Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[Br:3][C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]([NH:12][CH2:13][CH2:14][CH2:15][CH:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[NH2:17])[CH3:11])=[CH:6][CH:5]=1.CCN(C(C)C)C(C)C.Cl[C:34](Cl)([O:36]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl.CCOCC>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([C@@H:10]([N:12]2[CH2:13][CH2:14][CH2:15][CH:16]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:17][C:34]2=[O:36])[CH3:11])=[CH:8][CH:9]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: C[C@H](NCCCC(N)c1ccccc1)c1ccc(Br)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Solvent: ClCCl
Product: C[C@@H](c1ccc(Br)cc1)N1CCCC(c2ccccc2)NC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 25 %

Procedure:
A stirred solution of N1—((1S)-1-(4-bromophenyl)ethyl)-4-phenylbutane-1,4-diamine dihydrochloride (19.5 mg, 0.046 mmol) and i-Pr2NEt (0.10 mL, 0.56 mmol) in CH2Cl2 (8 mL) was cooled in an ice bath and solid triphosgene (4.6 mg, 0.015 mmol) was added. The ice bath was allowed to melt and the mixture was stirred overnight at rt. The mixture was diluted with ether (90 mL), washed with 5% aq HCl (20 mL) and satd aq NaHCO3 (20 mL), and dried over MgSO4. Removal of the solvent left a residue (17.5 mg) which was purified by preparative HPLC to afford 1-((S)-1-(4-bromophenyl)ethyl)-4-phenyl-1,3-diazepan-2-one (1.4 mg, 8%). LC-MS (3 min) tR=2.05 min, m/z=375, 373.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:11])=[N:4][CH:5]=[C:6]([CH:10]=1)C(O)=O.[I:12]I.[I-]>>[Cl:1][C:2]1[C:3]([OH:11])=[N:4][CH:5]=[C:6]([I:12])[CH:10]=1
Reactant: O=C(O)c1cnc(O)c(Cl)c1
Reactant: II
Agent: [I-]
Product: Oc1ncc(I)cc1Cl

Procedure:
Alternatively, the present compound is prepared by reacting 5-chloro-6-hydroxynicotinic acid with I2 in an aqueous alkaline iodide solution to form 3-chloro-5-iodo-2-pyridinol. This reaction is conveniently conducted at an elevated temperature of between 40° C. and 150° C. and preferably at about 100° C. Lowering the pH of the reaction mixture to ≤1 such as, for example, by addition to the reaction mixture of SO2, will precipitate the 3-chloro-5-iodo-2-pyridinol from the reaction mixture.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([N+:42]([O-:44])=[O:43])[CH:37]=2)[C:7]([C:13]([O:15][CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][NH:28]C(OC(C)(C)C)=O)=[CH:21][CH:20]=2)=[O:14])=[C:8]([CH3:12])[NH:9][C:10]=1[CH3:11])=[O:4]>C(O)=O>[CH3:1][O:2][C:3]([C:5]1[CH:6]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([N+:42]([O-:44])=[O:43])[CH:37]=2)[C:7]([C:13]([O:15][CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][NH2:28])=[CH:21][CH:20]=2)=[O:14])=[C:8]([CH3:12])[NH:9][C:10]=1[CH3:11])=[O:4]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCOc2ccc(OCCNC(=O)OC(C)(C)C)cc2)C1c1cccc([N+](=O)[O-])c1
Solvent: O=CO
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCOc2ccc(OCCN)cc2)C1c1cccc([N+](=O)[O-])c1
Reaction time: 6 h

Procedure:
14.6 g of the product obtained in step (2c) are dissolved in 50 ml of formic acid. The solution is allowed to stand for 6 hours at room temperature and is worked up analogously to Example (1d). A crystalline crude product is thus obtained, which, after recrystallisation from acetonitrile, yields 1,4-dihydro-2,6-dimethyl-4-(m-nitrophenyl)-pyridine-3,5-dicarboxylic acid 3-{2-[p-(2-aminoethoxy)-phenoxy]-ethyl}-ester 5-methyl ester, which has a melting point of 153°-154°.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:8][CH2:7][N:6]1[S:9]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:11])=[O:10])=[O:4].[Li+].[OH-].Cl>CO.O>[C:13]1([CH2:12][S:9]([N:6]2[CH2:7][CH2:8][C@H:5]2[C:3]([OH:4])=[O:2])(=[O:11])=[O:10])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COC(=O)[C@@H]1CCN1S(=O)(=O)Cc1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)[C@@H]1CCN1S(=O)(=O)Cc1ccccc1
Reaction time: 8 h
Yield: 94 %

Procedure:
To a solution of (2S)-Methyl-1-(α-toluenesulfonyl)azetidine-2-carboxylate from Reference Example 7 (378.4 mg; 1.40 mmol) in methanol (7.0 mL) was added 1N LiOH in water (2.6 mL) at about 0° C. The mixture was warmed to about room temperature and stirred under argon overnight. The pH was adjusted to about pH 1 by adding 1N HCl and then the mixture was diluted with water and extracted into ethyl acetate. The organic layer was dried over magnesium sulfate and then concentrated to give 335.7 mg (94% yield) of the product as a white solid. 1H NMR (CDCl3) δ 2.37-2.57 (m, 2H); 3.21-3.31 (m, 1H); 4.01 (q, 1H, J=8.6); 4.33 (d, 1H, J=13.7); 4.44 (d, 1H, J=13.7); 4.98 (dd, 1H, J=9.4, 8.6); 7.34-7.53 (series of m, 5H).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]([CH3:18])[C:16]([C:19]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[CH2:23][CH2:22]3)=[O:20])=[C:15](I)[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[N:35]1[CH:40]=[C:39](B(O)O)[CH:38]=[N:37][CH:36]=1>>[F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]([CH3:18])[C:16]([C:19]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[CH2:23][CH2:22]3)=[O:20])=[C:15]([C:39]3[CH:40]=[N:35][CH:36]=[N:37][CH:38]=3)[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: Cn1c(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)nc(I)c1C(=O)N1CCC(N2CCCC2)CC1
Reactant: OB(O)c1cncnc1
Product: Cn1c(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)nc(-c2cncnc2)c1C(=O)N1CCC(N2CCCC2)CC1

Procedure:
In analogy to the procedure described for example 7, [2-(3,5-bis-trifluoromethyl-phenyl)-5-iodo-3-methyl-3H-imidazol-4-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 60) was reacted with pyrimidine-5-yl-boronic acid to give the title compound as yellow solid. MS: 553.1 (MH+).
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8](OS(C(F)(F)F)(=O)=O)[CH:9]=2)[C:4](=[O:19])[CH2:3]1.[Cl:21][C:22]1[S:26][C:25](B(O)O)=[CH:24][CH:23]=1>>[Cl:21][C:22]1[S:26][C:25]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[C:4](=[O:19])[CH2:3][C:2]3([CH3:1])[CH3:20])=[CH:24][CH:23]=1
Reactant: OB(O)c1ccc(Cl)s1
Reactant: CC1(C)CC(=O)c2ccc(OS(=O)(=O)C(F)(F)F)cc21
Product: CC1(C)CC(=O)c2ccc(-c3ccc(Cl)s3)cc21

Procedure:
The title compound was prepared from trifluoro-methanesulfonic acid 3,3-dimethyl-1-oxo-indan-5-yl ester and 5-chlorothien-2-yl boronic acid according to the procedure described in example 21. MS m/z 277; HRMS: calcd for C15H13ClOS+H+, 277.04484; found (ESI, [M+H]+), 277.0444.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([OH:28])[CH2:8]OS(C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)(=O)=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:29][C:30]1[C:38]([Cl:39])=[CH:37][C:33]2[N:34]=[CH:35][NH:36][C:32]=2[CH:31]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH:1]1([CH2:6][C@H:7]([OH:28])[CH2:8][N:34]2[C:33]3[CH:37]=[C:38]([Cl:39])[C:30]([Cl:29])=[CH:31][C:32]=3[N:36]=[CH:35]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Clc1cc2nc[nH]c2cc1Cl
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)OC[C@@H](O)CC2CCCC2)c(C(C)C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O[C@@H](CC1CCCC1)Cn1cnc2cc(Cl)c(Cl)cc21
Temperature: 160 °C
Yield: 39.3 %

Procedure:
Two large (2-5 mL) microwave reactor tubes were charged with (S)-2,4,6-Triisopropyl-benzenesulfonic acid 3-cyclopentyl-2-hydroxy-propyl ester (Example 6, Step A, 1.88 g, 4.6 mmol), 5,6-dichlorobenzimidazole (859 mg, 4.6 mmol), K2CO3 (1.27 g, 9.2 mmol) and DMF (4 mL). The tubes were then heated to 160° C. for 6 minutes. The reaction was partitioned between ethyl acetate and water. The aqueous layer was extracted a total of 2 times with ethyl acetate and the combined organics were dried over MgSO4. The solvent was removed and the resulting oil was chromatographed over silica gel using a linear gradient of 0-100% ethyl acetate in hexane to afford 566 mg (40%) of the title compound as a solid: HPLC-MS calcd. for C15H18Cl2N2O (M+H+) 313.1, found 313.2.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH:4]([NH:13][C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:5][CH:6]=[CH:7][CH2:8]OC(=O)C.[CH3:23][O:24][C:25](=[O:34])[CH:26]([NH:30][C:31](=[O:33])[CH3:32])CC=C>>[CH3:23][O:24][C:25](=[O:34])[CH:26]([NH:30][C:31](=[O:33])[CH3:32])[CH2:8][CH:7]=[CH:6][CH2:5][CH:4]([NH:13][C:14](=[O:21])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:3]([O:2][CH3:1])=[O:22]
Reactant: C=CCC(NC(C)=O)C(=O)OC
Reactant: COC(=O)C(CC=CCOC(C)=O)NC(=O)c1ccccc1
Product: COC(=O)C(CC=CCC(NC(=O)c1ccccc1)C(=O)OC)NC(C)=O

Procedure:
2-Acetylamino-7-benzoylamino-4-octenedioic acid dimethyl ester 142 was synthesised using standard solution-phase metathesis conditions (refer to section 7.5) from 6-acetoxy-2-benzoylamino-4-hexenoic acid methyl ester 141 and methyl-2-acetylamino-4-pentenoate 121a. The desired compound was obtained as a brown oil, and purified via column chromatography (SiO2; EtOAc:Hexane; 2:1).
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][NH2:5].[C:6]([N:9]1[C:18]2[C:13](=[CH:14][C:15]([C:19](O)=[O:20])=[CH:16][CH:17]=2)[C:12]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([CH3:22])[CH2:11][C:10]1([CH3:30])[CH3:29])(=[O:8])[CH3:7].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>ClCCl>[C:6]([N:9]1[C:18]2[C:13](=[CH:14][C:15]([C:19]([NH:5][CH2:4][CH2:3][S:2][CH3:1])=[O:20])=[CH:16][CH:17]=2)[C:12]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([CH3:22])[CH2:11][C:10]1([CH3:30])[CH3:29])(=[O:8])[CH3:7]
Reactant: CSCCN
Reactant: CC(=O)N1c2ccc(C(=O)O)cc2C(C)(c2ccccc2)CC1(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CSCCNC(=O)c1ccc2c(c1)C(C)(c1ccccc1)CC(C)(C)N2C(C)=O

Procedure:
Condensation of 2-(methylthio)ethylamine (4.1 mg) with 1-acetyl-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline-6-carboxylic acid (10 mg), under the agency of HATU (23 mg) and N,N-diisopropylethylamine (19 μl) in dichloromethane (2 ml) was performed according to the method described in example 11.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[C:14]([N+:16]([O-:18])=[O:17])=[CH:13][CH:12]=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.Cl.[CH3:20][N:21]([C:23]1[S:24][CH:25]=[CH:26][N:27]=1)[NH2:22]>CN(C)C=O>[ClH:1].[CH3:20][N:21]([C:23]1[S:24][CH:25]=[CH:26][N:27]=1)[N:22]=[C:2]1[C:15]2[C:14]([N+:16]([O-:18])=[O:17])=[CH:13][CH:12]=[CH:11][C:10]=2[NH:9][C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2
Reactant: O=[N+]([O-])c1cccc2nc3ccccc3c(Cl)c12
Reactant: CN(N)c1nccs1
Agent: Cl
Solvent: CN(C)C=O
Product: CN(N=c1c2ccccc2[nH]c2cccc([N+](=O)[O-])c12)c1nccs1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 2.3 g of 9-chloro-1-nitroacridine, 1.65 g of N-methyl-N-(2-thiazolyl)hydrazine hydrochloride and 100 ml of dimethylformamide is stirred at room temperature for about 18 hours. The dark red solution is evaporated, whereupon the residue is made alkaline with sodium carbonate solution and extracted with methylene chloride. The extract is washed with water, dried over sodium sulfate and evaporated. The residue is taken up in ethanol, acidified with ethanolic hydrochloric acid and the product is precipitated by the addition of ether. After filtration and washing with ether and petroleum ether, the hygroscopic salt is dried over phosphorus pentoxide. There is obtained 1-nitro-9-acridanone methyl (2-thiazolyl)hydrazone hydrochloride of melting point 185° (decomposition).
Reaction SMILES: [CH2:1]([OH:9])[CH:2]([OH:8])[CH:3]([OH:7])[CH2:4][CH:5]=[CH2:6].[Si:10](Cl)([C:23]([CH3:26])([CH3:25])[CH3:24])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(Cl)Cl.CN(C)C=O.C(OCC)C>[CH3:26][C:23]([Si:10]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[O:9][CH2:1][CH:2]([OH:8])[CH:3]([OH:7])[CH2:4][CH:5]=[CH2:6])([CH3:24])[CH3:25]
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: C=CCC(O)C(O)CO
Solvent: CCOCC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C=CCC(O)C(O)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 73 %

Procedure:
A 0° C. solution of 7.33 g of product from Example 273 in 120 ml of 5:1 dry methylene chloride/N,N-dimethylformamide is treated with 5.29 g ofimidazole and 16.77 g of t-butyl diphenylsilyl chloride. The reaction mixture is warmed to room temperature and stirred vigorously for 16 hours,diluted with diethyl ether and filtered. The filtrate is concentrated and purified by chromatography (Silica Gel: 0-50% ethyl acetate/hexane) to give 15 g of the desired product.
Reaction SMILES: C(C1C=CC(CO)=CC=1)C1C=CC=CC=1.Br.CO[C:19]1[CH:33]=[CH:32][C:22]([CH2:23][C:24]2[CH:31]=[CH:30][C:27]([CH2:28][Br:29])=[CH:26][CH:25]=2)=[CH:21][CH:20]=1>>[CH2:23]([C:24]1[CH:25]=[CH:26][C:27]([CH2:28][Br:29])=[CH:30][CH:31]=1)[C:22]1[CH:21]=[CH:20][CH:19]=[CH:33][CH:32]=1
Reactant: COc1ccc(Cc2ccc(CBr)cc2)cc1
Agent: Br
Agent: OCc1ccc(Cc2ccccc2)cc1
Product: BrCc1ccc(Cc2ccccc2)cc1

Procedure:
4-Benzylbenzyl bromide was prepared from 20 g. of 4-benzylbenzyl alcohol [Maquin et al., Compt. rend. 234, 629-31, 1952] and hydrogen bromide according to the procedure of Example 1, part (e). An oil (25.7 g.) was obtained which was used directly in the next reaction.
Reaction SMILES: [C@H:1]12[CH2:26][C@H:4]([N:5]([C:7]3[CH:12]=[CH:11][C:10]([N:13]4[CH2:17][C@@H:16]([CH2:18]CS([O-])(=O)=O)[O:15][C:14]4=[O:24])=[CH:9][C:8]=3[F:25])[CH2:6]1)[CH2:3][O:2]2.[N-:27]=[N+:28]=[N-:29].[Na+].CO.C(Cl)(Cl)Cl>CCOC(C)=O>[C@H:1]12[CH2:26][C@H:4]([N:5]([C:7]3[CH:12]=[CH:11][C:10]([N:13]4[CH2:17][C@H:16]([CH2:18][N:27]=[N+:28]=[N-:29])[O:15][C:14]4=[O:24])=[CH:9][C:8]=3[F:25])[CH2:6]1)[CH2:3][O:2]2
Reactant: O=C1O[C@H](CCS(=O)(=O)[O-])CN1c1ccc(N2C[C@@H]3C[C@H]2CO3)c(F)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: [N-]=[N+]=NC[C@H]1CN(c2ccc(N3C[C@@H]4C[C@H]3CO4)c(F)c2)C(=O)O1
Temperature: 65 °C
Yield: 91.9 %

Procedure:
A solution of (R)-[[3-[4-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]-3-fluorophenyl]-2-oxo-5-oxazolidinyl]methyl]methanesulfonate (0.869 g, 2.26 mmol) in dry DMP (10 mL) was treated with solid NaN3 (0.732 g, 11.3 mmol) at ambient temperature under N2. The mixture was then heated to 65° C. and reaction progress monitored by TLC. After 7.5 h at this temperature, TLC analysis (5% MeOH/CHCl3) revealed the reaction to complete. The reaction mixture was diluted with EtOAc (100 mL), washed with H2O (3×15 mL) and brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give 0.692 g (92%) of the title compound as a tan solid. An analytical sample was prepared by recrystallization from 1:1 EtOc/hexane as an off-white solid with mp 101-102.5° C. and MS(EI) 333 (M+).
Reaction SMILES: C(OC([NH:8][C:9]1[S:13][C:12]([C:14]2[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=2[F:21])=[N:11][C:10]=1[C:22]([OH:24])=O)=O)(C)(C)C.[NH2:25][C:26]1[C:27]([N:35]2[CH2:40][C@H:39]([CH3:41])[C@:38]([OH:43])([CH3:42])[C@H:37]([NH:44]C(=O)OC(C)(C)C)[CH2:36]2)=[C:28]2[CH2:34][CH2:33][O:32][C:29]2=[N:30][CH:31]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:8][C:9]1[S:13][C:12]([C:14]2[C:15]([F:21])=[CH:16][CH:17]=[CH:18][C:19]=2[F:20])=[N:11][C:10]=1[C:22]([NH:25][C:26]1[C:27]([N:35]2[CH2:40][C@H:39]([CH3:41])[C@:38]([OH:43])([CH3:42])[C@H:37]([NH2:44])[CH2:36]2)=[C:28]2[CH2:34][CH2:33][O:32][C:29]2=[N:30][CH:31]=1)=[O:24]
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Reactant: C[C@H]1CN(c2c(N)cnc3c2CCO3)C[C@@H](NC(=O)OC(C)(C)C)[C@]1(C)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@H]1CN(c2c(NC(=O)c3nc(-c4c(F)cccc4F)sc3N)cnc3c2CCO3)C[C@@H](N)[C@]1(C)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 32.3 %

Procedure:
To a mixture of 5-[(tert-butoxycarbonyl)amino]-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxylic acid (55 mg, 0.15 mmol), tert-butyl [(3R,4R,5S)-1-(5-amino-2,3-dihydrofuro[2,3-b]pyridin-4-yl)-4-hydroxy-4,5-dimethylpiperidin-3-yl]carbamate (44 mg, 0.12 mmol) and HATU (134 mg, 0.353 mmol), DMF (2.0 mL) was added, followed by DIPEA (86 mg, 0.67 mmol). The reaction mixture was stirred at room temperature for 3 h, and then concentrated under reduced pressure. DCM (2.0 mL) was added to the resulting residue followed by TFA (2.0 mL). The mixture was stirred at room temperature for 30 min. and then concentrated under reduced pressure. The resulting residue was purified using RP-HPLC (XBridge™ C18 column, eluting with a gradient of MeCN/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min.) to afford the title compound as a white solid (20 mg, 34%). LCMS calc. for C24H27F2N6O3s (M+H)+: m/z=517.2. found 517.0. 1H NMR (500 MHz, DMSO-d6) δ 9.17 (s, 1H), 8.61 (s, 1H), 7.59-7.45 (m, 3H), 7.21 (t, J=8.6 Hz, 2H), 4.52-4.42 (m, 2H), 4.06 (s, 1H), 3.37 (t, J=8.5 Hz, 2H), 2.99-2.92 (m, 1H), 2.90-2.79 (m, 2H), 2.77-2.64 (m, 2H), 1.93-1.82 (m, 1H), 1.46 (br, 2H), 0.92 (s, 3H), 0.71 (d, J=6.9 Hz, 3H) ppm.
Reaction SMILES: [OH:1][N:2]=[C:3]([NH:5][C:6]1[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][NH:8][N:7]=1)[CH3:4].N1C=CC=CC=1.[C:22]1([CH3:32])[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>CN(C)C=O.C(OCC)(=O)C.O>[C:22]1([CH3:32])[CH:27]=[CH:26][C:25]([S:28]([O:1][N:2]=[C:3]([NH:5][C:6]2[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][NH:8][N:7]=2)[CH3:4])(=[O:30])=[O:29])=[CH:24][CH:23]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(=O)c1c[nH]nc1NC(C)=NO
Solvent: O
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CCOC(=O)c1c[nH]nc1NC(C)=NOS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.6 %

Procedure:
To a solution of ethyl 3-[[1-(hydroxyimino)ethyl]amino]-pyrazole-4-carboxylate (1.50 g) and pyridine (1.12 g) in N,N-dimethylformamide (20 ml) was added dropwise p-toluenesulfonyl chloride (1.39 g) under ice bath cooling and stirred at ambient temperature for 3 hours. The reaction mixture was diluted with ethyl acetate and water. The organic layer was separated and washed with saturated sodium hydrogen carbonate aqueous solution and brine. The solution was dried over magnesium sulfate and concentrated in vacuo to give ethyl 3-[1-(p-toluenesulfonyloxyimino)ethyl]amino-1H-pyrazole-4-carboxylate (2.14 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:29])=[C:4]([NH:10][C:11]([N:13]2[CH2:17][CH2:16][C@@H:15]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[C@:14]2([CH2:27]O)[CH3:26])=[O:12])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].CC(C)([O-])C.[K+].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C1COCC1.O.CCOC(C)=O>[Si:19]([O:18][C@H:15]1[C@:14]2([CH3:26])[N:13]([C:11](=[O:12])[N:10]([C:4]3[CH:5]=[CH:6][C:7]([C:8]#[N:9])=[C:2]([Cl:1])[C:3]=3[CH3:29])[CH2:27]2)[CH2:17][CH2:16]1)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:20])[CH3:21]
Reactant: Cc1c(NC(=O)N2CC[C@@H](O[Si](C)(C)C(C)(C)C)[C@@]2(C)CO)ccc(C#N)c1Cl
Agent: CC(C)(C)[O-]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(N2C[C@]3(C)[C@H](O[Si](C)(C)C(C)(C)C)CCN3C2=O)ccc(C#N)c1Cl
Reaction time: 0.17 h
Yield: 40.5 %

Procedure:
To a solution of (2R,3R)-3-(tert-Butyldimethylsilanyloxy)-2-hydroxymethyl-2-methylpyrrolidine-1-carboxylic acid (3-chloro-4-cyano-2-methyl-phenyl)-amide (58D) (43 mg, 0.10 mmol) in THF (1 mL) at 0° C. was added a 1 M solution of potassium tert-butoxide in THF (0.24 mL, 0.24 mmol) followed by a solution of p-toluenesulfonyl chloride (22 mg, 0.12 mmol) in THF (0.5 mL). After 10 min, additional potassium tert-butoxide (50 □L) and p-toluenesulfonyl chloride (3 mg) were added. After another 10 min, the reaction was diluted with water and EtOAc and the layers were separated. The organic layer was washed with brine, dried (MgSO4), filtered and concentrated and purified via preparative HPLC (Luna C-18, 100×21.2 mm, eluting with 60-100% solvent B (A=90% H2O-10% MeOH-0.1% TFA and B=10% H2O-90% MeOH-0.1% TFA) over 12 min; Flow rate at 20 mL/min; UV detection at 220 nm) to provide the title compound (17 mg). LC/MS m/z 420 [M+H]+.
Reaction SMILES: BrC(Br)C.C[Si](Cl)(C)C.[C:10]([O:18][CH2:19]I)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl[C:22]1[C:23]2[N:31]=[C:30]([CH:32]3[CH2:37][CH2:36][C:35]([CH3:39])([CH3:38])[CH2:34][CH2:33]3)[S:29][C:24]=2[N:25]=[C:26]([CH3:28])[N:27]=1>C1COCC1.[Zn].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>[C:10]([O:18][CH2:19][C:22]1[C:23]2[N:31]=[C:30]([CH:32]3[CH2:37][CH2:36][C:35]([CH3:39])([CH3:38])[CH2:34][CH2:33]3)[S:29][C:24]=2[N:25]=[C:26]([CH3:28])[N:27]=1)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Cc1nc(Cl)c2nc(C3CCC(C)(C)CC3)sc2n1
Reactant: O=C(OCI)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(Br)Br
Agent: C[Si](C)(C)Cl
Solvent: C1CCOC1
Product: Cc1nc(COC(=O)c2ccccc2)c2nc(C3CCC(C)(C)CC3)sc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.7 %

Procedure:
Under an argon atmosphere, to a suspension of zinc powder (7.5 g) in THF (50 mL) were added dibromoethane (200 μL) and trimethylsilylchloride (200 μL), and then a solution of iodomethyl benzoate (15 g) in THF (50 mL) was added thereto, followed by stirring at room temperature for 1 hour. Then, a solution of 7-chloro-2-(4,4-dimethylcyclohexyl)-5-methyl[1,3]thiazolo[5,4-d]pyrimidine (10.9 g) in THF (50 mL) and Pd(PPh3)4 (4.25 g) were added thereto, followed by stirring at room temperature for 15 hours. The reaction mixture was filtered through Celite and then concentrated under reduced pressure. To the residue was added a 1 M aqueous NH4Cl solution, followed by extraction with EtOAc. To the organic layer were added MgSO4 and basic silica gel, followed by stirring, filtrating, and then concentrating under reduced pressure. The residue was purified by silica gel column (hexane/EtOAc) to obtain [2-(4,4-dimethylcyclohexyl)-5-methyl[1,3]thiazolo[5,4-d]pyrimidin-7-yl]methyl benzoate (13.8 g).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][OH:9])=[C:4]([NH:10][CH3:11])[CH:3]=1>C(Cl)Cl.O=[Mn]=O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:10][CH3:11])[C:5]([CH:8]=[O:9])=[CH:6][N:7]=1
Reactant: CNc1cc(Cl)ncc1CO
Agent: O=[Mn]=O
Solvent: ClCCl
Product: CNc1cc(Cl)ncc1C=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(6-Chloro-4-(methylamino)pyridin-3-yl)methanol (20 g, 116 mmol) was dissolved in DCM (250 mL) and MnO2 (100 g, 1.16 mol) was added. The reaction mixture was stirred at rt overnight, then filtered through a celite plug and washed with ethyl acetate. The filtrate was concentrated to obtain the title compound. 1H NMR (300 MHz, CDCl3) δ 9.85 (s, 1H), 8.59 (bs, 1H), 8.31 (s, 1H), 6.59 (s, 1H), 2.96 (d, J=5.1 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH:4]([C:6]12[CH2:11][CH:10]1[CH2:9][CH2:8][CH2:7]2)[OH:5]>CCOCC.[O-2].[Mn+4].[O-2]>[CH3:1][O:2][C:3](=[O:12])[C:4]([C:6]12[CH2:11][CH:10]1[CH2:9][CH2:8][CH2:7]2)=[O:5]
Reactant: COC(=O)C(O)C12CCCC1C2
Agent: [Mn+4]
Agent: [O-2]
Solvent: CCOCC
Product: COC(=O)C(=O)C12CCCC1C2
Temperature: 25 °C
Reaction time: 4 h
Yield: 80.3 %

Procedure:
2×40 g active manganese(IV)oxide were added one after the other over 2 hours to a well-stirred solution of 13.6 g (80 mmol) 2-(bicyclo[3.1.0]hex-1-yl)-2-hydroxyacetic acid methyl ester in 500 ml anhydrous ether, and the mixture was stirred at room temperature for a further 4 hours until all the starting material was used up (DC control). The reaction mixture was then filtered over diatomaceous earth (Celite®). After the solvent was evaporated off in vacuum at room temperature, 10.8 g (80%) of 2-(bicyclo[3.1.0]hex-1-yl)-2-oxoacetic acid methyl ester was obtained as clear light-yellow liquid (purity >96% according to GC), which does not have to be purified further.