Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([O:4][C@H:5]1[C:14]2[C@@:15]3([CH3:30])[C@@H:26]([CH2:27][O:28][CH3:29])[O:25][C:23](=[O:24])[C:17]4=[CH:18][O:19][C:20]([C:21](=[O:22])[C:13]=2[C@@H:8]2[CH2:9][CH2:10][C@H:11]([OH:12])[C@@:7]2([CH3:31])[CH2:6]1)=[C:16]34)=[O:3].[CH3:32][N:33]([CH3:38])[CH2:34][CH2:35][CH2:36][NH2:37]>C(Cl)Cl>[C:2]([O:4][C@H:5]1[C:14]2[C@:15]3([CH3:30])[C:16](/[C:17](=[CH:18]/[NH:37][CH2:36][CH2:35][CH2:34][N:33]([CH3:38])[CH3:32])/[C:23](=[O:24])[O:25][C@@H:26]3[CH2:27][O:28][CH3:29])=[C:20]([OH:19])[C:21](=[O:22])[C:13]=2[CH:8]2[C@@:7]([CH3:31])([C@@H:11]([OH:12])[CH2:10][CH2:9]2)[CH2:6]1)(=[O:3])[CH3:1]
Reactant: COC[C@H]1OC(=O)c2coc3c2[C@@]1(C)C1=C(C3=O)[C@@H]2CC[C@H](O)[C@@]2(C)C[C@H]1OC(C)=O
Reactant: CN(C)CCCN
Solvent: ClCCl
Product: COC[C@H]1OC(=O)/C(=C\NCCCN(C)C)C2=C(O)C(=O)C3=C([C@H](OC(C)=O)C[C@@]4(C)C3CC[C@@H]4O)[C@]21C
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.4 %

Procedure:
To a solution of 100 mg (0.23 mmol) 17-hydroxywortmannin in 2 mL CH2Cl2 is added 58 μL (0.46 mmol) N,N-dimethyl-1,3-propanediamine. The reaction mixture is stirred at room temperature overnight. CH2Cl2 is removed in vacuo. The residue is triturated with Et2O to give 74 mg (60%) product as an orange powder. MS (ESI) m/z 533 (M+1).
Reaction SMILES: [CH2:1]([OH:5])[CH:2]([OH:4])[CH3:3].C1(C)C=CC(S(O)(=O)=O)=CC=1.[Cl:17][C:18]1[C:19]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([CH:35](OC)OC)[CH:29]=2)=[N:20][CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1>C1(C)C=CC=CC=1>[Cl:17][C:18]1[C:19]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([CH:35]3[O:4][CH:2]([CH3:3])[CH2:1][O:5]3)[CH:29]=2)=[N:20][CH:21]=[C:22]([C:24]([F:26])([F:27])[F:25])[CH:23]=1
Reactant: CC(O)CO
Reactant: COC(OC)c1cc(-c2ncc(C(F)(F)F)cc2Cl)ccc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC1COC(c2cc(-c3ncc(C(F)(F)F)cc3Cl)ccc2Cl)O1
Temperature: 23 °C
Reaction time: 16 h

Procedure:
2.0 g of 1,2-propanediol and 100 mg of p-toluenesulfonic acid were added to 3.2 g of 3-chloro-2-(4-chloro-3-dimethoxymethylphenyl)-5-trifluoromethylpyridine in 100 ml of anhydrous toluene. The mixture was then refluxed for two hours and stirred at 23° C. for 16 hours. Extraction was carried out first with 50 ml of a 10% by weight sodium bicarbonate solution and then three times with 80 ml of water each time, after which the organic solution was dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel with cyclohexane/ethyl acetate (10:1). Yield: 3.1 g (94%) of a colorless oil (1:1 mixture of diastereomers);
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1.[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(Cl)Cl.CO.[BH4-].[Na+]>C1(C)C=CC=CC=1.CO>[CH2:18]([N:13]1[CH2:12][CH:11]=[C:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[O:3][C:2]([F:1])([F:16])[F:17])[CH2:15][CH2:14]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: FC(F)(F)Oc1ccccc1-c1ccncc1
Reactant: BrCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: ClCCl
Product: FC(F)(F)Oc1ccccc1C1=CCN(Cc2ccccc2)CC1
Temperature: 0 °C
Yield: 61 %

Procedure:
To a solution of 4-(2-trifluoromethoxy-phenyl)-pyridine in toluene was added (1 eq.) benzyl bromide, and reaction mixture was stirred under reflux for 2 h. Reaction was monitored by TLC (CH2Cl2/MeOH 95:5) and revealed total conversion to the first intermediate. Complete evaporation of solvent gave a white solid which was pure enough to carry out the next step. The white solid was dissolved in MeOH under argon and cooled down to 0° C., (4 eq.) NaBH4 was added portion-wise (exothermic reaction). The reaction mixture was then stirred for 3 h at RT, reaction again monitored by TLC (CH2Cl2/MeOH 95:5) and revealed total conversion. Evaporation of MeOH, redissolution in CH2Cl2, and washing with 1N NaHCO3 then brine, and evaporation, followed by SiO2 gel chromatography (CH2Cl2/MeOH) gave the title compound in 61% yield.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:4]([CH3:15])[CH:3]=1.[Br:16][C:17]1[N:22]=[C:21]([CH:23](O)[CH2:24][O:25][CH2:26][CH3:27])[CH:20]=[CH:19][CH:18]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C(Cl)Cl>[Br:16][C:17]1[N:22]=[C:21]([CH:23]([S:1][C:2]2[CH:7]=[CH:6][C:5]([O:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:4]([CH3:15])[CH:3]=2)[CH2:24][O:25][CH2:26][CH3:27])[CH:20]=[CH:19][CH:18]=1
Reactant: CCOC(=O)COc1ccc(S)cc1C
Reactant: CCOCC(O)c1cccc(Br)n1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOCC(Sc1ccc(OCC(=O)OCC)c(C)c1)c1cccc(Br)n1
Temperature: 25 °C

Procedure:
A solution of (ethyl [(4-mercapto-2-methylphenyl)oxy]acetate) (386 mg, 1.71 mmol), 1-(6-bromo-2-pyridinyl)-2-(ethyloxy)ethanol (352 mg, 1.43 mmol) and PPh3 (450 mg, 1.72 mmol) in DCM (17 mL) at 0° C. under nitrogen was stirred for 10 mins and then treated drop-wise with DIAD (0.34 mL, 1.73 mmol). The resulting mixture was then stirred, with slow warming to ambient temperature over 18 h. The mixture was then reduced under vacuum and the resulting yellow oil purified by SPE (silica, 20 g cartridge), eluting with cyclohexane:EtOAc (gradient 15:1 to 5:1). Further purification using the OPTIX-SPE (C18 cartridge, 50 g) eluting with 60-80% MeCN (+0.05% HCOOH) in H2O (+0.01% HCOOH) over 56 mins afforded the title compound as an oil (232 mg).
Reaction SMILES: [Cl:1][C:2]1[C:7](I)=[C:6]([CH3:9])[N:5]=[C:4]([NH2:10])[N:3]=1.[CH3:11][Si:12]([C:15]#[CH:16])([CH3:14])[CH3:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[C:7]([C:16]#[C:15][Si:12]([CH3:14])([CH3:13])[CH3:11])=[C:6]([CH3:9])[N:5]=[C:4]([NH2:10])[N:3]=1
Reactant: C#C[Si](C)(C)C
Reactant: Cc1nc(N)nc(Cl)c1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nc(N)nc(Cl)c1C#C[Si](C)(C)C

Procedure:
The title compound is synthesized according to general procedure GP2 starting from 5.0 g (19 mmol) 4-chloro-5-iodo-6-methyl-pyrimidin-2-ylamine (GP3) and 3.6 mL (26 mmol) trimethylsilylethyne using 352 mg (1.9 mmol) CuI, 485 mg triphenylphosphine (1.9 mmol), 1.3 g (1.9 mmol) PdCl2(PPh3)2 and 26 mL (185 mmol) triethylamine in 100 mL dry DMF. For the work-up the solvent is removed in vacuo and the product is purified by RP-MPLC (ACN/H2O gradient). Yield: 1.6 g (38%).
Reaction SMILES: C([Li])CCC.[C:6]([O:10][C:11](=[O:37])[N:12]([C:14]1[CH:19]=[C:18]([CH3:20])[C:17]([CH2:21][CH2:22][S:23]([N:26]2[CH2:35][CH2:34][C:29]3([O:33][CH2:32][CH2:31][O:30]3)[CH2:28][CH2:27]2)(=[O:25])=[O:24])=[C:16]([CH3:36])[CH:15]=1)[CH3:13])([CH3:9])([CH3:8])[CH3:7].Br[CH2:39][CH2:40][Cl:41].[Cl-].[NH4+]>C1COCC1>[C:6]([O:10][C:11](=[O:37])[N:12]([C:14]1[CH:19]=[C:18]([CH3:20])[C:17]([CH2:21][CH:22]([S:23]([N:26]2[CH2:27][CH2:28][C:29]3([O:33][CH2:32][CH2:31][O:30]3)[CH2:34][CH2:35]2)(=[O:24])=[O:25])[CH2:39][CH2:40][Cl:41])=[C:16]([CH3:36])[CH:15]=1)[CH3:13])([CH3:9])([CH3:8])[CH3:7]
Reactant: ClCCBr
Reactant: Cc1cc(N(C)C(=O)OC(C)(C)C)cc(C)c1CCS(=O)(=O)N1CCC2(CC1)OCCO2
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1cc(N(C)C(=O)OC(C)(C)C)cc(C)c1CC(CCCl)S(=O)(=O)N1CCC2(CC1)OCCO2
Reaction time: 0.33 h
Yield: 60 %

Procedure:
n-Butyllithium (1.6 M solution in hexane, 0.58 ml, 0.93 mmol) was added to a solution of {4-[2-(1,4-dioxa-8-aza-spiro[4.5]decane-8-sulfonyl)-ethyl]-3,5-dimethyl-phenyl}-methyl-carbamic acid tert-butyl ester (195.7 mg, 0.4176 mmol) in THF (4.2 ml) at −78° C. over six minutes, and the mixture was stirred at the same temperature for 20 minutes. 1-Bromo-2-chloro-ethane (105 μl, 1.26 mmol) was added to the reaction solution at −78° C. within 10 minutes. The mixture was then stirred while warming from −78° C. to 0° C. over one hour, and further stirred at room temperature for one hour. A 50% saturated aqueous ammonium chloride solution was added, followed by extraction with ethyl acetate. The organic layer was then dried over MgSO4 and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=5/2) to give {4-[4-chloro-2-(1,4-dioxa-8-aza-spiro[4.5]decane-8-sulfonyl)-butyl]-3,5-dimethyl-phenyl}-methyl-carbamic acid tert-butyl ester (133 mg, 60%).
Reaction SMILES: Cl.[C:2]([C:4]1[CH:5]=[C:6]([N:10]([CH:27]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[C:11]([NH:13][CH:14]2[CH2:19][CH2:18][N:17]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:16][CH2:15]2)=[O:12])[CH:7]=[CH:8][CH:9]=1)#[N:3].C(=O)([O-])[O-].[NH4+:38].[NH4+]>C(O)C>[C:2]([C:4]1[CH:5]=[C:6]([N:10]([CH:27]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[C:11]([NH:13][CH:14]2[CH2:19][CH2:18][N:17]([CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:16][CH2:15]2)=[O:12])[CH:7]=[CH:8][CH:9]=1)(=[NH:38])[NH2:3]
Reactant: [NH4+]
Reactant: N#Cc1cccc(N(C(=O)NC2CCN(Cc3ccccc3)CC2)C2CCCCCC2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: N=C(N)c1cccc(N(C(=O)NC2CCN(Cc3ccccc3)CC2)C2CCCCCC2)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Dry hydrogen chloride gas was bubbled through an ice cooled solution of N-(3-cyanophenyl)-N′-(1-benzylpiperidin-4-yl)cycloheptylurea (0.03 g, 0.077 mmol) in anhydrous ethanol (10 ml) under a nitrogen atmosphere for 15 min. The reaction was stoppered, allowed to warm to ambient temperature and stirred for 24 h. The reaction was concentrated to a solid and dissolved in anhydrous ethanol (5 ml) and ammonium carbonate (0.023 g, 0.23 mmol) was added. The reaction mixture was stirred at ambient temperature overnight then was concentrated in vacuo. N-(3-Amidinophenyl)-N′-(1-benzylpiperidin-4-yl)cycloheptylurea was purified by HPLC on a Vydec® C-18 column eluting with solvent mixture A (acetonitrile:water:TFA 80:20:0.3) and solvent mixture B (water:TFA 99.7:0.3) using a gradient starting with A:B at 3:97 and changing to A:B at 70:30 over 15 min. The major fraction eluting at 15 minutes was concentrated to give N-(3-amidinophenyl)-N′-(1-benzylpiperidin-4-yl)cycloheptylurea as an amorphous solid; LRMS (M+H)+ m/z 406, (M+2H)+2 m/z 203.8; 1H NMR (DMSO-d6): 9.52(broad s, 1H), 9.27(s, 2H), 9.02(s, 2H), 7.5(m, 9H), 4.3(m,m, 2H), 3.95(m, 1H), 3.67(m, 2H), 3.42(m, 2H), 3.2(m,2H), 3.1(m, 2H), 2.05-1.6(m, 8H).
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[CH2:9]([O:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1)[CH2:10][CH2:11][CH3:12]>>[CH2:9]([O:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([NH:1][C:2]2[O:6][N:5]=[C:4]([CH3:7])[C:3]=2[Br:8])(=[O:22])=[O:21])=[CH:16][CH:15]=1)[CH2:10][CH2:11][CH3:12]
Reactant: Cc1noc(N)c1Br
Reactant: CCCCOc1ccc(S(=O)(=O)Cl)cc1
Product: CCCCOc1ccc(S(=O)(=O)Nc2onc(C)c2Br)cc1
Yield: 33 %

Procedure:
4-Butoxy-N-(4-bromo-3-methyl-5-isoxazolyl) benzenesulfonamide was prepared from 5-amino-4-bromo-3-methylisoxazole and 4-butoxybenzenesulfonyl chloride according to the procedures described in Example 30. The crude product was purified by recrystallization from ethyl acetate/hexanes to give a crystalline solid, m.p. 98-100° C., yield 33%.
Reaction SMILES: C([Li])CCC.N1CCOCC1.[O:12]1[CH:16]=[CH:15][C:14]([CH:17]=[O:18])=[CH:13]1.C([Li])(CC)C.[CH2:24]([Si:26](Cl)([CH2:29][CH3:30])[CH2:27][CH3:28])[CH3:25].Cl>CCCCCC.O1CCCC1.C1CCCCC1>[CH2:24]([Si:26]([CH2:29][CH3:30])([CH2:27][CH3:28])[C:16]1[O:12][CH:13]=[C:14]([CH:17]=[O:18])[CH:15]=1)[CH3:25]
Reactant: O=Cc1ccoc1
Reactant: CC[Si](Cl)(CC)CC
Agent: Cl
Agent: [Li]C(C)CC
Agent: [Li]CCCC
Solvent: C1COCCN1
Solvent: C1CCCCC1
Solvent: CCCCCC
Product: CC[Si](CC)(CC)c1cc(C=O)co1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
n-Butyl lithium (a 2.5 M solution in hexane; 30.6 ml, 76.5 mmol) was added to a solution of morpholine (6.66 ml, 76.5 mmol) in tetrahydrofuran (500 ml) at -78° under argon. After 15 minutes, 3-furaldehyde (6.3 ml, 72.8 mmol) was added. After another 20 minutes, sec-butyl lithium (a 1.3 M solution in cyclohexane; 59.0 ml, 76.5 mmol) was added dropwise and stirring continued at -78° for about 2 hours before triethylsilylchloride (13.4 ml, 80.1 mmol) was added. Stirring was continued overnight (14 hours) while the cooling bath was allowed to attain room temperature. The solution was poured into ice cold 10% (v/v) hydrochloric acid (100 ml) and after stirring at 0° for 10 minutes, the layers were separated. The aqueous phase was extracted with diethyl ether. All the organic phases were combined, dried (magnesium sulfate) and evaporated down to give an oil, which was distilled under high vacuum to give the 5-triethylsily-3-furaldehyde as a pale yellow oil, boiling point 85°-90°/0.4 torr.
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[C:6]([N:9]2[CH2:14][CH2:13][N:12]([CH3:15])[C@H:11]([CH3:16])[CH2:10]2)[N:5]=[C:4]([CH3:17])[N:3]=1.O.[NH2:19][NH2:20]>CS(C)=O>[CH3:16][C@H:11]1[N:12]([CH3:15])[CH2:13][CH2:14][N:9]([C:6]2[C:7]([F:8])=[C:2]([NH:19][NH2:20])[N:3]=[C:4]([CH3:17])[N:5]=2)[CH2:10]1
Reactant: NN
Reactant: Cc1nc(Cl)c(F)c(N2CCN(C)[C@H](C)C2)n1
Solvent: CS(C)=O
Solvent: O
Product: Cc1nc(NN)c(F)c(N2CCN(C)[C@H](C)C2)n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 33 %

Procedure:
To 4-chloro-6-[(3R)-3,4-dimethyl-1-piperazinyl]-5-fluoro-2-methylpyrimidine (0.242 g, 0.94 mmol) in DMSO (3 mL) was added hydrazine monohydrate (2 mL). The reaction was stirred at room temperature for 3 days. Removed volatiles in vacuo and purified by RP-HPLC to provide 4-[(3R)-3,4-dimethyl-1-piperazinyl]-5-fluoro-6-hydrazino-2-methylpyrimidine as a yellow solid (0.079 g, 33%). LCMS: (M+H)+=255.3.
Reaction SMILES: C([O:8][C:9](=[O:78])[CH2:10][C@@H:11]([C:23](=[O:77])[NH:24][CH2:25][CH2:26][CH2:27][NH:28][C@@H:29]([C@H:37]([CH:39]1[C@@H:43]([O:44][Si:45]([C:48]([CH3:51])([CH3:50])[CH3:49])([CH3:47])[CH3:46])[C@@H:42]([O:52][Si:53]([C:56]([CH3:59])([CH3:58])[CH3:57])([CH3:55])[CH3:54])[C@H:41]([N:60]2[CH:65]=[CH:64][C:63](=[O:66])[N:62]([CH2:67][C:68]3[CH:73]=[CH:72][C:71]([O:74][CH3:75])=[CH:70][CH:69]=3)[C:61]2=[O:76])[O:40]1)[OH:38])[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[NH:12]C(=O)OCC1C=CC=CC=1)C1C=CC=CC=1>CO.[Pd]>[NH2:12][C@H:11]([C:23]([NH:24][CH2:25][CH2:26][CH2:27][NH:28][C@H:29]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C@@H:37]([CH:39]1[C@@H:43]([O:44][Si:45]([C:48]([CH3:51])([CH3:49])[CH3:50])([CH3:47])[CH3:46])[C@@H:42]([O:52][Si:53]([C:56]([CH3:59])([CH3:58])[CH3:57])([CH3:55])[CH3:54])[C@H:41]([N:60]2[CH:65]=[CH:64][C:63](=[O:66])[N:62]([CH2:67][C:68]3[CH:73]=[CH:72][C:71]([O:74][CH3:75])=[CH:70][CH:69]=3)[C:61]2=[O:76])[O:40]1)[OH:38])=[O:77])[CH2:10][C:9]([OH:78])=[O:8]
Reactant: COc1ccc(Cn2c(=O)ccn([C@@H]3OC([C@H](O)[C@H](NCCCNC(=O)[C@H](CC(=O)OCc4ccccc4)NC(=O)OCc4ccccc4)C(=O)OC(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]3O[Si](C)(C)C(C)(C)C)c2=O)cc1
Agent: [Pd]
Solvent: CO
Product: COc1ccc(Cn2c(=O)ccn([C@@H]3OC([C@@H](O)[C@H](NCCCNC(=O)[C@@H](N)CC(=O)O)C(=O)OC(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]3O[Si](C)(C)C(C)(C)C)c2=O)cc1
Yield: 99.4 %

Procedure:
By using an analogous procedure to that described for Example 2, tert-butyl (5S,12S)-5-[2-(benzyloxy)-2-oxoethyl]-12-[(R)-[(3R,4R,5R)-3,4-bis{[tert-butyl(dimethyl)silyl]oxy}-5-(3-(4-methoxybenzyl)-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl)tetrahydro-2-furanyl](hydroxy)methyl]-3,6-dioxo-1-phenyl-2-oxa-4,7,11-triazatridecan-13-oate (20 mg, 0.018 mmol, obtained from Example 16) was hydrogenated in methanol (1.5 ml) using 10% palladium on carbon (10 mg) to provide (3S)-3-amino-4-[(3-{[(1S,2S)-2-[(3R,4R,5R)-3,4-bis{[tert-butyl(dimethyl)silyl]oxy}-5-(3-(4-methoxybenzyl)-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl)tetrahydro-2-furanyl]-1-(tert-butoxycarbonyl)-2-hydroxyethyl]amino}propyl)amino]-4-oxobutanoic acid (16 mg, 99%) as a white solid.
Reaction SMILES: [ClH:1].[NH:2]1[CH2:12][CH2:11][CH2:10][CH2:9][CH:3]1[C:4]([O:6]CC)=[O:5].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[ClH:1].[CH2:13]([N:2]1[CH2:12][CH2:11][CH2:10][CH2:9][CH:3]1[C:4]([OH:6])=[O:5])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCOC(=O)C1CCCCN1
Reactant: BrCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)C1CCCCN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.5 %

Procedure:
A mixture of ethyl pipecolinate hydrochloride (10 g, 52 mmol), benzylbromide (7 mL, 57 mmol) and potassium carbonate (15 g, 114 mmol) in DMF (80 mL) was stirred at room temperature overnight. The solvent was removed in vacuo. The residue was partitioned between dichloromethane (100 mL) and water (50 mL). The aqueous layer was extracted with dichloromethane (2×100 mL), dried over Na2SO4, then evaporated to give a yellow oil. The crude product was chromatographed (500 g silica gel) eluting with a stepgradient of 8%-15% ethyl acetate in hexane. Pure fractions were combined to give title compound (12.3 g, 96%) as a colorless oil.
Reaction SMILES: C([O:3][C:4](=[O:42])[C:5]([O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][C:24]2[N:25]=[C:26]([C:30]3[CH:31]=[C:32]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[CH:33]=[CH:34][CH:35]=3)[O:27][C:28]=2[CH3:29])=[CH:17][CH:16]=1)([CH3:13])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)C.[OH-].[Na+]>CO>[C:32]1([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:33]=[CH:34][CH:35]=[C:30]([C:26]2[O:27][C:28]([CH3:29])=[C:24]([CH2:23][CH2:22][O:21][C:18]3[CH:19]=[CH:20][C:15]([O:14][C:5]([CH3:13])([CH2:6][C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)[C:4]([OH:42])=[O:3])=[CH:16][CH:17]=3)[N:25]=2)[CH:31]=1
Reactant: CCOC(=O)C(C)(Cc1ccccc1)Oc1ccc(OCCc2nc(-c3cccc(-c4ccccc4)c3)oc2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1oc(-c2cccc(-c3ccccc3)c2)nc1CCOc1ccc(OC(C)(Cc2ccccc2)C(=O)O)cc1
Reaction time: 0.5 h

Procedure:
2-{4-[2-(2-Biphenyl-3-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenoxy}-2-methyl-3-phenyl-propionic acid ethyl ester (24.7 mmol) was dissolved in methanol (200 mL) and 2N NaOH (150 mL) was added. The resulting cloudy solution became clear after 30 min and the reaction was stirred vigorously overnight. The solution was concentrated under reduced pressure, diluted with H2O (100 mL) and acidified to pH=1 with 5N HCl. The mixture was extracted with ethyl acetate (2×200 mL), dried (MgSO4), and concentrated under reduced pressure to provide an oil. The oil (8.23 g) was recrystallized from ethyl acetate (24 mL) and hexanes (56 mL) to afford 2-{4-[2-(2-biphenyl-3-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenoxy}-2-methyl-3-phenyl-propionic acid as colorless needles after drying at 50° C. under vacuum for 6 h: 1H NMR (400 MHz, CDCl3) δ8.23-8.21 (m, 1H), 7.94 (d, 1H, J=7.43 Hz), 7.65 (dd, 3H, J=7.04 Hz, J=1.17 Hz), 7.50 (t, 1H, J=7.63 Hz), 7.45 (t, 2H, J=7.04 Hz), 7.38-7.28 (m, 1H), 7.28-7.25 (m, 5H), 6.84 (d, 2H, J=8.99 Hz), 6.75 (d, 2H, J=8.99 Hz), 4.16 (t, 2H, J=6.45 Hz), 3.31 (d, 1H, J=13.69 Hz), 3.14 (d, 1H, J=13.69 Hz), 3.01 (t, 2H, J=6.45 Hz), 2.40 (s, 3H), 1.34 (s, 3H); HRMS (ES+) m/z exact mass calculated for C34H32NO5 534.2280, found 534.2278.
Reaction SMILES: [F:1][C:2]1([F:25])[CH2:7][CH2:6][CH2:5][C:4]([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17](Cl)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])([OH:8])[CH2:3]1.CCN(C(C)C)C(C)C.[F:35][C:36]1([F:40])[CH2:39][NH:38][CH2:37]1>>[F:1][C:2]1([F:25])[CH2:7][CH2:6][CH2:5][C:4]([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([N:38]4[CH2:39][C:36]([F:40])([F:35])[CH2:37]4)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])([OH:8])[CH2:3]1
Reactant: FC1(F)CNC1
Reactant: O=C(NCC1(O)CCCC(F)(F)C1)c1c(Cl)ccc2nc(Cl)ccc12
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC1(O)CCCC(F)(F)C1)c1c(Cl)ccc2nc(N3CC(F)(F)C3)ccc12

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid (3,3-difluoro-1-hydroxycyclohexylmethyl)-amide, DIPEA and 3,3-difluoroazetidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.75 (1H), 7.94 (m, 1H), 7.66 (2H), 7.05 (1H), 4.57 (m, 4H), 3.49 (m, 2H), 2.44 (m, 2H), 2.06 (m, 2H), 1.85 (m, 2H), 1.74-1.76 (m, 5H), 1.27-1.32 (m, 2H). m/z: 446 [M+H]
Reaction SMILES: [NH2:1][C:2]1[C:3](=[S:17])[NH:4][C:5]([C:8]2([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1.[F:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1.NC1C(=S)NC=CC=1>>[F:18][C:19]1[CH:26]=[CH:25][C:22]([C:23]2[S:17][C:3]3[C:2]([N:1]=2)=[CH:7][CH:6]=[C:5]([C:8]2([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[CH2:10][CH2:9]2)[N:4]=3)=[CH:21][CH:20]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: Nc1ccc(C2(c3ccccc3)CC2)[nH]c1=S
Agent: Nc1ccc[nH]c1=S
Product: Fc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)cc1

Procedure:
Reaction of 3-amino-6-(1-phenylcyclopropyl)pyridine-2(1H)-thione (52.6 mg, 0.217 mmol) and 4-fluorobenzaldehyde (22 μl, 0.206 mmol) according to Reference V and the general procedure for the condensation of 3-aminopyridine-2-thione with aryl acid chlorides gave 2-(4-fluorophenyl)-5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine as a white solid. MS (ESI) m/z: Calculated: 346.1; Observed: 347.1 (M++1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:15]4[CH:17]=[C:18]([N+:21]([O-:23])=[O:22])[CH:19]=[CH:20][C:14]=4[CH2:13][CH2:12][C:11]=3[C:10]([C:24]([O:26]CC)=[O:25])=[N:9]2)=[CH:4][CH:3]=1.[OH-].[Na+].Cl>C1COCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:15]4[CH:17]=[C:18]([N+:21]([O-:23])=[O:22])[CH:19]=[CH:20][C:14]=4[CH2:13][CH2:12][C:11]=3[C:10]([C:24]([OH:26])=[O:25])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1nn(-c2ccc(Br)cc2)c2c1CCc1ccc([N+](=O)[O-])cc1-2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(O)c1nn(-c2ccc(Br)cc2)c2c1CCc1ccc([N+](=O)[O-])cc1-2
Reaction time: 8 h
Yield: 97.1 %

Procedure:
A suspension of ethyl 1-(4-bromophenyl)-8-nitro-4,5-dihydro-1H-benzo[g]indazole-3-carboxylate (4.4 g) in THF (80 mL) was treated with 1 N aq. NaOH (80 mL) and stirred vigorously overnight. The reaction mixture was diluted with ethyl acetate and acidified to pH=2 with 1 N aq. HCl. The organic layer was separated and the aqueous fraction extracted with EtOAc (3×). Combined extracts were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to afford 4.0 g (97%) of 1-(4-bromophenyl)-8-nitro-4,5-dihydro-1H-benzo[g]indazole-3-carboxylic acid as a solid: MS(ESI+) 414 [M+H]+. 1H NMR (400 MHz, d6 DMSO) δ 8.07 (dd, 1H), 7.83 (d, 2H), 7.66 (d, 1H), 7.56 (d, 2H), 7.42 (d, 1H), 3.10 (m, 2H), 2.99 (m, 2H).
Reaction SMILES: C([O:5][C:6](=[O:24])[CH2:7][N:8]1[CH2:12][CH2:11][CH:10]([C:13](=[O:23])[NH:14][C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([Cl:22])[CH:16]=2)[CH2:9]1)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Cl:22][C:17]1[CH:16]=[C:15]([NH:14][C:13]([CH:10]2[CH2:11][CH2:12][N:8]([CH2:7][C:6]([OH:24])=[O:5])[CH2:9]2)=[O:23])[CH:20]=[CH:19][C:18]=1[OH:21]
Reactant: CC(C)(C)OC(=O)CN1CCC(C(=O)Nc2ccc(O)c(Cl)c2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CN1CCC(C(=O)Nc2ccc(O)c(Cl)c2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
[3-(3-Chloro-4-hydroxy-phenylcarbamoyl)-pyrrolidin-1-yl]-acetic acid tert-butyl ester was dissolved in TFA/DCM (90:10) solution. After stirring at RT for 30 min, the reaction mixture was concentrated and acetonitrile/water (10 ml, 3:1) was added. After removal of solvent, the residue was purified using Prep-HPLC to give 450 mg of product.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([CH3:30])[CH:20]=[C:21]([C:22]4[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=4[Cl:29])[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:31][NH2:32]>>[Cl:29][C:23]1[CH:24]=[CH:25][CH:26]=[C:27]([Cl:28])[C:22]=1[C:21]1[C:15]2[O:14][CH:13]([CH2:12][NH:32][CH3:31])[CH2:17][C:16]=2[CH:18]=[C:19]([CH3:30])[CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(C)cc(-c4c(Cl)cccc4Cl)c3O2)cc1
Reactant: CN
Product: CNCC1Cc2cc(C)cc(-c3c(Cl)cccc3Cl)c2O1

Procedure:
The title compound was prepared (0.073 g, 78%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[7-(2,6-dichlorophenyl) 5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.12 g, 0.26 mmol) and methylamine (0.080 g, 2.6 mmol). mp 192-195° C.