Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[N:7][C:6]([C:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[O:10])=[CH:5][CH:4]=1.[H][H]>C(O)C.O.[Pt](=O)=O>[CH3:1][O:2][C:3]1[N:8]=[N:7][C:6]([CH:9]([CH:11]2[CH2:16][CH2:15][CH2:14][NH:13][CH2:12]2)[OH:10])=[CH:5][CH:4]=1
Reactant: [H][H]
Reactant: COc1ccc(C(=O)c2cccnc2)nn1
Agent: O=[Pt]=O
Solvent: CCO
Solvent: O
Product: COc1ccc(C(O)C2CCCNC2)nn1
Yield: 92.5 %

Procedure:
(6-Methoxypyridazin-3-yl)pyrdin-3-ylmethanone (1.31 g, 6.1 mmol) were dissolved in ethanol (100 ml), platinum(IV) oxide hydrate (80% of Pt, 0.5 g, 2.2 mmol) was added, and the mixture was stirred with supply of hydrogen. Conventional work-up gave 1.26 g (93% yield) of (6-methoxypyridazin-3-yl)piperidin-3-ylmethanol as crude product, which was employed directly in the next step;
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11]([NH:13][NH2:14])=[O:12])[NH:8][C:5]2=[CH:6][N:7]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C.[C:45](O)(=[O:55])[C:46]1[CH:54]=[CH:53][C:52]2[O:51][CH2:50][O:49][C:48]=2[CH:47]=1>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11]([NH:13][NH:14][C:45]([C:46]3[CH:54]=[CH:53][C:52]4[O:51][CH2:50][O:49][C:48]=4[CH:47]=3)=[O:55])=[O:12])[NH:8][C:5]2=[CH:6][N:7]=1
Reactant: O=C(O)c1ccc2c(c1)OCO2
Reactant: NNC(=O)c1cc2cc(Cl)ncc2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NNC(=O)c1cc2cc(Cl)ncc2[nH]1)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid hydrazide (Preparation 10—route 2, 0.100 g, 0.48 mmol) in DMF (4 mL) was added HOBt (0.064 g, 0.48 mmol), EDCI (0.110 g, 0.58 mmol), DIPEA (200 μL, 0.96 mmol) and piperonylic acid (0.079 g, 0.48 mmol). The reaction mixture was stirred at rt for 16 h. The reaction mixture was poured into water (75 mL) and extracted with ethyl acetate (2×150 mL). The combined organic extract was washed with saturated sodium chloride (75 mL), dried (MgSO4) and concentrated in vacuo to give a solid. The solid obtained was purified by recrystallisation from methanol to give the title compound. m/z (ES+)=359 [M+H]+; RT=2.92 min.
Reaction SMILES: [F:1][C:2]1([F:49])[CH2:7][CH2:6][C@H:5]([O:8][C:9]2[C:14]([CH3:15])=[CH:13][C:12]([S:16]([N:19](CC3C=CC(OC)=CC=3OC)[C:20]3[CH:25]=[CH:24][N:23]=[CH:22][N:21]=3)(=[O:18])=[O:17])=[C:11]([F:37])[CH:10]=2)[C@@H:4]([C:38]2[N:42](COCCOC)[N:41]=[CH:40][CH:39]=2)[CH2:3]1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O.Cl>CO.ClCCl>[F:49][C:2]1([F:1])[CH2:7][CH2:6][C@H:5]([O:8][C:9]2[C:14]([CH3:15])=[CH:13][C:12]([S:16]([NH:19][C:20]3[CH:25]=[CH:24][N:23]=[CH:22][N:21]=3)(=[O:18])=[O:17])=[C:11]([F:37])[CH:10]=2)[C@@H:4]([C:38]2[NH:42][N:41]=[CH:40][CH:39]=2)[CH2:3]1
Reactant: COCCOCn1nccc1[C@H]1CC(F)(F)CC[C@@H]1Oc1cc(F)c(S(=O)(=O)N(Cc2ccc(OC)cc2OC)c2ccncn2)cc1C
Agent: CC[SiH](CC)CC
Agent: Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: Cc1cc(S(=O)(=O)Nc2ccncn2)c(F)cc1O[C@H]1CCC(F)(F)C[C@@H]1c1ccn[nH]1
Yield: 65.8 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 155i by using the 4-{[(1S*,2R*)-4,4-difluoro-2-{1-[(2-methoxyethoxy)methyl]-1H-pyrazol-5-yl}cyclohexyl]oxy}-N-(2,4-dimethoxybenzyl)-2-fluoro-5-methyl-N-(pyrimidin-4-yl)benzenesulfonamide (356 mg, 0.504 mmol) prepared in Example 157d, triethylsilane (0.50 mL), trifluoroacetic acid (5.0 mL), dichloromethane (5.0 mL), 6 M hydrochloric acid (5.0 mL) and methanol (15 mL), to yield the title compound (155 mg, 66%) as a colorless solid.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:6]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][CH2:19][C@H:20]1[CH2:22][O:21]1)[N:14]=[CH:13][CH:12]=[C:11]2[O:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:33][CH:34]2[CH2:36][CH2:35]2)=[O:32])=[C:26]([CH3:37])[C:25]=1[CH3:38])#[N:7]>O1CCCC1>[C:6]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][CH2:19][C@H:20]([OH:21])[CH2:22][N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)[N:14]=[CH:13][CH:12]=[C:11]2[O:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:33][CH:34]2[CH2:36][CH2:35]2)=[O:32])=[C:26]([CH3:37])[C:25]=1[CH3:38])#[N:7]
Reactant: Cc1c(NC(=O)NC2CC2)ccc(Oc2ccnc3cc(OC[C@H]4CO4)c(C#N)cc23)c1C
Reactant: C1CCNC1
Solvent: C1CCOC1
Product: Cc1c(NC(=O)NC2CC2)ccc(Oc2ccnc3cc(OC[C@H](O)CN4CCCC4)c(C#N)cc23)c1C
Temperature: 60 °C

Procedure:
After adding tetrahydrofuran (2.0ml) and pyrrolidine (0.20 ml) to N-(4-(6-cyano-7-((2R)-oxiran-2-yl)methoxy-quinolin-4-yloxy)-2,3-dimethylphenyl)-N′-cyclopropylurea (110 mg), the mixture was heated at 60° C. for 2 hours. After allowing the reaction solution to cool, the precipitated crystals were filtered out to obtain the title compound (18 mg) as light brown crystals.
Reaction SMILES: [Br-].[C:2]([C:5]1[CH:6]=[N+:7]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])[CH:8]=[CH:9][C:10]=1[CH2:11][CH:12]1[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([Cl:21])[CH:18]=2)[C:13]1=[O:22])(=[O:4])[CH3:3].C1C(C(N)=O)=CN(CC2C=CC=CC=2)C=C1>>[C:2]([C:5]1[CH:10]([CH2:11][CH:12]2[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([Cl:21])[CH:18]=3)[C:13]2=[O:22])[CH:9]=[CH:8][N:7]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])[CH:6]=1)(=[O:4])[CH3:3]
Reactant: CC(=O)c1c[n+](Cc2ccccc2C)ccc1CC1Cc2cc(Cl)ccc2C1=O
Agent: NC(=O)C1=CN(Cc2ccccc2)C=CC1
Agent: [Br-]
Product: CC(=O)C1=CN(Cc2ccccc2C)C=CC1CC1Cc2cc(Cl)ccc2C1=O

Procedure:
The title compound 167 is prepared according to the procedure reported in Example 39.1 with compound 136 (42 mg, 0.08 mmol) and BNAH (19 mg, 1 equiv) as reactants. Yellow solid. (Yield 17.5 mg, 50%).
Reaction SMILES: [BH4-].[Na+].B(F)(F)F.CCOCC.[CH2:12]([O:19][C:20]([N:22]1[CH2:26][C@H:25]([O:27][S:28]([CH3:31])(=[O:30])=[O:29])[CH2:24][C@H:23]1[CH2:32][O:33][CH2:34][C:35]([NH:37][C:38]([NH2:40])=[O:39])=O)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CO>O1CCCC1>[CH2:12]([O:19][C:20]([N:22]1[CH2:26][C@H:25]([O:27][S:28]([CH3:31])(=[O:29])=[O:30])[CH2:24][C@H:23]1[CH2:32][O:33][CH2:34][CH2:35][NH:37][C:38]([NH2:40])=[O:39])=[O:21])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](COCC(=O)NC(N)=O)N(C(=O)OCc2ccccc2)C1
Agent: FB(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOCC
Product: CS(=O)(=O)O[C@@H]1C[C@@H](COCCNC(N)=O)N(C(=O)OCc2ccccc2)C1
Reaction time: 0.5 h
Yield: 39.4 %

Procedure:
To a suspension of sodium borohydride (0.1 g) in tetrahydrofuran (10 ml) was added boron trifluoride etherate (0.3 ml) with stirring at 0°-10° C. After 30 minutes, a solution of (2S,4R)-1-benzyloxycarbonyl-4-methanesulfonyloxy-2- [(ureidocarbonylmethyl)oxymethyl]pyrrolidine (0.63 g) in tetrahydrofuran (5 ml) was added to the mixture at 0°-10° C. The mixture was stirred at the same condition for 2 hours and at ambient temperature for 15 hours. Methanol (5 ml) was added to the mixture at 0°-10° C. The mixture was stirred at ambient temperature for 3 hours and concentrated under reduced pressure to give a syrup. The syrup was subjected to a column chromatography on silica gel (25 g) and eluted with a mixture of methanol and chloroform (2:98 V/V) to give (2S,4R)-1-benzyloxycarbonyl-4-methanesulfonyloxy-2-[(2-ureidoethyl)oxymethyl]pyrrolidine (0.24 g).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]2[C:13]([Cl:14])=[CH:12][C:11]([F:15])=[C:10]([C:16]3[C:20]([Cl:21])=[C:19]([O:22][CH:23]([F:25])[F:24])[N:18]([CH3:26])[N:17]=3)[N:9]2[CH:27]=1)=[O:5])C.[OH-].[Na+].Cl>CS(C)=O>[Cl:14][C:13]1[C:8]2[N:9]([CH:27]=[C:6]([C:4]([OH:5])=[O:3])[N:7]=2)[C:10]([C:16]2[C:20]([Cl:21])=[C:19]([O:22][CH:23]([F:25])[F:24])[N:18]([CH3:26])[N:17]=2)=[C:11]([F:15])[CH:12]=1
Reactant: CCOC(=O)c1cn2c(-c3nn(C)c(OC(F)F)c3Cl)c(F)cc(Cl)c2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: Cn1nc(-c2c(F)cc(Cl)c3nc(C(=O)O)cn23)c(Cl)c1OC(F)F
Temperature: 22 °C
Reaction time: 1 h
Yield: 73.5 %

Procedure:
0.51 g of 8-chloro-5-(4-chloro-5-difluoromethoxy-1-methyl-[1H]-pyrazol-3-yl)-6-fluoro-imidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester (Example P58) is dissolved in 3 ml of dimethyl sulfoxide and, with cooling in an ice-bath, 0.63 ml of a 2N aqueous sodium hydroxide solution is added. The mixture is then stirred for 1 hour at 22° C. Because the TLC analysis of a worked-up sample indicates that starting material is still present, a further 0.1 ml of 2N sodium hydroxide solution is added. After subsequently stirring for 30 minutes, the mixture is rendered strongly acidic with dilute hydrochloric acid, the resulting slurry is filtered, and the filtration residue is subsequently washed with cold water and dried in vacuo at 50° C. 0.35 g of the desired title compound is obtained in the form of a white solid (crude product).
Reaction SMILES: [C:1]([N:9]1[CH2:17][C@@H:16]([O:18][S:19]([C:22]2[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH2:15][C@H:10]1[C:11]([O:13]C)=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.O.[OH-].[Li+]>C1COCC1>[C:1]([N:9]1[CH2:17][C@@H:16]([O:18][S:19]([C:22]2[CH:23]=[CH:24][C:25]([CH3:26])=[CH:27][CH:28]=2)(=[O:20])=[O:21])[CH2:15][C@H:10]1[C:11]([OH:13])=[O:12])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@@H]1C[C@H](OS(=O)(=O)c2ccc(C)cc2)CN1C(=O)c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)O[C@H]2C[C@@H](C(=O)O)N(C(=O)c3ccccc3)C2)cc1
Reaction time: 3 h

Procedure:
A solution of (cis)-1-benzoyl-4-tosyloxy-L-proline, methyl ester (from the previous step) in THF.H2O (25 ml-5 ml) was stirred under argon and treated with lithium hydroxide mono hydrate (672 mg, 16 mmole). The reaction was stirred for 3 hours, concentrated in vacuo, acidified to pH 1.5 with HCl, and extracted with ethyl acetate. The organic extracts were dried, filtered and concentrated in vacuo to a white solid which was recrystallized twice from ethyl acetate to afford the title compound.
Reaction SMILES: C(O[C:4]([C:6]1([CH2:13][CH2:14]OC)[CH2:11][CH2:10][C:9](=[CH2:12])[CH2:8][CH2:7]1)=[O:5])C.[CH:17]1([C:20]2[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=2)[CH2:19][CH2:18]1.[Cl-].C[Al+]C.Cl>C1(C)C=CC=CC=1.O>[CH:17]1([C:20]2[CH:26]=[CH:25][C:23]([N:24]3[CH2:14][CH2:13][C:6]4([CH2:7][CH2:8][C:9](=[CH2:12])[CH2:10][CH2:11]4)[C:4]3=[O:5])=[CH:22][CH:21]=2)[CH2:19][CH2:18]1
Reactant: Nc1ccc(C2CC2)cc1
Reactant: C=C1CCC(CCOC)(C(=O)OCC)CC1
Agent: C[Al+]C
Agent: Cl
Agent: [Cl-]
Solvent: O
Solvent: Cc1ccccc1
Product: C=C1CCC2(CC1)CCN(c1ccc(C3CC3)cc1)C2=O
Temperature: 100 °C
Reaction time: 4 h

Procedure:
A mixture of 0.3 g (1.3 mmol) 1-(2-methoxy-ethyl)-4-methylene-cyclohexanecarboxylic acid ethyl ester and 0.264 g (1.98 mmol) 4-cyclopropylaniline in 6 mL toluene was treated with 2.65 mL (2.65 mmol) dimethylaluminium chloride (1M in toluol) and stirred for 4 h at 100° C. After cooling to room temperature water and 1N HCl aq. was carefully added and the mixture poured onto water and extracted with ethyl acetate. The combined organic layers were washed with water, dried with MgSO4, filtered and evaporated to dryness. The residue was purified by flash column chromatography over silica eluting with a gradient formed from hexane and ethyl acetate to yield after evaporation of the product containing fractions 0.264 g (71%) of the title compound as yellow crystals. MS (m/e): 282.4 [MH+].
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([CH3:16])[C:10]([F:15])=[C:11](Br)[CH:12]=3)[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.S(Cl)([Cl:23])=O.[OH-].[Na+]>>[CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([CH3:16])[C:10]([F:15])=[C:11]([Cl:23])[CH:12]=3)[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: Cc1c(F)c(Br)cc2c1c(=O)c(C(=O)O)cn2C1CC1
Reactant: O=S(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1c(F)c(Cl)cc2c1c(=O)c(C(=O)O)cn2C1CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To 1-cyclopropyl-6-fluoro-7-bromo-5-methyl-1,4- dihydro-4-oxoquinoline-3-carboxylic acid (0.2 g) is added thionyl chloride (2 ml) and the mixture is refluxed for 1 hour. After cooling, the reaction mixture is poured into ice-water and made alkaline with 10% aqueous sodium hydroxide solution. After stirring for 30 minutes, the resultant is extracted with dichloromethane. The aqueous layer is made acidic with 10% hydrochloric acid and then extracted with dichloroethane. The solvent is concentrated and the residue is recrystallized from acetic acid to give 1-cyclopropyl-6-fluoro-7-chloro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (80 mg), as white crystals, m.p. 258°-260° C.
Reaction SMILES: [OH-:1].[Na+].[CH2:3]([O:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15]Cl)=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>[N+](CCCC)(CCCC)(CCCC)CCCC.[I-].C1C=CC=CC=1.O>[CH2:3]([O:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][C:4]([CH3:9])([CH3:5])[CH:3]=[O:1])=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: ClCc1ccc(OCc2ccccc2)cc1
Reactant: [OH-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: CC(C)(C=O)Cc1ccc(OCc2ccccc2)cc1
Temperature: 70 °C
Reaction time: 3 h
Yield: 99.1 %

Procedure:
A mixture of NaOH (0.7 g), and (Bu)4NI (0.15 g) in benzene (2.0 mL) and water (0.7 mL) was heated at 70° C. under argon to obtain a homogeneous mixture. To this mixture was added dropwise a mixture of isobutylaldehyde (1.44 g, Aldrich), and 4-benzyloxybenzyl chloride (3.5 g, Aldrich) in benzene (5.0 mL). After the addition, the resulting mixture was stirred at 70° C. for 3 h under argon. It was cooled, diluted with water, and extracted with EtOAc (3×25 mL). The combined organic extracts were washed with water, dried (anhydrous Na2SO4) and concentrated to dryness. This residue was purified by silica gel flash chromatography using 5% EtOAC in hexane. The appropriate fractions (monitored by TLC and ES mass spectrometry) were combined and concentrated to dryness to give the desired product (2.0 g, ˜50%) as a white powder: Rf=0.28 (10% EtOAc/Hexane), 1H -NMR (CDCl3) δ9.56 (s, 1H), 7.4 (m, 5H), 6.99 (d, 2H), 6.83 (d, 2H), 5.02 (s, 2H), 2.71 (s, 2H), 1.02 (6H); ES-MS m/z 286 (M+18); HRMS calcd C18H20O20NH4 (M+NH4) 286.2100, found 286.1833.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[N:16][C:17]([N+:20]([O-:22])=[O:21])=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:23][C:24]([F:29])([F:28])[C:25]([OH:27])=[O:26]>ClCCl>[N+:20]([C:17]1[N:16]=[CH:15][C:14]([N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[CH:19][CH:18]=1)([O-:22])=[O:21].[C:25]([OH:27])([C:24]([F:29])([F:28])[F:23])=[O:26]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])nc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=[N+]([O-])c1ccc(N2CCNCC2)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 4-(6-nitropyridin-3-yl)piperazine-1-carboxylic acid tert-butyl ester obtaine above (0.821 g, 0.27 mmol) in 10 mL of a 1:4 mixture of trifluoroacetic acid and dichloromethane was stirred at room temperature for 2 h. The mixture was concentrated in vacuo to yield 1-(6-nitropyridin-3-yl)piperazine as a brown oil (0.086 g, TFA salt, 100% yield). MS (ES+) m/z 209.4 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][NH:4][C:3]=1[CH:7]=O.[CH3:9][C:10]1[C:15]([CH3:16])=[CH:14][C:13]([NH2:17])=[C:12]([NH2:18])[CH:11]=1.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>C(O)C>[Br:1][C:2]1[CH:6]=[N:5][NH:4][C:3]=1[C:7]1[NH:18][C:12]2[CH:11]=[C:10]([CH3:9])[C:15]([CH3:16])=[CH:14][C:13]=2[N:17]=1
Reactant: Cc1cc(N)c(N)cc1C
Reactant: O=Cc1[nH]ncc1Br
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1cc2nc(-c3[nH]ncc3Br)[nH]c2cc1C

Procedure:
Starting with 100 mg of commercial 4-bromo-2H-pyrazole-3-carboxaldehyde, 77.8 mg of 4,5-dimethyl-1,2-phenylenediamine, and 108.6 mg of sodium metabisulphite, in 1 ml of ethanol and 2 ml of dimethylformamide, and after purification by SPE (SCX phase, washing with methanol, extraction with 2N ammoniacal methanol) followed by a chromatography under pressure on silica, 143.2 mg of 2-(4-bromo-2H-pyrazol-3-yl)-5,6-dimethyl-1H-benzimidazole are obtained in the form of a yellow foam.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=N)N.[CH:13]1(C(Cl)=O)[CH2:18][CH2:17]C[CH2:15][CH2:14]1>P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+]>[NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[C:17]2[C:7](=[CH:15][CH:14]=[CH:13][CH:18]=2)[NH:6][CH:5]=1
Reactant: O=C(Cl)C1CCCCC1
Reactant: N=C(N)NCCC[C@H](N)C(=O)O
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Product: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O

Procedure:
A stock solution of 9.1 mg/mL α-interferon in 20 mM sodium phosphate buffer at pH 7.2 was prepared. A stock solution of perturbant was prepared by dissolving 800 mg of perturbant (L-arginine acylated with cyclohexanoyl chloride) in 2 mL of 20 mM Sodium Phosphate buffer (pH7).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[N:6][C:5]=1[CH3:20].[Br:22]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:17])([F:18])[F:19])=[CH:12][CH:11]=2)=[N:6][C:5]=1[CH2:20][Br:22]
Reactant: COC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)nc1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)nc1CBr
Temperature: 95 °C
Reaction time: 5 h
Yield: 55.7 %

Procedure:
1.97 g (6.67 mmol) of 2-methyl-6-(4-trifluoromethyl-phenyl)-nicotinic acid methyl ester (example 1L]) was dissolved in 20 ml of CCl4 and treated with 1.781 g (10.0 mmol) of N-bromosuccinimide and 0.126 g (0.669 mmol) of dibenzoyl peroxide. The mixture was refluxed (oilbath temperature 95° C.) and the course of the bromination followed by GC. After 5 h, the reaction mixture was poured onto crashed ice, extracted twice with AcOEt, washed with water and brine, and dried over magnesium sulfate. Evaporation of the solvents i. V., followed by careful flash chromatography (SiO2, hexane/AcOEt=92/8), afforded 1.39 g of the title compound as white crystals, contaminated with roughly 5% of the dibromo-analogue.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:28])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[N:9]2[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)=[CH:4][CH:3]=1.[OH:29][CH2:30][C:31]([CH3:35])([CH2:33]O)[CH3:32]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([O:28][CH2:32][C:31]([CH3:35])([CH3:33])[CH2:30][OH:29])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[N:9]2[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(CO)CO
Reactant: O=C1c2ccccc2C(O)(c2ccc(Cl)cc2)N1Cc1ccc([N+](=O)[O-])cc1
Product: CC(C)(CO)COC1(c2ccc(Cl)cc2)c2ccccc2C(=O)N1Cc1ccc([N+](=O)[O-])cc1
Yield: 55 %

Procedure:
The named compound was synthesised from 3-(4-Chlorophenyl)-3-hydroxy-2-(4-nitrobenzyl)-2,3-dihydroisoindol-1-one (400 mg, 1.01 mmol, 1 equiv.) and neopentyl glycol (526 mg, 5.05 mmol, 5 equiv.) using General Procedure A and obtained as an off-white solid (267 mg, 55%). 1H NMR (300 MHz, CDCl3): 8.02-7.98 (m, 2H, O2N—C—CH), 7.96-7.93 (m, 1H, C(O)═C═CH), 7.58-7.55 (m, 2H, Ar—H), 7.32-7.28 (m, 2H, Ar—H), 7.15-7.12 (m, 5H, Ar—H), 4.58 and 4.44 (dd: AB, J=15.3 Hz, 2H, N—CH2), 3.39 (s, 2H, HO—CH2), 2.78 and 2.63 (dd: AB, J=8.7 Hz, 2H, N—CH2), 0.83 (d, J=3.9 Hz, CH3). 13C NMR (75 MHz, CDCl3): 168.30, 147.33, 145.19, 144.60, 137.31, 134.90, 133.08, 131.64, 130.17, 129.85, 128.61, 127.95, 123.81, 123.23, 123.16, 94.54, 69.57, 69.02, 42.42, 36.41, 21.75. m/z (ES): 481 [M+H]+. Anal.: calc. for C26H25ClN2O5+0.25 H2O: C, 64.32; H, 5.31; N, 5.77. Found: C, 64.32; H, 5.34; N, 5.57.
Reaction SMILES: [N:1]1[C:6]([C:7]([O:9]C)=O)=[CH:5][CH:4]=[CH:3][C:2]=1[C:11]([O:13][CH3:14])=O.[N:15]1C=C(C(OC)=O)C=C(C(OC)=O)[CH:16]=1>>[O:13]1[C:11]([C:2]2[N:1]=[C:6]([CH2:7][OH:9])[CH:5]=[CH:4][CH:3]=2)=[CH:16][N:15]=[CH:14]1
Reactant: COC(=O)c1cncc(C(=O)OC)c1
Reactant: COC(=O)c1cccc(C(=O)OC)n1
Product: OCc1cccc(-c2cnco2)n1

Procedure:
When the same reaction as in Referential Example 39 is carried out using dimethyl pyridine-2,6-dicarboxylate instead of the starting dimethyl pyridine-3,5-dicarboxylate, 6-(5-oxazolyl)-2-pyridinemethanol is obtained.
Reaction SMILES: [OH:1][C@H:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[N+:29]([C:32]1[CH:33]=[C:34](O)[CH:35]=[CH:36][CH:37]=1)([O-:31])=[O:30].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.N>C1COCC1.C(Cl)(Cl)Cl>[CH3:20][CH:19]([CH3:21])[C:18]([NH:17][C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([CH:8]2[CH2:9][CH2:10][N:5]([CH2:4][CH2:3][C@@H:2]([O:1][C:36]3[CH:35]=[CH:34][CH:33]=[C:32]([N+:29]([O-:31])=[O:30])[CH:37]=3)[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:6][CH2:7]2)[CH:12]=1)=[O:22]
Reactant: O=[N+]([O-])c1cccc(O)c1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](O)c3ccccc3)CC2)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@@H](Oc3cccc([N+](=O)[O-])c3)c3ccccc3)CC2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 40.7 %

Procedure:
A mixture of N-(3-{1-[(3S)-3-hydroxy-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide (5.20 mg, 0.0137 mmol), 3-nitrophenol (100 mg), triphenylphosphine (30.0 mg, 0.115 mmol) and diethyl azodicarboxylate (7.42 mg, 0.0426 mmol) in THF (0.50 mL) was stirred at room temperature for 3 days. Chromatography using silica preparative TLC plates [2.5% of NH3 (2.0 M in methanol) in CHCl3] gave the desired product (2.80 mg, 40.8% yield) as a thick oil: 1H NMR (400 MHz, CDCl3) δ 7.76 (dm, 1H), 7.71 (t, 1H, J=1.8 Hz), 7.50–7.40 (m, 2H), 7.40–7.25 (m, 7H), 7.17 (apparent dd, 1H, J=2.4, 8.2), 6.97 (apparent d, 1H, J=7.7 Hz), 5.45 (apparent dd, 1H, J=5.0, 8.1 Hz), 3.45 (m, 2H), 2.89 (m, 2H), 2.53 (apparent sept, partially hidden, 2H, J=8.3 Hz), 2.30–2.10 (m, 6H), 1.92 (m, 2H), 1.25 (d, 6H, J=6.8 Hz); ESMS m/e: 502.3 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1([CH2:15][OH:16])[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[O:17]1[C:22]2[CH:23]=[CH:24][C:25]([CH:27]=O)=[CH:26][C:21]=2[O:20][CH2:19][CH2:18]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.C(O)(=O)C.ClCCl>[O:17]1[C:22]2[CH:23]=[CH:24][C:25]([CH2:27][NH:1][C:2]3([CH2:15][OH:16])[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:4][CH2:3]3)=[CH:26][C:21]=2[O:20][CH2:19][CH2:18]1
Reactant: O=Cc1ccc2c(c1)OCCO2
Reactant: CC(C)(C)OC(=O)N1CCC(N)(CO)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCC(CO)(NCc2ccc3c(c2)OCCO3)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 10 mL of a dichloromethane solution containing 0.39 g of tert-butyl 4-amino-4-(hydroxymethyl)piperidine-1-carboxylate, 0.25 g of 2,3-dihydro-1,4-benzodioxin-6-carbaldehyde and 86 μL of acetic acid were added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was added with 0.48 g of sodium triacetoxyborohydride, and stirred at the same temperature for 2 hours. Thereto were added chloroform and an aqueous saturated sodium hydrogen carbonate solution. The organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, and the resultant solution was washed sequentially with water and an aqueous saturated sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by flash silica gel column chromatography [chloroform:gradient elution of methanol=100:0 to 80:20] to obtain 91 mg of a colorless oily substance, tert-butyl 4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)-4-(hydroxymethyl)piperidine-1-carboxylate.