Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[N:9]3[N:10]=[CH:11][C:12]([C:13]([OH:15])=O)=[C:8]3[N:7]=[C:6]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[CH:5]=2)[CH2:3][CH2:2]1.O[NH:27][C:28]([C:30]1[S:31][C:32]([S:35](=[O:38])(=[O:37])[NH2:36])=[CH:33][CH:34]=1)=[NH:29]>>[CH:1]1([C:4]2[N:9]3[N:10]=[CH:11][C:12]([C:13]4[O:15][N:29]=[C:28]([C:30]5[S:31][C:32]([S:35]([NH2:36])(=[O:38])=[O:37])=[CH:33][CH:34]=5)[N:27]=4)=[C:8]3[N:7]=[C:6]([C:16]3[CH:17]=[CH:18][C:19]([C:22]([F:25])([F:23])[F:24])=[CH:20][CH:21]=3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: N=C(NO)c1ccc(S(N)(=O)=O)s1
Reactant: O=C(O)c1cnn2c(C3CC3)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: NS(=O)(=O)c1ccc(-c2noc(-c3cnn4c(C5CC5)cc(-c5ccc(C(F)(F)F)cc5)nc34)n2)s1

Procedure:
The title compound was prepared from 7-cyclopropyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.29) (174 mg, 0.5 mmol) N-hydroxy-5-sulfamoyl-thiophene-2-carboxamidine (example B.2) (166 mg, 0.75 mmol) and according to general procedure II. Obtained after purification by flash chromatography (ethyl acetate/heptane) and crystallization (dichloromethane/ethyl acetate) as a yellow solid (180 mg, 68%). MS (ISP) 533.3 [(M+H)+]; mp 290° C.
Reaction SMILES: [NH2:1][CH:2]([CH2:5][OH:6])[CH2:3][OH:4].Cl[C:8]([O:10][CH2:11][CH:12]([CH3:14])[CH3:13])=[O:9]>>[OH:4][CH2:3][CH:2]([NH:1][C:8](=[O:9])[O:10][CH2:11][CH:12]([CH3:14])[CH3:13])[CH2:5][OH:6]
Reactant: CC(C)COC(=O)Cl
Reactant: NC(CO)CO
Product: CC(C)COC(=O)NC(CO)CO

Procedure:
Isobutyl 1,3-dihydroxypropan-2-yl-carbamate (iBuDHPC) was prepared using serinol and isobutyl chloroformate according to the general procedure described in Example 2.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=2[F:18])[N:3]=1.FC1C(F)=CC=CC=1CSC1N=C(NS(N2CCC2)(=O)=O)C=C([O:43][CH:44]([CH2:47]O)[CH2:45]O)N=1.[H-].[Na+]>CC(O)C>[Cl:8][C:6]1[CH:7]=[C:2]([O:43][CH:44]([CH3:47])[CH3:45])[N:3]=[C:4]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=2[F:18])[N:5]=1
Reactant: Fc1cccc(CSc2nc(Cl)cc(Cl)n2)c1F
Reactant: O=S(=O)(Nc1cc(OC(CO)CO)nc(SCc2cccc(F)c2F)n1)N1CCC1
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)O
Product: CC(C)Oc1cc(Cl)nc(SCc2cccc(F)c2F)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4,6-dichloro-2-[(2,3-difluorobenzyl)thio]pyrimidine ((the product of example 1 step 3 g) in propan-2-ol (20 ml) was added NaH (0.43 g) slowly and the reaction was then allowed to stir overnight at RT. The reaction mixture was then partitioned between DCM (100 ml) and H2O (100 ml). The organics were separated and the aqueous layer was re-extracted with DCM (2×100 ml). Organics were combined, dried (MgSO4) and reduced in vacuo to give the subtitle compound as a pale yellow solid. Yield: 1.8 g
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15]3[CH:25]=[C:24]([CH2:26][CH3:27])[S:23][C:16]=3[N:17]=[C:18]([C:20](=O)[NH2:21])[N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(OCC)(=O)C.CCCCCC>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[C:15]3[CH:25]=[C:24]([CH2:26][CH3:27])[S:23][C:16]=3[N:17]=[C:18]([C:20]#[N:21])[N:19]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCc1cc2c(N3CCN(C(=O)OC(C)(C)C)CC3)nc(C(N)=O)nc2s1
Solvent: CCCCCC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cc2c(N3CCN(C(=O)OC(C)(C)C)CC3)nc(C#N)nc2s1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 46 %

Procedure:
4-(2-Carbamoyl-6-ethyl-thieno[2,3-d]pyrimidin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester (28.2 mg) was dissolved in methylene chloride (1.00 mL) and diisopropyl-ethylamine (0.13 mL) and trifluroacetic anhydride (40.7 μL) was added. After stirring at room temperature for 2.5 hours, the product was isolated from silica gel chromatography (15% to 35% ethyl acetate/hexane over 40 minutes). Yield=46%, ES-MS: (M+H)+ 374.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:24]([F:27])([F:26])[F:25])[O:13][N:12]=[C:11]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[C:16]([I:23])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH3:28]O>S(=O)(=O)(O)O>[CH3:28][O:19][C:18](=[O:20])[C:17]1[CH:21]=[CH:22][C:14]([C:11]2[CH2:10][C:9]([C:4]3[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=3)([C:24]([F:26])([F:25])[F:27])[O:13][N:12]=2)=[CH:15][C:16]=1[I:23]
Reactant: CO
Reactant: O=C(O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1I
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1I

Procedure:
In a solution of 0.60 g of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-iodo benzoic acid synthesized similarly to Steps 1 to 4 of Synthetic Example 4 in 10 ml of methanol, 2 drops of concentrated sulfuric acid was added, and stirred under reflux with heat for 20 hours. After the completion of the reaction, the solvent was distilled off under reduced pressure, the residue was neutralized with 10 ml of saturated sodium hydrogen carbonate aqueous solution, then extracted with ethyl acetate (10 ml×2). The organic phase was washed with water, dehydrated with saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified with silica gel column chromatography that was eluated with ethyl acetate-hexane (1:4), and 0.56 g of the aimed product was obtained as colorless oily substance.
Reaction SMILES: [C:1]1([C:7]2[O:11][C:10]([SH:12])=[N:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([S:27]([NH:30][CH:31]([CH2:36][CH:37]3[O:39][CH2:38]3)[C:32]([O:34]C)=[O:33])(=[O:29])=[O:28])=[CH:23][CH:22]=2)=[CH:17][CH:16]=1>>[CH3:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]2[CH:22]=[CH:23][C:24]([S:27]([NH:30][CH:31]([CH2:36][CH:37]([OH:39])[CH2:38][S:12][C:10]3[O:11][C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[N:8][N:9]=3)[C:32]([OH:34])=[O:33])(=[O:28])=[O:29])=[CH:25][CH:26]=2)=[CH:19][CH:20]=1
Reactant: COC(=O)C(CC1CO1)NS(=O)(=O)c1ccc(-c2ccc(OC)cc2)cc1
Reactant: Sc1nnc(-c2ccccc2)o1
Product: COc1ccc(-c2ccc(S(=O)(=O)NC(CC(O)CSc3nnc(-c4ccccc4)o3)C(=O)O)cc2)cc1

Procedure:
Example 35 is prepared from 5-phenyl-1,3,4-oxadiazole-2-thiol and 1d using the procedure described for compound 20.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].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.FC(F)(F)C(O)=O.[CH:59]1[C:71]2[CH:70]([CH2:72][O:73][C:74](=[O:94])[NH:75][C@H:76]3[CH2:80][C@@H:79]([C:81](=[O:93])[NH:82][C@H:83]4[C:92]5[C:87](=[CH:88][CH:89]=[CH:90][CH:91]=5)[CH2:86][CH2:85][CH2:84]4)[NH:78][CH2:77]3)[C:69]3[C:64](=[CH:65][CH:66]=[CH:67][CH:68]=3)[C:63]=2[CH:62]=[CH:61][CH:60]=1>CN(C=O)C>[CH:68]1[C:69]2[CH:70]([CH2:72][O:73][C:74](=[O:94])[NH:75][C@H:76]3[CH2:80][C@@H:79]([C:81](=[O:93])[NH:82][C@H:83]4[C:92]5[C:87](=[CH:88][CH:89]=[CH:90][CH:91]=5)[CH2:86][CH2:85][CH2:84]4)[N:78]([C:10](=[O:12])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH:13]4[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]4)[CH2:77]3)[C:71]3[C:63](=[CH:62][CH:61]=[CH:60][CH:59]=3)[C:64]=2[CH:65]=[CH:66][CH:67]=1
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C1CCCCC1
Reactant: O=C(N[C@@H]1CN[C@H](C(=O)N[C@@H]2CCCc3ccccc32)C1)OCC1c2ccccc2-c2ccccc21
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: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H](C(=O)N1C[C@@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C[C@H]1C(=O)N[C@@H]1CCCc2ccccc21)C1CCCCC1
Temperature: 0 °C

Procedure:
To a solution of (S)-tert-butoxycarbonylamino-cyclohexyl-acetic acid (Aldrich) (4.529 g, 17.622 mmol) in DMF (100 mL) were added HATU (6.7 g, 17.622 mmol) followed by DIPEA (13.87 mL, 80.101 mmol). The mixture was cooled to 0° C. and ({(3S,5S)-5-[(R)-(1,2,3,4-tetrahydro-naphthalen-1-yl)carbamoyl]-pyrrolidin-3-yl}-carbamic acid 9H-fluoren-9-ylmethyl ester trifluoroacetate (Intermediate 22) (9.5 g, 16.02 mmol) in DMF (50 mL) was added dropwise and then the cooling bath removed. After 4 h the mixture was diluted with ethyl acetate, washed with water, dried over sodium sulfate and concentrated to give the title compound as an off white solid (10 g) which was used without purification. LC-MS: 721 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][NH:4][N:3]=1.[N:7]([CH2:10][CH2:11][C:12](Cl)=O)=[N+]=[N-]>>[NH2:7][CH2:10][CH2:11][CH2:12][NH:1][C:2]1[CH:6]=[CH:5][NH:4][N:3]=1
Reactant: [N-]=[N+]=NCCC(=O)Cl
Reactant: Nc1cc[nH]n1
Product: NCCCNc1cc[nH]n1

Procedure:
Reaction of 3-aminopyrazole with β-azidopropionyl chloride by the procedure of Example 40 gives 3-(3-aminopropylamino)pyrazole.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:20]=[C:19]([OH:21])[C:14]3[N:15]([CH3:18])[CH:16]=[N:17][C:13]=3[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].CS(O[C@H:27]([C@@H:29]1[CH2:33][C:32](=[O:34])[N:31]([C@@H:35]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH3:36])[CH2:30]1)[CH3:28])(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:20]=[C:19]([O:21][C@@H:27]([C@H:29]3[CH2:30][N:31]([C@@H:35]([C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)[CH3:36])[C:32](=[O:34])[CH2:33]3)[CH3:28])[C:14]3[N:15]([CH3:18])[CH:16]=[N:17][C:13]=3[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: C[C@H](OS(C)(=O)=O)[C@@H]1CC(=O)N([C@H](C)c2ccccc2)C1
Reactant: COc1ccc(-c2cc(O)c3c(c2)ncn3C)cc1OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2cc(O[C@H](C)[C@@H]3CC(=O)N([C@H](C)c4ccccc4)C3)c3c(c2)ncn3C)cc1OC
Temperature: 90 °C

Procedure:
To a solution of 5-(3,4-dimethoxyphenyl)-1-methyl-1H-benzo[d]imidazol-7-ol 2.53 (42 mg, 0.148 mmol) in DMF (3 mL) was added (S)-1-((R)-5-oxo-1-((R)-1-phenylethyl)pyrrolidin-3-yl)ethyl methanesulfonate 1.17 (55 mg, 0.177 mmol) and Cs2CO3 (72 mg, 0.22 mmol) and the reaction mixture was heated at 90° C. for 2 h. The reaction mixture was concentrated and purified by flash chromatography (SiO2, 2% MeOH/EtOAc 25% MeOH/EtOAc) to give (R)-4-((R)-1-(5-(3,4-dimethoxyphenyl)-1-methyl-1H-benzo[d]imidazol-7-yloxy)ethyl)-1-((R)-1-phenylethyl)pyrrolidin-2-one 2.55.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[C:14]([OH:16])=O)=[CH:5][CH:4]=1.[CH2:19]([CH:26]1[CH2:30][CH2:29][CH2:28][NH:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:19]([CH:26]1[CH2:30][CH2:29][CH2:28][N:27]1[C:14]([C:10]1[CH:11]=[N:12][O:13][C:9]=1[C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:18])[F:17])=[CH:8][CH:7]=1)=[O:16])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: c1ccc(CC2CCCN2)cc1
Reactant: O=C(O)c1cnoc1-c1ccc(C(F)(F)F)cc1
Product: O=C(c1cnoc1-c1ccc(C(F)(F)F)cc1)N1CCCC1Cc1ccccc1

Procedure:
The title compound was prepared from 5-(4-trifluoromethylphenyl)isoxazole-4-carboxylic acid (12.9 mg, 0.050 mmol) and 2-benzylpyrrolidine (9.7 mg, 0.060 mmol) as described in synthetic method C and thereafter purified by preparative HPLC method B to give a solid (12.5 mg). Calcd for C22H19F3N2O2: 400.1399, found 400.1398.
Reaction SMILES: C([O:3][C:4]([CH2:6][O:7][C:8]1[CH:9]=[C:10]([CH:31]=[CH:32][C:33]=1[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:11][NH:12][C:13]1[N:17]([C@@H:18]2[O:24][C@H:23]([CH2:25][OH:26])[C@@H:21]([OH:22])[C@H:19]2[OH:20])[C:16]2[CH:27]=[CH:28][CH:29]=[CH:30][C:15]=2[N:14]=1)=O)C.[BH4-].[Na+].Cl>CO>[OH:3][CH2:4][CH2:6][O:7][C:8]1[CH:9]=[C:10]([CH:31]=[CH:32][C:33]=1[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:11][NH:12][C:13]1[N:17]([C@@H:18]2[O:24][C@H:23]([CH2:25][OH:26])[C@@H:21]([OH:22])[C@H:19]2[OH:20])[C:16]2[CH:27]=[CH:28][CH:29]=[CH:30][C:15]=2[N:14]=1
Reactant: CCOC(=O)COc1cc(CNc2nc3ccccc3n2[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)ccc1-c1ccccc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCCOc1cc(CNc2nc3ccccc3n2[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)ccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 43 %

Procedure:
2-(3-Ethoxycarbonylmethyloxy-4-phenylbenzylamino)-1-(β-D-ribofuranosyl)-1H-benzimidazole (53 mg) was dissolved in methanol (5 mL). To the mixture was added sodium tetrahydroborate (8 mg), and the mixture was stirred at room temperature for 1 hours. To the reaction mixture was added 1 mol/L hydrochloric acid (0.5 mL), and the solvent was removed under reduced pressure. The obtained residue was purified by preparative reverse phase column chromatography (Shiseido CAPSELL PAC C18UG80, 5 μm, 20×50 mm, flow rate 30 mL/minutes linear gradient, water/methanol=70/30-10/90) to give the title compound (21 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][CH2:8][C:9]1[CH:14]=[C:13](Br)[CH:12]=[C:11]([Cl:16])[C:10]=1[F:17])([CH3:4])([CH3:3])[CH3:2].[CH2:19]([NH:21][CH2:22][CH3:23])[CH3:20].CC(C)([O-])C.[Na+]>>[C:1]([O:5][C:6](=[O:18])[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([N:21]([CH2:22][CH3:23])[CH2:19][CH3:20])[CH:12]=[C:11]([Cl:16])[C:10]=1[F:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCc1cc(Br)cc(Cl)c1F
Reactant: CCNCC
Agent: CC(C)(C)[O-]
Agent: [Na+]
Product: CCN(CC)c1cc(Cl)c(F)c(CNC(=O)OC(C)(C)C)c1

Procedure:
was prepared according to Scheme C1 (step A) from (5-bromo-3-chloro-2-fluoro-benzyl)-carbamic acid tert-butyl ester (300 mg, 0.89 mmol), diethylamine (0.14 mL, 1.3 mmol), sodium tert-butoxide (170 mg, 1.8 mmol) and di-μ-bromobis(tri-tert-butylphosphino)dipalladium (I) [CAS 185812-86-6] (34 mg, 0.04 mmol). MS (LC-MS): 331.2 [M]+; tR (HPLC conditions c): 4.08 min.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1.[N+:10]([C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][CH:14]=1)([O-:12])=[O:11]>C(O)C>[N:5]1([CH2:4][CH2:3][CH2:2][NH:1][C:17]([C:16]2[CH:15]=[CH:14][C:13]([N+:10]([O-:12])=[O:11])=[CH:21][CH:20]=2)=[O:18])[CH:9]=[CH:8][N:7]=[CH:6]1
Reactant: NCCCn1ccnc1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: CCO
Product: O=C(NCCCn1ccnc1)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 53 %

Procedure:
A solution of 1-(3-aminopropyl)imidazole (3.87 ml, 33 mmol) in ethanol (65 ml) was added to 4-nitrobenzoyl chloride (4.0 g, 22 mmol) and the mixture stirred at ambient temperature for 24 hours. The volatiles were removed by evaporation and the residue was dissolved in ethyl acetate, washed with water and dried. The solvent was removed by evaporation, the residue was triturated with hexane and the product collected by filtration to give the title compound (3.2 g, 55%). NMR: 1.98 (t, 2H), 3.24 (q, 2H), 4.01 (t, 2H), 6.87 (s, 1H), 7.19 (s, 1H), 7.64 (s, 2H), 8.15 (d, 2H), 8.30 (d, 2H); 8.80 (t, 1H); m/z 275 (MH)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[CH:17]([CH2:21][NH2:22])[CH2:16][CH2:15][CH2:14]3)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH3:23][N:24]=[C:25]=[O:26]>>[F:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[C@H:17]([CH2:21][NH:22][C:25]([NH:24][CH3:23])=[O:26])[CH2:16][CH2:15][CH2:14]3)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: CN=C=O
Reactant: NCC1CCCc2cc(S(=O)(=O)c3cccc(F)c3)ccc21
Product: CNC(=O)NC[C@@H]1CCCc2cc(S(=O)(=O)c3cccc(F)c3)ccc21

Procedure:
(R)-1-[6-(3-Fluoro-benzenesulfonyl)-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-3-methyl-urea was prepared by treatment of C-[6-(3-Fluoro-benzenesulfonyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-methylamine with methyl isocyanate according to the procedure of Najer et al.; Bull. Soc. Chim. Fr.; 1069-1071 (1957).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:16]=[C:17]([O:20][CH2:21][CH3:22])[C:18]=1I)[CH2:7][C:8]1[C:9]([NH2:15])=[N:10][C:11]([NH2:14])=[N:12][CH:13]=1)[CH3:2].[CH:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][C:24]=1[B].C(OC1C=C(CC2C(N)=NC(N)=NC=2)C=C(OCC)C=1C1C=CC=CC=1)C>>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:16]=[C:17]([O:20][CH2:21][CH3:22])[C:18]=1[C:25]1[CH:24]=[CH:23][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=1)[CH2:7][C:8]1[C:9]([NH2:15])=[N:10][C:11]([NH2:14])=[N:12][CH:13]=1)[CH3:2]
Reactant: CCOc1cc(Cc2cnc(N)nc2N)cc(OCC)c1I
Reactant: [B]c1ccc2ccccc2c1
Agent: CCOc1cc(Cc2cnc(N)nc2N)cc(OCC)c1-c1ccccc1
Product: CCOc1cc(Cc2cnc(N)nc2N)cc(OCC)c1-c1ccc2ccccc2c1

Procedure:
Starting from 5-(3,5-diethoxy-4-iodo-benzyl)-pyrimidine-2,4-diamine (example 1) (414 mg; 1 mmol) and naphthalen-2-yl-boron acid (690 mg; 4 mmol), 327 mg (79%) 5-(2,6-diethoxy-biphenyl-4-ylmethyl)-pyrimidine-2,4-diamine [sic] are obtained as a colourless powder.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].[OH:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1>>[OH:17][C:18]1[CH:23]=[CH:22][C:21]([C:2]2[CH:16]=[CH:15][CH:14]=[C:4]([CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH:3]=2)=[CH:20][CH:19]=1
Reactant: OB(O)c1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)NCc1cccc(Br)c1
Product: CC(C)(C)OC(=O)NCc1cccc(-c2ccc(O)cc2)c1

Procedure:
The title compound was prepared in a similar manner to that described in Reference Example 2 using tert-butyl N-(3-bromobenzyl)carbamate instead of tert-butyl N-(4-bromobenzyl)carbamate and 4-hydroxyphenylboronic acid instead of 3-benzyloxyphenylboronic acid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:32][CH2:31][C:11]3([CH2:15][N:14](C(OCC4C=CC=CC=4)=O)[C@H:13]([C:26]([O:28]CC)=[O:27])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:33][C@H:34]([C:39]2[CH:44]=[CH:43][C:42]([CH2:45][CH3:46])=[CH:41][C:40]=2[N:47]2[CH:51]=[CH:50][C:49]([CH3:52])=[N:48]2)[C:35]([F:38])([F:37])[F:36])[N:3]=1.[Li+].[OH-]>>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:9][CH2:10][C:11]3([CH2:15][NH:14][C@H:13]([C:26]([OH:28])=[O:27])[CH2:12]3)[CH2:31][CH2:32]2)[CH:5]=[C:4]([O:33][C@H:34]([C:39]2[CH:44]=[CH:43][C:42]([CH2:45][CH3:46])=[CH:41][C:40]=2[N:47]2[CH:51]=[CH:50][C:49]([CH3:52])=[N:48]2)[C:35]([F:38])([F:37])[F:36])[N:3]=1
Reactant: CCOC(=O)[C@@H]1CC2(CCN(c3cc(O[C@H](c4ccc(CC)cc4-n4ccc(C)n4)C(F)(F)F)nc(N)n3)CC2)CN1C(=O)OCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Product: CCc1ccc([C@@H](Oc2cc(N3CCC4(CC3)CN[C@H](C(=O)O)C4)nc(N)n2)C(F)(F)F)c(-n2ccc(C)n2)c1

Procedure:
Hydrolysis of (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-1-(4-ethyl-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate using the LiOH general method provided the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH2:15]O.P(Br)(Br)[Br:18].CCOC(C)=O>C1COCC1>[Br:18][CH2:15][C:3]1[CH:4]=[CH:5][C:6]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:7][C:2]=1[F:1]
Reactant: BrP(Br)Br
Reactant: OCc1ccc(Oc2ccccc2)cc1F
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Fc1cc(Oc2ccccc2)ccc1CBr
Temperature: 0 °C
Reaction time: 1 h
Yield: 71.7 %

Procedure:
Dissolve under nitrogen atmosphere (2-fluoro-4-phenoxyphenyl)-methanol (1.41 g, 6.5 mmol) in anhydrous THF (60 mL). Cool to 0° C. in an ice bath. Add phosphorous tribromide (2.11 g, 7.8 mmol). Stir at cold for 1 h, then remove the ice bath and stir at ambient temperature for 16 h. Quench the reaction with saturated aqueous NaHCO3. Extract aqueous phase three times with EtOAc. Combine organic fractions, wash with brine, dry over Na2SO4 and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (9:1). Evaporate the solvent to obtain the title compound (1.31 g, 72%).
Reaction SMILES: Cl[C:2]1[C:7]2[N:8]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=3)[C:9]([N:11]3[CH2:16][CH2:15][O:14][C@@H:13]4[CH2:17][CH2:18][CH2:19][C@@H:12]34)=[N:10][C:6]=2[CH:5]=[C:4]([Cl:31])[N:3]=1.[Cl:32][C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[N:37][CH:38]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[Cl:31][C:4]1[N:3]=[C:2]([C:35]2[CH:36]=[N:37][CH:38]=[C:33]([Cl:32])[CH:34]=2)[C:7]2[N:8]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]([C:27]([F:29])([F:28])[F:30])=[CH:25][CH:26]=3)[C:9]([N:11]3[CH2:16][CH2:15][O:14][C@@H:13]4[CH2:17][CH2:18][CH2:19][C@@H:12]34)=[N:10][C:6]=2[CH:5]=1
Reactant: OB(O)c1cncc(Cl)c1
Reactant: FC(F)(F)c1ccc(Cn2c(N3CCO[C@@H]4CCC[C@H]43)nc3cc(Cl)nc(Cl)c32)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Product: FC(F)(F)c1ccc(Cn2c(N3CCO[C@@H]4CCC[C@H]43)nc3cc(Cl)nc(-c4cncc(Cl)c4)c32)cc1
Temperature: 90 °C

Procedure:
4,6-dichloro-2-[(trans)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[4-(trifluoromethyl)benzyl]-3H-imidazo[4,5-c]pyridine (racemate, 180 mg, 0.38 mmol), 5-chloropyridine-3-boronic acid (65.7 mg, 0.42 mmol), cesium carbonate (617 mg, 1.9 mmol), and 1,1′-Bis(diphenylphosphino) ferrocene-palladium(II)dichloride (46.3 mg, 0.076 mmol) were combined in a vial that had been oven-dried and flushed with nitrogen. Dioxane (75 mL) was added, and the vial was sealed and heated to 90° C. for 4 hours. The reaction mixture was cooled to room temperature, filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-100% ethyl acetate/hexanes, linear gradient) to afford 6-chloro-4-(5-chloropyridin-3-yl)-2-[(trans)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[4-(trifluoromethyl)benzyl]-3H-imidazo[4,5-c]pyridine (racemic). MS APCl calc'd. for C26H22Cl2F3N5O [M+H]+ 548. found 548.
Reaction SMILES: Cl.[CH3:2][C@:3]1([OH:8])[CH2:7][O:6][NH:5][CH2:4]1.C(N(C(C)C)CC)(C)C.[CH:18]1([CH2:24][N:25]2[C:29]3[CH:30]=[CH:31][C:32]([C:34](O)=[O:35])=[CH:33][C:28]=3[N:27]=[C:26]2[C:37]([CH3:41])([CH3:40])[CH2:38][CH3:39])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[CH:18]1([CH2:24][N:25]2[C:29]3[CH:30]=[CH:31][C:32]([C:34]([N:5]4[CH2:4][C@@:3]([CH3:2])([OH:8])[CH2:7][O:6]4)=[O:35])=[CH:33][C:28]=3[N:27]=[C:26]2[C:37]([CH3:40])([CH3:41])[CH2:38][CH3:39])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: CCC(C)(C)c1nc2cc(C(=O)O)ccc2n1CC1CCCCC1
Reactant: C[C@@]1(O)CNOC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCC(C)(C)c1nc2cc(C(=O)N3C[C@@](C)(O)CO3)ccc2n1CC1CCCCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 87.5 %

Procedure:
Following the same procedure in Example 3, Step A, using (4R)-4-methylisoxazolidin-4-ol hydrochoride (36.0 mg, 0.25 mmol), diisopropylethylamine (144 μL, 106.6 mg, 0.83 mmol) and a solution of 1-(cyclohexylmethyl)-2-(1,1-dimethylpropyl)-1H-benzimidazole-5-carboxylic acid (82.1 mg, 0.25 mmol) (for preparation, see in Example 4, Step E) in DMF (5 mL) at 0° C., and later, HATU ( 14.0 mg, 0.30 mmol). The mixture was stirred for 4 h at room temperature, added H2O (5 mL). Upon evapoartion, the desired title compound was purified by reversed-phase HPLC (C-18 column) using 20-50% CH3CN/H2O to give 90.5 mg (69%) of a white solid. [a]D: +16.6° (c 0.15,EtOH). 1H NMR (400 MHz, CD3OD): δ 0.86 (t, J=7.42 Hz, 3H), 1.26 (m, 5H), 1.50 (s, 3H), 1.66 (m, 3H), 1.69 (s, 6H), 1.79 (m, 2H), 2.04 (q, J=7.49 Hz, 2H), 2.13 (m, 1H), 3.82 (d, J=11.33 Hz, 1H), 3.89 (d, J=8.40 Hz, 1H), 3.97 (m, 2H), 4.50 (d, J=7.81 Hz, 2H), 7.99 (m,2H), 8.19 (s, 1H). MS (ESI) (M+H)+=414.2. Anal. Calcd for C24H35N3O3+1.50 TFA+1.10 H2O (604.42): C, 53.65; H, 6.45; N, 6.95. Found: C, 53.55; H, 6.44; N, 7.18.
Reaction SMILES: C(Br)C1C=CC=CC=1.[F:9][C:10]([F:20])([F:19])[C:11]1[CH:18]=[CH:17][C:14]([CH2:15]Br)=[CH:13][CH:12]=1.[CH3:21][C:22]1[N:23]=[C:24]([N:27]2[CH2:31][CH2:30][NH:29][C:28]2=[O:32])[S:25][CH:26]=1>>[CH3:21][C:22]1[N:23]=[C:24]([N:27]2[CH2:31][CH2:30][N:29]([CH2:15][C:14]3[CH:17]=[CH:18][C:11]([C:10]([F:20])([F:19])[F:9])=[CH:12][CH:13]=3)[C:28]2=[O:32])[S:25][CH:26]=1
Reactant: Cc1csc(N2CCNC2=O)n1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Agent: BrCc1ccccc1
Product: Cc1csc(N2CCN(Cc3ccc(C(F)(F)F)cc3)C2=O)n1
Yield: 42 %

Procedure:
Following the procedure as described in Example 5, making variations to replace benzyl bromide with 4-(trifluoromethyl)benzyl bromide to react with 1-(4-methylthiazol-2-yl)imidazolidin-2-one, the title compound was obtained in 42% yield: mp 102-103° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 7.58 (d, J=8.1 Hz, 2H), 7.39 (d, J=8.1 Hz, 2H), 6.42 (s, 1H), 4.51 (s, 2H), 4.10-4.04 (m, 2H), 3.45-3.39 (m, 2H), 2.29 (s, 3H); MS (ES+) m/z 342.2 (M+1).