Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1(C2C=CC(C[C:11]3[C:12]([O:24][CH3:25])=[N:13][C:14]4[C:19]([C:20]=3[Cl:21])=[CH:18][C:17]([Br:22])=[CH:16][C:15]=4C)=CC=2)C=CC=N1.[S:28]1[C:32]([CH2:33]C2C(Cl)=NC3C(C=2Cl)=CC(Br)=CC=3)=[CH:31][C:30]2[CH:47]=[CH:48][CH:49]=[CH:50][C:29]1=2.N1(C2C=CC(CC3C(OC)=NC4C(C=3Cl)=CC(Br)=CC=4)=CC=2)C=CC=N1>>[S:28]1[C:32]([CH2:33][C:11]2[C:12]([O:24][CH3:25])=[N:13][C:14]3[C:19]([C:20]=2[Cl:21])=[CH:18][C:17]([Br:22])=[CH:16][CH:15]=3)=[CH:31][C:30]2[CH:47]=[CH:48][CH:49]=[CH:50][C:29]1=2
Reactant: Clc1nc2ccc(Br)cc2c(Cl)c1Cc1cc2ccccc2s1
Reactant: COc1nc2c(C)cc(Br)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Agent: COc1nc2ccc(Br)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Product: COc1nc2ccc(Br)cc2c(Cl)c1Cc1cc2ccccc2s1

Procedure:
The title compound was prepared by substituting 3-(4-(1H-pyrazol-1-yl)benzyl)-6-bromo-2,4-dichloroquinoline (Intermediate 6: step c) with 3-(benzo[b]thiophen-2-ylmethyl)-6-bromo-2,4-dichloroquinoline (Intermediate 10: step c) then following the procedure described for the preparation of 3-(4-(1H-pyrazol-1-yl)benzyl)-6-bromo-4-chloro-2-methoxyquinoline (Intermediate 16).
Reaction SMILES: [CH2:1]1[CH2:5][O:4][CH2:3][CH2:2]1.[CH3:6][O:7][CH2:8][C:9]1C=[C:11]([CH:14]=[C:15]([CH2:17]OC)[CH:16]=1)C=O.CC(C)([O-])C.[K+]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[CH3:6][O:7][CH2:8][C:9]1[CH:16]=[C:15]([CH:17]=[C:1]([CH2:5][O:4][CH3:3])[CH:2]=1)[CH:14]=[CH2:11]
Reactant: C1CCOC1
Reactant: COCc1cc(C=O)cc(COC)c1
Agent: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: O
Product: C=Cc1cc(COC)cc(COC)c1
Yield: 67 %

Procedure:
Then 30 ml of THF solution containing 8.36 g (43.0 mmol) 3,5-bis(methoxymethyl)benzaldehyde was added dropwise into 40 ml of THF solution containing 18.5 g (51.7 mmol) of methyltriphenylphosphonium bromide and 7.24 g (64.5 mmol) of potassium tertiary butoxide at 0° C. After agitating the reaction liquid for 3 hours at 0° C., 30 ml of water was added to deactivate the remaining potassium tertiary butoxide. The organic layer was aliquoted and the aqueous layer was extracted 3 times with 50 ml of ether and the organic layer was collected and dried with anhydrous magnesium sulfate. Excess methyltriphenylphosphonium bromide and triphenylphosphine oxide were precipitated by adding 80 ml of n-hexane to the residues obtained by the removal of solvent. After removing insolubles by filtration, the concentrated filtrate was purified by silica gel column chromatography to obtain 5.52 g (28.7 mmol) of the target 3,5-bis(methoxymethyl)styrene as a colorless oily matter.
Reaction SMILES: Br.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2(O)[N:16]3[C:12](=[N:13][C:14]4[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=43)[S:11][CH:10]2[CH2:21][C:22]([OH:24])=[O:23])=[CH:5][CH:4]=1.CS(O)(=O)=O.C(OCC)(=O)C.C(O)(=O)C>O>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:16]3[C:12](=[N:13][C:14]4[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=43)[S:11][C:10]=2[CH2:21][C:22]([OH:24])=[O:23])=[CH:5][CH:4]=1
Reactant: O=C(O)CC1Sc2nc3ccccc3n2C1(O)c1ccc(Cl)cc1
Agent: Br
Agent: CS(=O)(=O)O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(O)Cc1sc2nc3ccccc3n2c1-c1ccc(Cl)cc1
Reaction time: 8 h
Yield: 96.6 %

Procedure:
A mixture of 100 g of 3-(p-Chlorophenyl)-2,3,-dihydro-3-hydroxythiazolo[3,2-a]benzimidazol-2-acetic acid, hydrobromide and 200 ml of methanesulphonic acid was stirred overnight in a 500 ml round bottom flask. Thin layer chromatography on silica plates (solvent ethyl acetate/acetic acid) indicated rapid formation of an intermediate. After 20 hours at room temperature thin layer chromatography (silica plates, ethyl acetate/acetic acid) showed the presence of a single component. The mixture was poured into water and the resulting crystals removed by filtration. The crystalline product was suspended in 5 volumes of hot water for 1/2 hour, filtered and the procedure repeated. After a final aqueous wash the material was dried in vacuo to yield the title compound (75 g, 91%) m.p. 242°-3° C.
Reaction SMILES: [C:1]([NH:9][C:10]1[N:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][N:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Pt].C(O)C>[C:1]([NH:9][C:10]1[N:11]=[CH:12][C:13]([NH2:16])=[CH:14][N:15]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Nc1ncc([N+](=O)[O-])cn1)c1ccccc1
Agent: [Pt]
Solvent: CCO
Product: Nc1cnc(NC(=O)c2ccccc2)nc1
Reaction time: 1 h
Yield: 14.2 %

Procedure:
10% Platinum on carbon (71 mg, 0.036 mmol) was added to a solution 2-(N-benzoyl)amino-5-nitropyrimidine (733 mg, 3.00 mmol) in ethanol (100 ml) at ambient temperature and the reaction stirred for 1 hour under an atmosphere of hydrogen. The reaction was filtered through a pad of celite and the solvents were evaporated in vacuo. Purification by flash chromatography on silica gel, eluting with 5% methanol in dichloromethane yielded 2-(N-benzoyl)amino-5-aminopyrimidine (91 mg, 14% yield) as white solid:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:23])[C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)=[CH:12][CH:11]=2)[CH:5]=[CH:6][CH:7]=1.[Cl:24][C:25]1[C:26]([F:38])=[C:27]([C:31]2[CH:36]=[CH:35][N:34]=[C:33]([NH2:37])[N:32]=2)[CH:28]=[CH:29][CH:30]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1(C)C=CC=CC=1.CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:24][C:25]1[C:26]([F:38])=[C:27]([C:31]2[CH:36]=[CH:35][N:34]=[C:33]([NH:37][C:2]3[CH:3]=[C:4]([NH:8][C:9](=[O:23])[C:10]4[CH:15]=[CH:14][C:13]([CH2:16][N:17]5[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]5)=[CH:12][CH:11]=4)[CH:5]=[CH:6][CH:7]=3)[N:32]=2)[CH:28]=[CH:29][CH:30]=1
Reactant: Nc1nccc(-c2cccc(Cl)c2F)n1
Reactant: O=C(Nc1cccc(Br)c1)c1ccc(CN2CCCCC2)cc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=C(Nc1cccc(Nc2nccc(-c3cccc(Cl)c3F)n2)c1)c1ccc(CN2CCCCC2)cc1
Temperature: 150 °C

Procedure:
A mixture of N-(3-bromophenyl)-4-(piperidin-1-ylmethyl)benzamide (20 mg, 0.054 mmol) and 4-(3-chloro-2-fluorophenyl)pyrimidin-2-amine (18 mg, 0.080 mmol), KOBut (12 mg, 0.11 mmol), Pd2(dba)3 (2.5 mg, 0.027 mmol) and Xantphos (2.5 mg, 0.043 mmol) in a microwave reaction vessel was suspended in 0.6 mL of toluene. The reaction mixture was heated in a microwave at 150° C. for 1 h. After cooling, the mixture was diluted with DMF, and then filtered with a 0.45 μm microfilter. The obtained filtrate was separated by a semi-preparative HPLC. Collected product fraction was lyophilized to give pure product as a while powder. MS (ESI+) m/z 516.2 [M+H]+.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6](=[O:36])[C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[C:9]([C:14]3[C:23]4[CH2:22][NH:21][C:20](=[O:24])[N:19]([C:25]5[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=5[F:32])[C:18]=4[N:17]=[C:16](S(C)=O)[N:15]=3)[CH:8]=2)[CH2:3][CH2:2]1.[CH3:37][NH:38][CH2:39][CH2:40][NH2:41]>C1COCC1>[NH2:41][CH2:40][CH2:39][N:38]([CH3:37])[C:16]1[N:15]=[C:14]([C:9]2[CH:8]=[C:7]([CH:12]=[CH:11][C:10]=2[CH3:13])[C:6]([NH:5][CH2:4][CH:1]2[CH2:3][CH2:2]2)=[O:36])[C:23]2[CH2:22][NH:21][C:20](=[O:24])[N:19]([C:25]3[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=3[F:32])[C:18]=2[N:17]=1
Reactant: CNCCN
Reactant: Cc1ccc(C(=O)NCC2CC2)cc1-c1nc(S(C)=O)nc2c1CNC(=O)N2c1c(F)cccc1F
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)NCC2CC2)cc1-c1nc(N(C)CCN)nc2c1CNC(=O)N2c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the solution of N-(Cyclopropylmethyl)-3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methylbenzamide (90 mg) in THF (10 mL) was added N-methyl ethylene diamine (70 uL) at r.t. The reaction mixture was stirred at r.t. overnight. The solution was then evaporated in vacuo and the residue was purified by column chromatography to provide the title compound as a white solid (in addition to compound 4c). LC-MS m/z 522 (M+H)+, 1.47 min (ret. time).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14]C(=O)C)[CH:2]=1.[OH-].[Na+]>Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH2:14])[CH:2]=1
Reactant: CC(=O)NCCCCCCCc1cccnc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: NCCCCCCCc1cccnc1
Yield: 81.2 %

Procedure:
A solution of 5.1 g of N-[7-(3-pyridyl)heptyl]acetamide was heated to reflux in diluted hydrochloric acid overnight. The mixture was cooled, made basic with 50% sodium hydroxide solution and was extracted with dichloromethane. The combined organic layers were dried over potassium carbonate and were evaporated. The residue was distilled to give 3.4 g of 3-pyridine heptanamine, bp 175°-180° C./0.4 mm.
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)=O.[CH3:12][C:13]1([CH3:26])[C@@H:15]2[CH2:16][C:17]3[C:21]([C@H:14]12)=[C:20]([CH3:22])[S:19][C:18]=3[C:23](=[O:25])[CH3:24].C[O-].[Na+]>CO.C(OCC)C>[O:25]=[C:23]([C:18]1[S:19][C:20]([CH3:22])=[C:21]2[C:17]=1[CH2:16][C@H:15]1[C:13]([CH3:26])([CH3:12])[C@H:14]12)[CH:24]=[CH:1][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: CC(=O)c1sc(C)c2c1C[C@@H]1[C@H]2C1(C)C
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Product: Cc1sc(C(=O)C=Cc2ccc(C(=O)O)cc2)c2c1[C@H]1[C@@H](C2)C1(C)C
Reaction time: 2 h
Yield: 57.3 %

Procedure:
A solution of 4-formyl-benzoic acid (1.04 g mg, 6.93 mmol), (1aS,5aR)-1-(1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-ethanone (850 mg, 3.86 mmol), NaOMe (4.17 g, 77.2 mmol) in methanol (30 mL) is stirred at 65° C. for 2 h. Another portion of 4-formyl-benzoic acid (400 mg, 2.66 mmol) is added and stirring is continued at 65° C. for 2 h. The reaction mixture is diluted with diethyl ether (200 mL) and washed with 5% aq. citric acid solution followed by water. The organic phase is dried over MgSO4 and evaporated. The crude product is purified by CC on silica gel eluting with DCM containing 2-7% methanol, followed by crystallisation from methanol:water 1:1 to give 4-[3-oxo-3-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-propenyl]-benzoic acid (780 mg) as beige yellow powder; LC-MS: tR=1.06 min, [M+1]+=353.03; 1H NMR (CDCl3): δ 8.13 (d, J=8.2 Hz, 2H), 7.76 (d, J=15.2 Hz, 1H), 7.68 (d, J=8.2 Hz, 2H), 7.29 8d, J=15.8 Hz, 1H), 3.14 (dd, J=5.9, 18.8 Hz, 1H), 2.96 (d, J=18.8 Hz, 1H), 2.44 (s, 3H), 2.00-1.91 (m, 2H), 1.15 (s, 3H), 0.75 (s, 3H).
Reaction SMILES: [OH:1][CH2:2][CH:3]([C:15]1[CH:16]=[C:17]([C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=2)[CH:18]=[CH:19][CH:20]=1)[CH:4]([C:6]1[CH:14]=[CH:13][C:9]([C:10]([O-:12])=[O:11])=[CH:8][CH:7]=1)[CH3:5].[CH3:32]C(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O>C(Cl)Cl>[CH3:5][CH:4]([C:6]1[CH:7]=[CH:8][C:9]([C:10]([O:12][CH3:32])=[O:11])=[CH:13][CH:14]=1)[CH:3]([C:15]1[CH:16]=[C:17]([C:21]2[CH:22]=[CH:23][C:24]([O:27][C:28]([F:29])([F:30])[F:31])=[CH:25][CH:26]=2)[CH:18]=[CH:19][CH:20]=1)[CH:2]=[O:1]
Reactant: CC(c1ccc(C(=O)[O-])cc1)C(CO)c1cccc(-c2ccc(OC(F)(F)F)cc2)c1
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: COC(=O)c1ccc(C(C)C(C=O)c2cccc(-c3ccc(OC(F)(F)F)cc3)c2)cc1
Reaction time: 1 h

Procedure:
The intermediate from Step D was subjected to the Suzuki conditions described in EXAMPLE 1 Step A to give methyl 4-{3-hydroxy-1-methyl-2-[4′-(trifluoromethoxy)biphenyl-3-yl]propyl}benzoate as a mixture of diastereomers. LCMS1 3.92 min. (M−H2O)=427. LCMS1 4.08 min. (M−H2O)=427. A DCM (2 mL) solution containing 4-{3-hydroxy-1-methyl-2-[4′-(trifluoromethoxy)biphenyl-3-yl]propyl}benzoate (50 mg, 0.1 μmol) was treated with [1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one] (64 mg, 0.15 mmol). After stirring for 1 hour the solution was concentrated and the residue purified by silica gel chromatography using a hexanes/ethyl acetate gradient to give the title compounds as a mixture of diastereomers. 1H NMR (400 MHz, CDCl3): selected data δ 9.84 (d, J=2.3 Hz); 9.64 (d, J=2.3 Hz); 1.44 (d, J=6.7 Hz); 1.14 (d, J=7.0 Hz). LCMS1 4.11 min. (M+H)=443. LCMS1 4.24 min. (M+H)=443.
Reaction SMILES: C([O:8][NH:9][C:10]([C@H:12]1[C@H:15]([CH2:16][CH3:17])[CH2:14][N:13]1[C:18](=[O:32])[C:19]1[CH:24]=[C:23]([CH2:25][CH2:26][CH3:27])[C:22]([O:28][CH3:29])=[C:21]([O:30][CH3:31])[CH:20]=1)=[O:11])C1C=CC=CC=1.[H][H]>>[OH:8][NH:9][C:10]([C@H:12]1[C@H:15]([CH2:16][CH3:17])[CH2:14][N:13]1[C:18](=[O:32])[C:19]1[CH:24]=[C:23]([CH2:25][CH2:26][CH3:27])[C:22]([O:28][CH3:29])=[C:21]([O:30][CH3:31])[CH:20]=1)=[O:11]
Reactant: [H][H]
Reactant: CCCc1cc(C(=O)N2C[C@@H](CC)[C@@H]2C(=O)NOCc2ccccc2)cc(OC)c1OC
Product: CCCc1cc(C(=O)N2C[C@@H](CC)[C@@H]2C(=O)NO)cc(OC)c1OC
Yield: 90 %

Procedure:
(+)-trans-1-(3,4-Dimethoxy-5-propylbenzoyl)-3-ethylazetidine-2-carboxylic acid hydroxyamide was prepared from (+)-trans-1-(3,4-dimethoxy-5-propylbenzoyl)-3-ethylazetidine-2-carboxylic acid benzyloxyamide by following Method H in 90% yield. The reaction was conducted at room temperature using a balloon of hydrogen for 1 h. ESMS: 351.6 [M+H]. 1H NMR (300 MHz, CD3OD): 6.93 (s, 1H), 6.90 (s, 1H), 4.80 (m, 1H), 4.48 (m, 1H), 4.32 (m, 1H), 3.75 (s, 3H), 3.71 (s, 3H), 2.62 (m, 1H), 2.49 (t, 2H), 1.85 (m, 1H), 1.72 (m, 1H), 1.50 (m, 2H), 0.84 (t, 6H)
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]([F:17])([F:16])[C:9]([F:15])([F:14])[C:10]([F:13])([F:12])[F:11])=[N:4][NH:5][C:6]=1[CH3:7].C([O-])([O-])=O.[K+].[K+].Cl[CH2:25][C:26]([N:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=2)[CH2:30][CH2:29]1)=[O:27].CN(C=O)C>CCCCCC.C(OCC)(=O)C>[NH2:1][C:2]1[C:3]([C:8]([F:17])([F:16])[C:9]([F:14])([F:15])[C:10]([F:11])([F:12])[F:13])=[N:4][N:5]([CH2:25][C:26]([N:28]2[CH2:29][CH2:30][N:31]([C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=3)[CH2:32][CH2:33]2)=[O:27])[C:6]=1[CH3:7]
Reactant: O=C(CCl)N1CCN(c2ccc(F)cc2)CC1
Reactant: Cc1[nH]nc(C(F)(F)C(F)(F)C(F)(F)F)c1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: Cc1c(N)c(C(F)(F)C(F)(F)C(F)(F)F)nn1CC(=O)N1CCN(c2ccc(F)cc2)CC1

Procedure:
Protocol T was followed using 4-Amino-3-heptafluoropropyl-5-methyl-1H-pyrazole, K2CO3, 2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate=1/4) afforded the title compound as colorless oil. 1H NMR (400 MHz, CDCl3): 6.92–7.02 (m, 4H), 5.14 (s, 2H), 3.64–3.82 (m, 4H), 3.6 (s, 2H), 3.1–3.22 (m, 4H), 2.16 (s, 3H). 13C NMR (400 MHz, CD6CO): 160.4, 158, 146, 144.2, 119.8, 118.2, 52, 50.8, 50.6, 46, 42, 12.2.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[N:4]([CH2:8][C:9]([OH:11])=[O:10])[N:3]=1.[CH2:12](O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.CC#N>[CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[N:4]([CH2:8][C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[N:3]=1
Reactant: OCc1ccccc1
Reactant: Cc1cc(C)n(CC(=O)O)n1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CC#N
Product: Cc1cc(C)n(CC(=O)OCc2ccccc2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of (3,5-dimethyl-1H-pyrazol-1-yl)acetic acid (600 mg), benzyl alcohol (0.402 mL), DMAP (194 mg) and DCC (802 mg) in MeCN (40 mL) was stirred at RT overnight. The suspension was filtered off and the resulting solution was evaporated to dryness. The residue was purified by CC (Hept/EA 7/3) to afford benzyl 2-(3,5-dimethyl-1H-pyrazol-1-yl)acetate (460 mg, white solid). LC-MS (B): tR=0.80 min; [M+H]+: 245.18.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][C:7](=[CH2:24])[CH:8](O)[CH:9]([NH:20][CH:21]=[O:22])[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])(=[O:3])[CH3:2].C(Cl)Cl.S(Br)([Br:30])=O>O>[C:1]([O:4][CH2:5][CH2:6][C:7]([CH2:24][Br:30])=[CH:8][CH:9]([NH:20][CH:21]=[O:22])[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])(=[O:3])[CH3:2]
Reactant: O=S(Br)Br
Reactant: C=C(CCOC(C)=O)C(O)C(NC=O)C(=O)OCc1ccccc1
Solvent: O
Solvent: ClCCl
Product: CC(=O)OCCC(=CC(NC=O)C(=O)OCc1ccccc1)CBr
Reaction time: 2 h

Procedure:
10.5 g (31.3 mmol) of benzyl 6-acetoxy-2-formylamino-3-hydroxy-4-methylenehexanoate are dissolved in 100 ml of abs. CH2Cl2. Then 2.91 ml (37.6 mmol) of thionyl bromide are added to this solution at room temperature. After 2 hours, 80 ml of water are added and the mixture is stirred vigorously for 10 minutes. The organic phase is separated and washed once with water, once with a 1N solution of KHCO3 and twice with water. The aqueous phases are extracted twice with CH2Cl2. The combined organic phases are dried over MgSO4, filtered and concentrated by evaporation, giving benzyl 6-acetoxy-4-bromomethyl-2-formylamino-hex-3-enoate as a yellowish-brown oil which is further reacted without purification.
Reaction SMILES: [CH3:1][CH2:2][N:3]1[C:9]2[N:10]=[C:11]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[N:12]=[CH:13][C:8]=2[C:6](=[O:7])[C:5]([C:20]([OH:22])=[O:21])=[CH:4]1.[I:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[S:32])=[CH:26][CH:25]=1.C(N(CC)CC)C>>[I:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([N:17]2[CH2:18][CH2:19][N:14]([C:11]3[N:12]=[CH:13][C:8]4[C:6](=[O:7])[C:5]([C:20]([OH:22])=[O:21])=[CH:4][N:3]([CH2:2][CH3:1])[C:9]=4[N:10]=3)[CH2:15][CH2:16]2)=[S:32])=[CH:26][CH:25]=1
Reactant: S=C=Nc1ccc(I)cc1
Reactant: CCn1cc(C(=O)O)c(=O)c2cnc(N3CCNCC3)nc21
Solvent: CCN(CC)CC
Product: CCn1cc(C(=O)O)c(=O)c2cnc(N3CCN(C(=S)Nc4ccc(I)cc4)CC3)nc21

Procedure:
Pipemidic acid (25 mg, 0.0824 mmol), 4-iodophenyl isothiocyanate (21.5 mg, 0.0824 mmol) and triethylamine (23 μL, 0.165 mmol) were used. Purification on silica yielded compound 3 in Table 1, below (36 mg, 77%). 1H NMR (300 MHz, CDCl3) δ 9.32 (s, 1H), 8.66 (s, 1H), 7.66 (d, J=6.94 Hz, 1H), 7.37 (s, 1H), 7.27 (s, 1H), 7.00 (d, J=7.44 Hz, 1H), 4.33 (q, J=6.90 Hz, 2H), 4.21-3.99 (m, 8H), 1.49 (t, J=7.14 Hz, 3H) ppm.
Reaction SMILES: [CH:1]1([C:4]2[NH:5][C:6]3[C:11]([CH:12]=2)=[C:10]([C:13]([F:16])([F:15])[F:14])[C:9]([C:17]#[N:18])=[CH:8][CH:7]=3)[CH2:3][CH2:2]1.[F:19][C:20]([F:39])([F:38])[C:21]1[CH:22]=[C:23]([C:31]2[O:35][N:34]=[C:33]([CH2:36]Cl)[N:32]=2)[CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1>>[F:39][C:20]([F:19])([F:38])[C:21]1[CH:22]=[C:23]([C:31]2[O:35][N:34]=[C:33]([CH2:36][N:5]3[C:6]4[C:11](=[C:10]([C:13]([F:14])([F:15])[F:16])[C:9]([C:17]#[N:18])=[CH:8][CH:7]=4)[CH:12]=[C:4]3[CH:1]3[CH2:2][CH2:3]3)[N:32]=2)[CH:24]=[C:25]([C:27]([F:29])([F:28])[F:30])[CH:26]=1
Reactant: N#Cc1ccc2[nH]c(C3CC3)cc2c1C(F)(F)F
Reactant: FC(F)(F)c1cc(-c2nc(CCl)no2)cc(C(F)(F)F)c1
Product: N#Cc1ccc2c(cc(C3CC3)n2Cc2noc(-c3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)c1C(F)(F)F

Procedure:
Synthesized as described in Example 4 using 2-cyclopropyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile and 5-[3,5-bis(trifluoromethyl)phenyl]-3-(chloromethyl)-1,2,4-oxadiazole: 1H NMR (400 MHz, CDCl3) δ 8.50 (s, 2H), 8.09 (s, 1H), 7.67 (d, J=8.5 Hz, 1H), 7.56 (d, J=8.5 Hz, 1H), 6.50 (s, 1H), 5.68 (s, 2H), 2.14 (m, 1H), 1.16 (m, 2H), 0.93 (m, 2H); MS (ES) m/z 545 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[C@@H:10]([NH:14]CC2C=CC=CC=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)CCC.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[C@@H:10]([NH2:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C[C@H](NCc2ccccc2)[C@@H](O)C1
Agent: [Pd]
Solvent: CCCCO
Product: CC(C)(C)OC(=O)N1C[C@H](N)[C@@H](O)C1
Yield: 101.6 %

Procedure:
To a solution of (3S,4S)-3-benzylamino-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (0.054 mol, 16.0 g) in n-butanol (225 mL) add 10% Pd/C (5.0 g) and hydrogenate the mixture at 50 psi for 10 h. Filter the reaction mixture thorough a plug of diatomaceous earth and wash with ethanol. Evaporate the filtrate to obtain the title compound as a white solid (11.10 g, 99%). APCI MS m/z 203 [M+H]+; [α]23D +7.8° (c, 0.50, MeOH).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]([CH2:11][CH3:12])[CH3:10])[C:5]([N+:13]([O-:15])=[O:14])=[C:4]([CH3:16])[N:3]=1.[CH3:17][O-:18].[Na+]>CO>[CH3:17][O:18][C:2]1[N:7]=[C:6]([NH:8][CH:9]([CH2:11][CH3:12])[CH3:10])[C:5]([N+:13]([O-:15])=[O:14])=[C:4]([CH3:16])[N:3]=1
Reactant: C[O-]
Reactant: CCC(C)Nc1nc(Cl)nc(C)c1[N+](=O)[O-]
Agent: [Na+]
Solvent: CO
Product: CCC(C)Nc1nc(OC)nc(C)c1[N+](=O)[O-]
Reaction time: 8 h
Yield: 73.1 %

Procedure:
17.1 g of 2-chloro-4-sec. butylamino-5-nitro-6-methyl-pyrimidine (0.07 mole) are dissolved in 200 ml of methanol. To this solution is added a solution of 8.1 g of sodium methylate (0.15 mole) in 100 ml of methanol and the mixture is boiled overnight at 100° C bath temperature. After it has been cooled, the solution is evaporated and the resultant red substance is treated with ether and then filtered over Hyflo. The filter residue is washed 5 times with ether and the combined ethereal extracts are then evaporated to yield 12.3 g of 2-methoxy-4-sec. butylamino-5nitro-6-methylpyrimidine which boils at 110° C at 0.001 Torr (=73% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]2.N1C=CN=C1.[CH3:18][C:19]([Si:22](Cl)([CH3:24])[CH3:23])([CH3:21])[CH3:20]>C1COCC1.CCOCC>[O:12]([C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Br:1])[CH:3]=2)[CH:8]=1)[Si:22]([C:19]([CH3:21])([CH3:20])[CH3:18])([CH3:24])[CH3:23]
Reactant: Oc1ccc2cc(Br)ccc2c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)Oc1ccc2cc(Br)ccc2c1
Temperature: 25 °C
Reaction time: 40 h

Procedure:
To a solution of 6-bromo-2-napthol (1.12 g, 5 mmol) in anhydrous THF (15 mL) was added imidazole (0.476 g, 7 mmol) followed by TBSCl (1.05 g, 7 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 40 h and was diluted with ether, washed with brine and dried over anhydrous Mg2SO4. The solvent was removed to yield the crude product, which was recrystallized from methanol.
Reaction SMILES: C(OC(N1CC(O[CH:14]([F:16])[F:15])CC1C1NC(C2C=CC(Br)=CC=2)=CN=1)=O)(C)(C)C.C(OC(N1CC(O)CC1C1NC(C2C=CC(Br)=CC=2)=CN=1)=O)(C)(C)C.[C:54]([O:58][C:59]([N:61]1[CH2:65][CH:64]([OH:66])[CH2:63][CH:62]1[C:67]([O:69][CH2:70][C:71]([C:73]1[CH:78]=[CH:77][C:76]([Br:79])=[CH:75][CH:74]=1)=[O:72])=[O:68])=[O:60])([CH3:57])([CH3:56])[CH3:55]>>[C:54]([O:58][C:59]([N:61]1[CH2:65][CH:64]([O:66][CH:14]([F:16])[F:15])[CH2:63][CH:62]1[C:67]([O:69][CH2:70][C:71]([C:73]1[CH:78]=[CH:77][C:76]([Br:79])=[CH:75][CH:74]=1)=[O:72])=[O:68])=[O:60])([CH3:57])([CH3:55])[CH3:56]
Reactant: CC(C)(C)OC(=O)N1CC(O)CC1C(=O)OCC(=O)c1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)N1CC(OC(F)F)CC1c1ncc(-c2ccc(Br)cc2)[nH]1
Agent: CC(C)(C)OC(=O)N1CC(O)CC1c1ncc(-c2ccc(Br)cc2)[nH]1
Product: CC(C)(C)OC(=O)N1CC(OC(F)F)CC1C(=O)OCC(=O)c1ccc(Br)cc1

Procedure:
2-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl-4-difluoromethoxy-pyrrolidine-1-carboxylic acid tert-butyl ester: Title compound was prepared according to the method employed to prepare 2-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (Example 1), substituting 4-Difluoromethoxy-pyrrolidine-1,2-dicarboxylic acid 2-[2-(4-bromo-phenyl)-2-oxo-ethyl]ester 1-tert-butyl ester (305 mg) for 4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 2-[2-(4-bromo-phenyl)-2-oxo-ethyl]ester 1-tert-butyl ester (244 mg, 83%).