C:12]1[N:13]=[C:14]([N:17]=[C:18]([NH2:20])[NH2:19])[S:15][CH:16]=1)=O)(=[O:4])[CH3:3]>C(O)C>[C:2]([NH:5][CH2:6][C:7]1[S:8][CH:9]=[C:10]([C:12]2[N:13]=[C:14]([N:17]=[C:18]([NH2:20])[NH2:19])[S:15][CH:16]=2)[N:21]=1)(=[O:4])[CH3:3]
Reactant: CC(=O)NCC(=N)SCC(=O)c1csc(N=C(N)N)n1
Agent: Br
Solvent: CCO
Product: CC(=O)NCc1nc(-c2csc(N=C(N)N)n2)cs1
Yield: 74.4 %

Procedure:
A suspension of 4-[(2-acetylamino-1-iminoethylthio)acetyl]-2-(diaminomethyleneamino)thiazole hydrobromide (11.4 g) in ethanol (100 ml) was refluxed for 2.5 hours. The resulting precipitate was collected by filtration and suspended in water (150 ml). The mixture was alkalized to pH 11 with a saturated aqueous potassium carbonate solution. The resulting precipitate was collected by filtration. Recrystallization from water afforded 4-(2-acetylaminomethylthiazol-4-yl )-2-(diaminomethyleneamino)thiazole (6.36 g). IR (Nujol): 3250, 1640 cm-1
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:5]2[N:11]=[C:10]([CH2:12][NH:13][CH2:14][C:15]([CH3:18])([OH:17])[CH3:16])[CH:9]=[CH:8][C:6]=2[N:7]=1.[Si]([N:32]1[C:40]2[C:35](=[C:36](B3OC(C)(C)C(C)(C)O3)[C:37]([F:41])=[CH:38][CH:39]=2)[CH:34]=[CH:33]1)(C(C)(C)C)(C)C>>[F:41][C:37]1[C:36]([C:2]2[N:3]=[C:4]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[C:5]3[N:11]=[C:10]([CH2:12][NH:13][CH2:14][C:15]([CH3:18])([OH:17])[CH3:16])[CH:9]=[CH:8][C:6]=3[N:7]=2)=[C:35]2[C:40](=[CH:39][CH:38]=1)[NH:32][CH:33]=[CH:34]2
Reactant: CC1(C)OB(c2c(F)ccc3c2ccn3[Si](C)(C)C(C)(C)C)OC1(C)C
Reactant: CC(C)(O)CNCc1ccc2nc(Cl)nc(N3CCOCC3)c2n1
Product: CC(C)(O)CNCc1ccc2nc(-c3c(F)ccc4[nH]ccc34)nc(N3CCOCC3)c2n1

Procedure:
1-((2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methylamino)-2-methylpropan-2-ol (0.16 g) was reacted with 1-(tert-butyldimethylsilyl)-5-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole via General Procedure A to produce 75.9 mg of 143 following reverse phase HPLC purification. MS (Q1) 451.2 (M)+