Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[CH:6]=[C:5]([C:7]([C:17]2[CH:22]=[C:21]([I:23])[C:20]([O-:24])=[C:19]([I:25])[CH:18]=2)=[C:8]2[CH:14]=[C:13]([I:15])[C:11](=[O:12])[C:10]([I:16])=[CH:9]2)[C:4]([C:26]([O-:28])=[O:27])=[CH:3][CH:2]=1.[Na+:29].[Na+].C(OC([N:36]1[CH2:41][CH2:40][N:39]([C:42](=[O:54])[C@H:43]([CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[C:48]([C:52]#[N:53])[CH:47]=2)[NH2:44])[CH2:38][CH2:37]1)=O)C.Cl.[NH2:56][OH:57].C(N(CC)CC)C.[CH2:65]([OH:67])[CH3:66]>>[CH:1]1[CH:6]=[C:5]([C:7]([C:8]2[CH:9]=[C:10]([I:16])[C:11]([O-:12])=[C:13]([I:15])[CH:14]=2)=[C:17]2[CH:18]=[C:19]([I:25])[C:20](=[O:24])[C:21]([I:23])=[CH:22]2)[C:4]([C:26]([O-:28])=[O:27])=[CH:3][CH:2]=1.[Na+:29].[Na+:29].[CH2:65]([O:67][N:36]1[CH2:37][CH2:38][N:39]([C:42](=[O:54])[C@H:43]([CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[C:48]([C:52](=[NH:53])[NH:56][OH:57])[CH:47]=2)[NH2:44])[C:40](=[C:26]=[O:28])[CH2:41]1)[CH3:66]
Reactant: CCOC(=O)N1CCN(C(=O)[C@@H](N)Cc2cccc(C#N)c2)CC1
Reactant: NO
Reactant: CCO
Agent: Cl
Agent: O=C1C(I)=CC(=C(c2cc(I)c([O-])c(I)c2)c2ccccc2C(=O)[O-])C=C1I
Agent: [Na+]
Solvent: CCN(CC)CC
Product: CCON1CCN(C(=O)[C@@H](N)Cc2cccc(C(=N)NO)c2)C(=C=O)C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
TIPPS-3-cyano-(L)-phenylalanine-4-ethoxycarbonylpiperazide (130 g; 196 mmol; 90% purity), hydroxylamine hydrochloride (22 g; 313 mmol) and triethylamine (63 g; 626 mmol) were dissolved in 470 ml of ethanol and stirred at RT for 1 day. After evaporating the solvent, the residue was taken up in 300 ml of ethyl acetate and extracted in each case 2× with 5% KHSO4, 5% NaHCO3 and distilled water. After evaporating the solvent, the crude product was dried under vacuum and then recrystallized from ethyl acetate/ether.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[C:22]([C:23]3[CH:28]=[CH:27][N:26]=[C:25]([NH:29][CH:30]4[CH2:34][CH2:33][CH2:32][CH2:31]4)[N:24]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[C:15]([NH:16][CH:17]4[CH2:21][CH2:20][CH2:19][CH2:18]4)[N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[S:35]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36]1>>[CH:17]1([NH:16][C:15]2[N:10]3[N:9]=[C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([C:37]5[CH:38]=[CH:39][S:35][CH:36]=5)[CH:3]=4)[C:22]([C:23]4[CH:28]=[CH:27][N:26]=[C:25]([NH:29][CH:30]5[CH2:31][CH2:32][CH2:33][CH2:34]5)[N:24]=4)=[C:11]3[CH:12]=[CH:13][CH:14]=2)[CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: Brc1cccc(-c2nn3c(NC4CCCC4)cccc3c2-c2ccnc(NC3CCCC3)n2)c1
Reactant: OB(O)c1ccsc1
Product: c1cc(-c2ccsc2)cc(-c2nn3c(NC4CCCC4)cccc3c2-c2ccnc(NC3CCCC3)n2)c1
Yield: 47 %

Procedure:
In a similar manner as described in Example 29 from 2-(3-bromophenyl)-N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-amine (200 mg, 0.39mmol) and thiophene-3-boronic acid, N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-[3-(3-thienyl)phenyl]pyrazolo[1,5-a]pyridin-7-amine (94 mg, 47%) was obtained as a yellow foam. 1H NMR (CDCl3): δ 8.00 (d, 1H), 7.92 (s. 1H), 7.81 (d, 1H), 7.67 (d, 1H), 7.57 (d, 1H), 7.49–7.42 (m, 2H), 7.40–7.34 (m, 2H), 7.32–7.27 (m, 1H), 6.38 (d, 1H), 6.09–6.03 (m, 2H), 5.22 (d, 1H), 4.36 (m, 1H), 4.00 (m, 1H), 2.15–2.05 (m, 4H), 1.82–1.56 (m, 12H); MS m/z 521 (M+1).
Reaction SMILES: IC1C=C(N[N:9]=[C:10]([C:13]#[N:14])[C:11]#[N:12])C=CC=1.[I:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].C(#N)CC#N.O.[NH2:29][NH2:30]>>[I:15][C:16]1[CH:17]=[C:18]([NH:19][N:9]=[C:10]2[C:11]([NH2:12])=[N:30][N:29]=[C:13]2[NH2:14])[CH:20]=[CH:21][CH:22]=1
Reactant: NN
Reactant: Nc1cccc(I)c1
Reactant: N#CC(C#N)=NNc1cccc(I)c1
Solvent: N#CCC#N
Solvent: O
Product: NC1=NN=C(N)C1=NNc1cccc(I)c1

Procedure:
4-[(3-iodophenyl)hydrazono]-4H-pyrazole-3,5-diamine was prepared using 148 mg (0.5 mmol) of 2-[(3-iodophenyl)hydrazono]malononitrile, which was derived from 3-iodoaniline (219 mg, 1.0 mmol) and malononitrile (1.5 mmol), and hydrazine hydrate. The hydrazine hydrate was added to the solution at a temperature of 75° C. despite the fact that the starting material had not fully dissolved. The solution cleared briefly and then a precipitate formed. The resulting solid was isolated by filtration, washed with ethanol, and dried to yield 122 mg (74%) of the compound as a mustard coloured solid.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH:22]4[CH2:24][CH2:23]4)=[CH:20][C:19]([CH3:25])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[O:26]1[CH2:30][CH2:29][NH:28][C:27]1=[O:31]>>[CH:22]1([C:21]2[C:16]([N:13]3[CH2:14][CH2:15][N:10]([C:8]([C:5]4[CH:4]=[CH:3][C:2]([N:28]5[CH2:29][CH2:30][O:26][C:27]5=[O:31])=[N:7][CH:6]=4)=[O:9])[CH2:11][CH2:12]3)=[N:17][CH:18]=[C:19]([CH3:25])[CH:20]=2)[CH2:24][CH2:23]1
Reactant: O=C1NCCO1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)nc3)CC2)c(C2CC2)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCOC4=O)nc3)CC2)c(C2CC2)c1
Yield: 56.2 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using (6-bromopyridin-3-yl)[4-(3-cyclopropyl-5-methylpyridin-2-yl)piperazin-1-yl]methanone (170 mg) described in Preparation Example 144 and oxazolidin-2-one (55 mg), the title compound (97 mg) was obtained.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][OH:18])=[CH:13][C:12]=2[N:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:21][CH2:20]2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]>[O-2].[Mn+4].[O-2].C(Cl)(Cl)Cl>[C:1]([CH:5]1[CH2:6][CH2:7][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([CH:17]=[O:18])=[CH:13][C:12]=2[N:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:21][CH2:20]2)[CH2:9][CH2:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCN1CCN(c2cc(CO)ccc2C2CCC(C(C)(C)C)CC2)CC1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: CCCCN1CCN(c2cc(C=O)ccc2C2CCC(C(C)(C)C)CC2)CC1
Yield: 85.1 %

Procedure:
A mixture of the crude product of [4-(4-t-butylcyclohexyl)-3-(4-butylpiperazine-1-yl)phenyl]methanol produced in Example (101a) (294 mg), manganese(IV) oxide (1.3 g, 14.95 mmol) and chloroform (15 mL) was refluxed for 40 minutes. The reaction mixture was filtered and insoluble materials were filtered off. The filtrate was concentrated under reduced pressure to give 249 mg of a crude product of the title compound as an ochre oil. This product was directly used without purification for the following reaction.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:10][CH2:9][CH:8]([C:11]([N:13]3[CH2:17][C@H:16]([NH:18][CH3:19])[C@@H:15]([C:20]4[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=4)[CH2:14]3)=[O:12])[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.Cl[C:29]([O:31][C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=1)=[O:30]>>[Cl:38][C:35]1[CH:36]=[CH:37][C:32]([O:31][C:29](=[O:30])[N:18]([C@@H:16]2[C@@H:15]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=3)[CH2:14][N:13]([C:11]([CH:8]3[CH2:9][CH2:10][N:5]([CH2:4][CH:1]4[CH2:3][CH2:2]4)[CH2:6][CH2:7]3)=[O:12])[CH2:17]2)[CH3:19])=[CH:33][CH:34]=1
Reactant: CN[C@H]1CN(C(=O)C2CCN(CC3CC3)CC2)C[C@@H]1c1ccc(Cl)c(Cl)c1
Reactant: O=C(Cl)Oc1ccc(Cl)cc1
Product: CN(C(=O)Oc1ccc(Cl)cc1)[C@H]1CN(C(=O)C2CCN(CC3CC3)CC2)C[C@@H]1c1ccc(Cl)c(Cl)c1

Procedure:
In analogy to the procedure described for the synthesis of example 2 (step b), the title compound rac-[(3R,4S)-1-(1-cyclopropylmethyl-piperidine-4-carbonyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-chloro-phenyl ester was prepared from rac-(1-cyclopropylmethyl-piperidin-4-yl)-[(3S,4R)-3-(3,4-dichloro-phenyl)-4-methylamino-pyrrolidin-1-yl]-methanone instead of rac-{4-[(3S,4R)-3-(3,4-dichloro-phenyl)-4-methylamino-pyrrolidine-1-carbonyl]-piperidin-1-yl}-(1-methyl-cyclopropyl)-methanone using 4-chloro-phenyl chloroformate instead of fluorophenyl chloroformate and was obtained as a colorless oil. MS m/e: 564.2 [M]+.
Reaction SMILES: [C:1](Cl)(=[O:5])[O:2][CH2:3][CH3:4].[OH:7][C@@H:8]1[C@@:33]2([CH3:34])[C:12](=[CH:13][CH2:14][C@@H:15]3[C@@H:32]2[CH2:31][CH2:30][C@@:29]2([CH3:35])[C@H:16]3[CH2:17][CH2:18][C@@H:19]2[C@H:20]([CH3:28])[CH2:21][CH2:22][C@@H:23]([OH:27])[CH:24]([CH3:26])[CH3:25])[CH2:11][C@@H:10]([OH:36])[CH2:9]1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH2:3]([O:2][C:1]([O:7][C@@H:8]1[C@@:33]2([CH3:34])[C:12](=[CH:13][CH2:14][C@@H:15]3[C@@H:32]2[CH2:31][CH2:30][C@@:29]2([CH3:35])[C@H:16]3[CH2:17][CH2:18][C@@H:19]2[C@H:20]([CH3:28])[CH2:21][CH2:22][C@@H:23]([O:27][C:1]([O:2][CH2:3][CH3:4])=[O:5])[CH:24]([CH3:26])[CH3:25])[CH2:11][C@@H:10]([O:36][C:1]([O:2][CH2:3][CH3:4])=[O:5])[CH2:9]1)=[O:5])[CH3:4]
Reactant: CC(C)[C@H](O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Reactant: CCOC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)O[C@@H]1CC2=CC[C@H]3[C@@H]4CC[C@H]([C@H](C)CC[C@@H](OC(=O)OCC)C(C)C)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(=O)OCC)C1
Temperature: 0 °C

Procedure:
A ethyl chlorocarbonate (24.75 ml) was added dropwise to a solution of 1α,3β,24(R)-trihydroxycholest-5-ene (3.63 g), 4-dimethylaminopyridine (6.25 g) and methylenechloride (40 ml) with stirring at 0° C. After stirring for 27 hours at 60° C., the reaction mixture was poured into ice water and extracted with methylenechloride. The extracts were washed with 2 N hydrochloric acid, saturated sodium bicarbonate solution and saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure to give 4.98 g of residual product. The residue was recrystallized from methanol (10 ml) to afford 3.64 g of 1α,3β,24(R)-triethoxycarbonyoxycholest-5-ene as crystals.
Reaction SMILES: [CH3:1][C@@:2]1([CH2:5]OS(C2C=CC=C([N+]([O-])=O)C=2)(=O)=O)[CH2:4][O:3]1.[OH:19][C:20]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:21]=1[NH:28][C:29](=[O:31])[CH3:30].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH3:27][O:26][C:24]1[CH:23]=[CH:22][C:21]([NH:28][C:29](=[O:31])[CH3:30])=[C:20]([O:19][CH2:1][C@:2]2([CH3:5])[CH2:4][O:3]2)[CH:25]=1
Reactant: C[C@@]1(COS(=O)(=O)c2cccc([N+](=O)[O-])c2)CO1
Reactant: COc1ccc(NC(C)=O)c(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(NC(C)=O)c(OC[C@]2(C)CO2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of [(2S)-2-methyloxiran-2-yl]methyl3-nitrobenzenesulfonate (2.04 g, 7.46 mmol), N-(2-hydroxy-4-methoxyphenyl)acetamide ((1.04 g, 5.74 mmol) and Cs2CO3 (2.80 g, 8.61 mmol) in DMF (12 mL) was kept on stirring at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel flash chromatography (ethyl acetate:hexane 1:1) to give the subtitled compound (1.19 g).
Reaction SMILES: [CH2:1]([S:5][C:6]1[N:10]=[CH:9][NH:8][N:7]=1)[CH2:2][CH2:3][CH3:4].[CH2:11]([N:14]([CH2:18][CH:19]=[CH2:20])[C:15](Cl)=[O:16])[CH:12]=[CH2:13].O1CCCC1>C(N(CC)CC)C>[CH2:11]([N:14]([CH2:18][CH:19]=[CH2:20])[C:15]([N:8]1[CH:9]=[N:10][C:6]([S:5][CH2:1][CH2:2][CH2:3][CH3:4])=[N:7]1)=[O:16])[CH:12]=[CH2:13]
Reactant: C=CCN(CC=C)C(=O)Cl
Reactant: CCCCSc1nc[nH]n1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CCN(CC=C)C(=O)n1cnc(SCCCC)n1

Procedure:
A mixture of 6.3 g. 3-n-butylthio-1,2,4-triazole, 6.8 g. diallylcarbamoyl chloride, 25 ml. tetrahydrofuran and 8 ml. dry triethylamine was refluxed under anhydrous conditions for 4 hours. The reaction mixture was worked up as described in Example 1 to produce an oil which was distilled under reduced pressure to give 1-diallylcarbamoyl-3-n-butylthio-1,2,4-triazole, b.p. 157° C./0.6 mm. (95.0% 1-isomer by GLC assay). Elemental analysis satisfactory.
Reaction SMILES: [CH2:1]([O:3][CH2:4][N:5]1[C:9](B2OC(C)(C)C(C)(C)O2)=[CH:8][CH:7]=[N:6]1)[CH3:2].[C:19]([C:21]1[CH:22]=[C:23]([S:40]([N:43]([CH2:49][C:50]2[CH:55]=[CH:54][C:53]([O:56][CH3:57])=[CH:52][C:51]=2[O:58][CH3:59])[C:44]2[S:48][N:47]=[CH:46][N:45]=2)(=[O:42])=[O:41])[CH:24]=[CH:25][C:26]=1[O:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][C:35]([F:38])([F:37])[F:36])=[CH:30][C:29]=1I)#[N:20]>>[C:19]([C:21]1[CH:22]=[C:23]([S:40]([N:43]([CH2:49][C:50]2[CH:55]=[CH:54][C:53]([O:56][CH3:57])=[CH:52][C:51]=2[O:58][CH3:59])[C:44]2[S:48][N:47]=[CH:46][N:45]=2)(=[O:42])=[O:41])[CH:24]=[CH:25][C:26]=1[O:27][C:28]1[CH:29]=[CH:30][C:31]([O:34][C:35]([F:37])([F:36])[F:38])=[CH:32][C:33]=1[C:9]1[N:5]([CH2:4][O:3][CH2:1][CH3:2])[N:6]=[CH:7][CH:8]=1)#[N:20]
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc(Oc3ccc(OC(F)(F)F)cc3I)c(C#N)c2)c(OC)c1
Reactant: CCOCn1nccc1B1OC(C)(C)C(C)(C)O1
Product: CCOCn1nccc1-c1cc(OC(F)(F)F)ccc1Oc1ccc(S(=O)(=O)N(Cc2ccc(OC)cc2OC)c2ncns2)cc1C#N
Yield: 29 %

Procedure:
Prepared according to Method U (below) using 1-(ethoxymethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (Preparation 337, 197 mg, 0.714 mmol), and 3-cyano-N-(2,4-dimethoxybenzyl)-4-[2-iodo-4-(trifluoromethoxy)phenoxy]-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide (Preparation 497, 210 mg, 0.42 mmol). The material was purified by column chromatography eluting with ethyl acetate:heptane (1:1, by volume) to furnish the title compound as a white solid, 70 mg, 29% yield.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:5](OC)=[O:6].O.[NH2:14][NH2:15]>C(O)C>[NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:5]([NH:14][NH2:15])=[O:6]
Reactant: COC(=O)c1ccc(C)c(N)c1
Reactant: NN
Solvent: O
Solvent: CCO
Product: Cc1ccc(C(=O)NN)cc1N
Temperature: 100 °C
Reaction time: 2 h
Yield: 69.6 %

Procedure:
Into a round-bottom flask, was placed a solution of methyl 3-amino-4-methylbenzoate (6.60 g, 40.0 mmol, 1.00 equiv) in ethanol (100 mL). Hydrazine hydrate (10.0 g, 200 mmol, 5.00 equiv) was added to the reaction. The resulting solution was stirred for 2 h at 100° C. in an oil bath. After cooling to ambient temperature, the mixture was concentrated under reduced pressure. The residue was partitioned between water and ethyl acetate (20 mL). The aqueous layer was extracted with 4×20 mL of ethyl acetate and the combined organic layers were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and dried under high-vacuum to yield 4.60 g (70%) of the title compound as a brown solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH:10]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([F:22])[CH:16]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:23]Br>C(Cl)(Cl)Cl>[BrH:23].[Br:23][CH:12]1[CH2:13][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][CH:10]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([F:22])[CH:16]=2)[C:11]1=[O:14]
Reactant: BrBr
Reactant: O=C1CCN(Cc2ccccc2)CC1c1ccc(Cl)c(F)c1
Solvent: ClC(Cl)Cl
Product: Br
Product: O=C1C(Br)CN(Cc2ccccc2)CC1c1ccc(Cl)c(F)c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 186.5 %

Procedure:
Benzyl-3-(4-chloro-3-fluorophenyl)-piperidin-4-one (100 mg, 0.33 mmol) was dissolved in chloroform (1 mL). To this solution bromine (53 mg, 0.33 mmol) in chloroform (0.5 mL) was added drop wise at −11° C. The reaction was stirred for 1½ hours at 5° C., for 1 hour at room temperature and for 1 hours at 50° C. The solvent was removed under reduced pressure to yield the crude title compound (147 mg) which was used directly in the next step without further purification.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[CH:12]=[CH:11][C:10]([C:15]2[C:16]3[N:17]([N:23]=[C:24]([CH:30]([CH3:32])[CH3:31])[C:25]=3[C:26]([O:28]C)=[O:27])[C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Li+].Cl>C1COCC1.O.CO>[CH2:1]([N:8]1[C:13](=[O:14])[CH:12]=[CH:11][C:10]([C:15]2[C:16]3[N:17]([N:23]=[C:24]([CH:30]([CH3:32])[CH3:31])[C:25]=3[C:26]([OH:28])=[O:27])[C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1c(C(C)C)nn2c(OC)ccc(-c3ccc(=O)n(Cc4ccccc4)n3)c12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COc1ccc(-c2ccc(=O)n(Cc3ccccc3)n2)c2c(C(=O)O)c(C(C)C)nn12
Yield: 49.6 %

Procedure:
A solution of the compound of Example 266 (250 mg) and lithium hydroxide (140 mg) in a mixture of THF, water and methanol (6 mL, THF:water:methanol=3:2:1) was refluxed for 18 hours. Subsequently, water was added, followed by addition of 2 mol/L hydrochloric acid to adjust the pH to 4. The mixture was extracted with ethyl acetate and the organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was concentrated and the residue was purified by silica gel column chromatography (ethyl acetate:methanol=98:2) to afford the title compound as a colorless powder (120 mg).
Reaction SMILES: [Br-:1].[Br-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:25]([CH2:35]O)[CH:24]=1>C(Cl)(Cl)Cl>[Br:1][CH2:35][C:25]1[CH:24]=[C:23]([F:22])[CH:28]=[CH:27][C:26]=1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: [Br-]
Reactant: OCc1cc(F)ccc1-c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Product: Fc1ccc(-c2ccccc2)c(CBr)c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
Triphenylphosphine dibromide (35.5 g, 2 eq) was added in one portion to a solution of (4-fluoro-[1,1′-biphenyl]-2-yl)methanol (8.5 g, 42 mmol) in chloroform (250 mL). The reaction mixture was heated at 60° C. and left to stir overnight. The solid was filtered off and the solvent removed in vacuo. The resulting oil was purified by flash chromatography on silica, eluting with ethyl acetate/cyclohexane (0:100 to 30:70), to give the title compound as an oil.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([OH:16])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].[CH3:17][S:18](Cl)(=[O:20])=[O:19]>ClCCl>[CH3:17][S:18]([C:8](=[O:16])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])(=[O:20])=[O:19]
Reactant: CCCCCCCCO
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCC(=O)S(C)(=O)=O
Reaction time: 0.5 h
Yield: 97 %

Procedure:
To a solution of triethylamine (0.12 g, 1.15 mmol, 1.5 equiv.) in dichloromethane (3 mL) was added octanol (0.10 g, 0.77 mmol, 1.0 equiv.) at 0° C. followed by the addition of methanesulfonyl chloride (0.10 g, 0.85 mmol, 1.1 equiv.), over a period of 5 minutes. After 30 minutes at 0° C., the reaction mixture was diluted in dichloromethane (50 mL) and extracted with ice cold water (50 mL), ice cold 10% aqueous HCl (50 mL), saturated aqueous NaHCO3 (50 mL), and with saturated aqueous NaCl (50 mL). The organic layer was dried (MgSO4) and concentrated under reduced pressure to afford 17 (97%): 1H NMR (CDCl3, 400 MHz) δ 4.21 (t, J=6.5 Hz, 2H, CH2OSO2Me), 2.99 (s, 3H, CH3SO3), 1.77 (p, J=6.7 Hz, 2H), 1.35 (m, 10H), 0.87 (t, J=6.1 Hz, 3H).
Reaction SMILES: [CH2:1]1[CH2:11][CH2:10]N2[C:4](=NCCC2)[CH2:3][CH2:2]1.[C:12]1([CH3:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:12]1([CH2:18][C:4]2[CH:3]=[CH:2][CH:1]=[CH:11][CH:10]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[C:12]1([CH:18]([C:4]2[CH:3]=[CH:2][CH:1]=[CH:11][CH:10]=2)[C:1]2[CH:11]=[CH:10][CH:4]=[CH:3][CH:2]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cc1ccccc1
Reactant: C1CCC2=NCCCN2CC1
Product: c1ccc(C(c2ccccc2)c2ccccc2)cc1
Product: c1ccc(Cc2ccccc2)cc1

Procedure:
Mono-, di- or tri-phenylacetic acids were reacted with 1.5 molar equivalents of DBU to produce the corresponding toluene, diphenylmethane or triphenylmethane in yields of 80, 100 and 100% respectively. All reactions were carried out over a period of 2 to 3 hrs. using 240° C., 90° C. and 40° C., respectively, as the average reaction temperature.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11]([N:25]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[N:12][CH:13]=[C:14](B2OC(C)(C)C(C)(C)O2)[CH:15]=1.Br[C:41]1[C:42]([CH2:59][OH:60])=[N:43][N:44]([CH:46]2[CH2:51][CH2:50][N:49]([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[CH2:48][CH2:47]2)[CH:45]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>O.O1CCOCC1>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:15]=[C:14]([C:41]2[C:42]([CH2:59][OH:60])=[N:43][N:44]([CH:46]3[CH2:47][CH2:48][N:49]([C:52]([O:54][C:55]([CH3:56])([CH3:58])[CH3:57])=[O:53])[CH2:50][CH2:51]3)[CH:45]=2)[CH:13]=[N:12][C:11]=1[N:25]([C:26]([O:27][C:28]([CH3:30])([CH3:31])[CH3:29])=[O:32])[C:33]([O:35][C:36]([CH3:37])([CH3:39])[CH3:38])=[O:34]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(B2OC(C)(C)C(C)(C)O2)cc1-c1nc2ccccc2o1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(Br)c(CO)n2)CC1
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(-c4nc5ccccc5o4)c3)c(CO)n2)CC1
Temperature: 120 °C
Reaction time: 2 h
Yield: 49.2 %

Procedure:
Tert-butyl N-[3-(1,3-benzoxazol-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]-N-tert-butoxycarbonyl-carbamate (237 mg), tert-butyl 4-(4-bromo-3-(hydroxymethyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (159 mg), potassium phosphate (225 mg) and trisdibenzilideneacetone dipalladium (20.19 mg) and tricyclohexylphosphine (12.37 mg) were weighed out in a microwave vial, sealed and 1,4-dioxane (4 ml) and water (400 μl) were added. Argon was bubbled through the suspension at 25° C. for 5 minutes. The mixture was stirred at 120° C. for 2 hours. The reaction mixture was allowed to cool down, Dicalite Speed Plus (Acros Chemicals) was added and the mixture was concentrated. The crude product was purified by flash chromatography on silica gel eluting with 50 to 100% ethyl acetate in petroleum ether. The solvent was evaporated to dryness to afford tert-butyl 4-[4-[5-(1,3-benzoxazol-2-yl)-6-(bis(tert-butoxycarbonyl)amino)-3-pyridyl]-3-(hydroxymethyl)pyrazol-1-yl]piperidine-1-carboxylate (150 mg). The N-tert-butoxycarbonyl groups on the resultant product were removed by conventional treatment with trifluoroacetic acid to afford [4-[6-amino-5-(1,3-benzoxazol-2-yl)-3-pyridyl]-1-(4-piperidyl)pyrazol-3-yl]methanol (49.0 mg) as a solid.
Reaction SMILES: C1([C@@H]([N:9]2[C@@H:16]3[C@@H:11]([CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15]3)[CH2:10]2)C)C=CC=CC=1.CC(O)=O.[H][H]>CCO.[OH-].[OH-].[Pd+2]>[C@H:16]12[NH:9][CH2:10][C@H:11]1[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15]2
Reactant: [H][H]
Reactant: C[C@@H](c1ccccc1)N1C[C@@H]2CCN(C(=O)OC(C)(C)C)C[C@@H]21
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CC[C@@H]2CN[C@@H]2C1
Yield: 75 %

Procedure:
To a solution of (1R,6S)-tert-butyl 8-((S)-1-phenylethyl)-3,8-diazabicyclo[4.2.0]octane-3-carboxylate (1.5 g, 75%) in EtOH (50 mL) was added AcOH (1.5 mL). The resulting mixture was cycled through an ThalesNano H-Cube containing a 20% Pd(OH)2/C catalyst cartridge at 50° C. and 100 bar of hydrogen pressure. After 16 hours the resulting mixture was removed from the ThalesNano H-Cube and poured over a saturated sodium carbonate solution (100 mL). The aqueous layer was extracted with DCM (50 mL) four times. The organic layers were combined, dried over Na2SO4, filtered and concentrated under reduced pressure to yield the title compound (755 mg, 75%) which was used in the next step without purification. MS (ESI) mass calcd. for C11H20N2O2, 212.2; m/z found, 213.1 [M+H]+. 1H NMR (500 MHz, CDCl3): 4.18-4.00 (m, 1H), 3.85-3.57 (m, 3H), 3.44-3.34 (m, 1H), 3.28 (dt, J=13.1, 6.5 Hz, 1H), 3.24-3.13 (m, 1H), 2.82-2.72 (m, 1H), 1.93-1.83 (m, 1H), 1.82-1.70 (m, 1H), 1.48 (s, 9H).