Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.[NH:16]([C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32])[C@H:17]([C:28]([OH:30])=O)[CH2:18][C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[NH:21][CH:20]=1.[NH:41]1[CH2:52][CH2:51][CH2:50][C@H:42]1[C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44].C1C=CC2N(O)N=NC=2C=1>CN(C)C=O>[NH:16]([C:31]([O:33][CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)=[O:32])[C@H:17]([C:28]([N:41]1[CH2:52][CH2:51][CH2:50][C@H:42]1[C:43]([O:45][C:46]([CH3:48])([CH3:49])[CH3:47])=[O:44])=[O:30])[CH2:18][C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[NH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1
Reactant: O=C(N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)[C@@H]1CCCN1C(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
10.92 g (53 mmoles) of DCC are added at 0° C. to a solution of 16.9 g (50 mmoles) of Z-Trp-OH, 8.55 g (50 mmoles) of H-Pro-OBut and 6.75 g (50 mmoles) of HOBt in 75 ml of dimethylformamide. The mixture is stirred for 2 hours at 0° C. and left to stand overnight at room temperature. The precipitate is filtered off and the filtrate is concentrated. The residue is worked up analogously to Example 1 a. The residue is triturated with ether. Yield 19.49 g (79%), melting point 173°, [α]D25 =-54.2° (c=1, dimethylformamide).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][C:14]([OH:16])=[O:15].[CH2:17]([O:24][C:25](=[O:38])[C@@H:26]([O:35][CH2:36][CH3:37])[CH2:27][C:28]1[CH:33]=[CH:32][C:31](O)=[CH:30][CH:29]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:17]([O:24][C:25](=[O:38])[C@@H:26]([O:35][CH2:36][CH3:37])[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:15][C:14](=[O:16])[CH2:13][C:3]2[N:4]=[C:5]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[O:6][C:2]=2[CH3:1])=[CH:30][CH:29]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: Cc1oc(-c2ccccc2)nc1CC(=O)O
Reactant: CCO[C@@H](Cc1ccc(O)cc1)C(=O)OCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCO[C@@H](Cc1ccc(OC(=O)Cc2nc(-c3ccccc3)oc2C)cc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (5-methyl-2-phenyl-oxazol-4-yl)-acetic acid (3.29 g, 15.2 mmol) and (S)-2-ethoxy-3-(4-hydroxy-phenyl)-propionic acid benzyl ester (4.56 g, 15 2 mmol) in dry DCM (70 mL) was added EDCxHCl (3.49 g, 18.22 mmol) and DMAP (0.37 g, 3.03 mmol) under nitrogen atmosphere. After stirring for 1 h at ambient temperature the mixture was extracted with saturated aq. NaHCO3, aq. HCl (0.05N) and with saturated aq. NaHCO3 again. The organic layer was dried and the remaining crude product purified by HPLC. The title compound was obtained as an oil (4.15 g, 54.7%). 1H NMR (400 MHz, CDCl3): δ 7.99-7.80 (d, 2H), 7.25-7.43 (m, 8H), 7.18-7.20 (d, 2H), 6.99-7.01 (d, 2H), 5.12 (s, 2H), 4.01-4.04 (m, 1H), 3.80 (s, 2H), 3.57-3.61 (m, 1H), 3.31-3.35 (m, 1H), 2.98-3.00 (m, 2H), 2.41 (s, 3H), 1.11-1.15 (t, 3H).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[CH:18]1([CH2:21][C@H:22]([NH2:29])[C:23]2[N:27]=[C:26]([CH3:28])[O:25][N:24]=2)[CH2:20][CH2:19]1>>[CH:18]1([CH2:21][C@H:22]([NH:29][C:15]([C:7]2[CH:6]=[CH:5][C:4]([CH:1]3[CH2:2][CH2:3]3)=[C:9]([O:10][CH2:11][CH:12]3[CH2:13][CH2:14]3)[N:8]=2)=[O:17])[C:23]2[N:27]=[C:26]([CH3:28])[O:25][N:24]=2)[CH2:20][CH2:19]1
Reactant: Cc1nc([C@@H](N)CC2CC2)no1
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Product: Cc1nc([C@H](CC2CC2)NC(=O)c2ccc(C3CC3)c(OCC3CC3)n2)no1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 42 a) and (S)-2-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethylamine (Example 38 e) as starting materials, MS (EI): m/e=383.2 [M+H]+.
Reaction SMILES: C(OC([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:17][NH:18][CH:19]1[C:28]2[N:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH2:22][CH2:21][CH2:20]1)=O)(C)(C)C.C(OC(=O)[NH:35][CH2:36][CH2:37][CH:38]=O)(C)(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O>C1COCC1>[NH:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:17][N:18]([CH:19]1[C:28]2[N:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH2:22][CH2:21][CH2:20]1)[CH2:38][CH2:37][CH2:36][NH2:35]
Reactant: CC(C)(C)OC(=O)NCCC=O
Reactant: CC(C)(C)OC(=O)n1c(CNC2CCCc3cccnc32)nc2ccccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: NCCCN(Cc1nc2ccccc2[nH]1)C1CCCc2cccnc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.2 %

Procedure:
To a stirred solution of 2-[(5,6,7,8-tetrahydro-quinolin-8-ylamino)-methyl]-benzoimidazole-1-carboxylic acid tert-butyl ester (390 mg, 0.98 mmol), (3-oxo-propyl)-carbamic acid tert-butyl ester (170 mg, 0.98 mmol) from above and THF (9.8 mL) was added NaBH(OAc)3 (623 mg, 2.94 mmol) and the resulting mixture was stirred at room temperature for 1 hour. AcOH (56 μL, 0.98 mmol) was added and the mixture stirred at room temperature overnight. The mixture was concentrated under reduced pressure, diluted with CH2Cl2 (40 mL) and washed with 1N NaOH (10 mL). The aqueous was extracted with (2×20 mL) and the combined organic extracts were dried (MgSO4), filtered and concentrated under reduced pressure. A solution of the resulting orange foam in CH2Cl2 (4 mL) and TFA (4 mL) was stirred at room temperature for 2.5 hours. The mixture was concentrated under reduced pressure, partially dissolved in H2O (2 mL), basified with 1N NaOH and extracted with CH2Cl2 (3×25 mL). The combined organic extracts were dried (MgSO4), filtered and concentrated under reduced pressure. Purification by column chromatography on silica gel (CH2Cl2/MeOH/NH4OH, 100:7:1) afforded N1-(1H-benzoimidazol-2-ylmethyl)-N1-(5,6,7,8-tetrahydro-quinolin-8-yl)-propane-1,3-diamine (290 mg, 75% over 3 steps) as a white foam.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].C([O-])([O-])=O.[K+].[K+].Cl.Cl[CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>C(#N)C>[N:20]1([CH2:19][CH2:18][O:1][C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=2)[CH:5]=[O:6])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1
Reactant: ClCCN1CCOCC1
Reactant: O=Cc1cccc(O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=Cc1cccc(OCCN2CCOCC2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 124.3 %

Procedure:
To a solution of 3-Hydroxybenzaldehyde (3.05 g, 24.97 mmol) in acetonitrile (15 ml) was added K2CO3 (7.6 g), followed by N-(2-chloroethyl)morpholine hydrochloride (4.65 g). The reaction mixture was stirred at room temperature for 30 minutes, then at reflux overnight. Additional N-(2-chloroethyl)morpholine hydrochloride (0.93 g) and K2CO3 (0.7 g) were added and the mixture was refluxed for an additional 6 hours. The reaction mixture was cooled to room temperature, filtered and the filtrate was concentrated in vacuo. The residue was partitioned between water and chloroform, the layers were separated and the aqueous layer was extracted with chloroform (2×75 ml). The organic layers were combined, washed with brine, dried over MgSO4, filtered and stripped to afford 7.3 g of 3-[2-(4-morpholinyl)ethoxy]benzaldehyde, as an amber liquid.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].F[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:31]=[C:30]3[C:25]([N:26]=[CH:27][C:28]([N:32]4[CH2:37][CH2:36][O:35][CH2:34][CH2:33]4)=[N:29]3)=[CH:24][CH:23]=2)=[CH:18][C:17]=1[N+:38]([O-:40])=[O:39]>CN(C=O)C.CCOC(C)=O>[CH2:1]([NH:8][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:31]=[C:30]3[C:25](=[CH:24][CH:23]=2)[N:26]=[CH:27][C:28]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[N:29]3)=[CH:18][C:17]=1[N+:38]([O-:40])=[O:39])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: O=[N+]([O-])c1cc(-c2ccc3ncc(N4CCOCC4)nc3c2)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cc(-c2ccc3ncc(N4CCOCC4)nc3c2)ccc1NCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 94.3 %

Procedure:
Benzylamine (336 mg, 3.1 mmol) and potassium carbonate (865 mg, 6.2 mmol) were added to a solution of 7-(4-fluoro-3-nitrophenyl)-2-(morpholin-4-yl)quinoxalin (1.1 g, 3.1 mmol) in DMF (100 mL). The mixture was stirred 24 h at room temperature and then diluted with EtOAc. The organic phase was washed with water and saturated aqueous sodium chloride solution, then dried over sodium sulphate. After filtration and subsequent removal of solvent, the residue was purified by chromatography (silica gel, Hexane/EtOAc: 20%->100% EtOAc) giving rise to 1.29 g (93%) of the desired product.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C@@H:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:15][OH:16])[CH:5]=[CH:4][C:3]1=2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[C:43]1[CH:52]=[CH:51][C:46]([C:47]([O:49][CH3:50])=[O:48])=[CH:45][CH:44]=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.CCOCC>[CH3:1][C:2]1([CH3:22])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C@@H:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:15][O:16][C:43]3[CH:52]=[CH:51][C:46]([C:47]([O:49][CH3:50])=[O:48])=[CH:45][CH:44]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: COC(=O)c1ccc(O)cc1
Reactant: CCCCC[C@@H](CO)c1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCCC[C@@H](COc1ccc(C(=O)OC)cc1)c1ccc2c(c1)C(C)(C)CCC2(C)C
Yield: 81.5 %

Procedure:
850 mg of (R)-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-heptanol dissolved in 50 ml THF were treated with 810 mg of triphenylphosphine, 470 mg of methyl 4-hydroxybenzoate and 0.49 ml of diethyl azodicarboxylate. The reaction mixture was heated to reflux for 6 hours. The mixture was diluted with 100 ml of ether and washed with two portions of 25 ml of water and one portion of 25 ml of sat. aq. sodium chloride solution. The organic phase was dried over MgSO4. The solvents were removed in vacuo and the resulting yellow oil was purified by flash chromatography (SiO2, 3% ethyl acetate/hexanes), giving 1 g of (R)-methyl 4-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-heptyloxy]-benzoate as a colorless oil, [α]D=−23.3 (c=0.307, in CHCl3).
Reaction SMILES: C([O:3][C:4]([CH2:6][N:7]1[CH:12]=[CH:11][CH:10]=[C:9]([OH:13])[C:8]1=[O:14])=[O:5])C.[CH2:15](Cl)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[OH-].[Na+]>CO.O>[CH2:15]([O:13][C:9]1[C:8](=[O:14])[N:7]([CH2:6][C:4]([OH:3])=[O:5])[CH:12]=[CH:11][CH:10]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: ClCc1ccccc1
Reactant: CCOC(=O)Cn1cccc(O)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)Cn1cccc(OCc2ccccc2)c1=O
Yield: 41 %

Procedure:
1-Ethoxycarbonylmethyl-3-hydroxypyrid-2-one (10 g) is dissolved in methanol/water (9:1 v/v) (400 ml). To this solution is added benzyl chloride (3 molar excess) and NaOH until the pH is above 12. The mixture is then refluxed for six hours to give a clear orange solution. The methanol is removed by rotary evaporation and the aqueous solution is extracted with dichloromethane to remove excess benzyl chloride. The aqueous phase is diluted slightly by adding extra water and then acidified to pH 2 using concentrated hydrochloric acid which results in the precipitation of a beige solid. The mixture is cooled and the precipitate filtered off and washed with diethyl ether. The crude product is recrystallised from ethanol to give 3-benzyloxy-1-carboxymethylpyrid2-one (5.4 g, 41%), m.p. 176°-177° C.
Reaction SMILES: [C:1]1([O:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]2[CH:26]=[CH:25][C:19]([C:20]([O:22]CC)=[O:21])=[CH:18][CH:17]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[OH-].[K+].C(O)C.Cl>O>[C:1]1([O:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]2[CH:17]=[CH:18][C:19]([C:20]([OH:22])=[O:21])=[CH:25][CH:26]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)c1ccc(NCCCOc2cccc3ccccc23)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1ccc(NCCCOc2cccc3ccccc23)cc1

Procedure:
A solution of 6 g. of ethyl 4-[3-(1-naphthyloxy)propylamino]benzoate and 3.4 g. of 85% KOH in 75 ml. 95% ethanol is heated at 80° C. for 4 hours, the reaction then diluted with 150 ml. of water and adjusted to pH 3 with 37% HCl. The resulting oily solid is extracted using several portions of warm ether. The extracts are combined, dried, and evaporated to a solid which is crystallized from acetonitrile to yield crystals, m.p. 146°-147° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][CH:9]=[C:10]([C:16]([O:18]CC)=O)[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:5]=[N:6][CH:7]=1.O(C1C=CC=CC=1)C1C=CC=CC=1>CC#N>[Br:1][C:2]1[CH:3]=[C:4]2[C:5]([C:16](=[O:18])[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][NH:8]2)=[N:6][CH:7]=1
Reactant: CCOC(=O)C(=CNc1cncc(Br)c1)C(=O)OCC
Solvent: CC#N
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1c[nH]c2cc(Br)cnc2c1=O
Temperature: 25 °C

Procedure:
In a RBF fitted with a reflux condenser a mixture of diethyl 2-((5-bromopyridin-3-ylamino)methylene)malonate (1 g, 3 mmol) and 1-phenoxybenzene (10 mL, 63 mmol) was heated to reflux for 1 h. The reaction mixture was allowed to cool to RT and CH3CN was added. The resulting solids were filtered and dried to provide the desired product as a light brown solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH3:7])=[CH:3][CH:2]=1.C([Li])CCC.CCCCCC.[F:19][C:20]1[CH:34]=[CH:33][C:23]([C:24]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)=[O:25])=[CH:22][CH:21]=1.[Cl-].[NH4+]>O1CCCC1>[F:19][C:20]1[CH:34]=[CH:33][C:23]([C:24]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)([OH:25])[CH2:7][C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)=[CH:22][CH:21]=1
Reactant: Cc1ccncc1
Reactant: O=C(c1ccc(F)cc1)c1ccc(F)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OC(Cc1ccncc1)(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 67.6 %

Procedure:
A solution of 27.8 g (0.30 mole) of 4-picoline in 400 ml of tetrahydrofuran and under an atmosphere of nitrogen was cooled to -30° C. in a dry-ice acetone bath. A solution of 2.5 moles n-butyllithium in hexane (119 ml, 0.3 mole) was added over 1 hr and the mixture was stirred for an additional 30 min at -30° C. The reaction mixture was allowed to warm to room temperature over 1.5 hr, and 66.7 g (0.30 mole) of 4,4'-difluorobenzophenone in 100 ml of tetrahydrofuran was added. The mixture was stirred for 2 hr and then was poured into an icy solution of ammonium chloride. A white solid was collected. The aqueous mixture was extracted with several portions of methylene chloride and the methylene chloride then removed in vacuo to give additional solid. The solid fractions were combined and recrystallized from a mixture of ether-hexane to give 63.14 g (68% yield) of title compound as a white, crystalline solid, mp 158°-159.5° C.
Reaction SMILES: [C:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12](Cl)[N:13]=2)[C:8](=[O:16])[C:7]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:6]1)([CH3:4])([CH3:3])[CH3:2].[C:22]([O:26][C:27]([NH:29][CH:30]1[CH2:34][CH2:33][NH:32][CH2:31]1)=[O:28])([CH3:25])([CH3:24])[CH3:23].C(=O)([O-])[O-].[K+].[K+]>ClCCl>[C:22]([O:26][C:27]([NH:29][CH:30]1[CH2:34][CH2:33][N:32]([C:12]2[N:13]=[C:14]3[C:9]([C:8](=[O:16])[C:7]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:6][N:5]3[C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:10][CH:11]=2)[CH2:31]1)=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Reactant: CCOC(=O)c1cn(C(C)(C)C)c2nc(Cl)ccc2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CCOC(=O)c1cn(C(C)(C)C)c2nc(N3CCC(NC(=O)OC(C)(C)C)C3)ccc2c1=O
Reaction time: 18 h

Procedure:
A solution of Example 73C (0.19 g), 3-(tert-butoxycarbonylamino)pyrrolidine (0.344 g), and potassium carbonate (0.255 g) in dichloromethane (6.2 mL) was refluxed for 4 hours then cooled, stirred for 18 hours, diluted with dichloromethane (50 mL), washed with 0.1M HCl, saturated sodium bicarbonate, and brine, and dried (MgSO4), filtered, and concentrated; and the concentrate was recrystallized from diethyl ether.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[Cl:8].C([Li])CCC.[CH2:14]([N:21]1[CH2:26][CH2:25][CH:24]([CH2:27][CH:28]=[O:29])[CH2:23][CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>O1CCCC1>[CH2:14]([N:21]1[CH2:26][CH2:25][CH:24]([CH2:27][CH:28]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[Cl:8])[OH:29])[CH2:23][CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=CCC1CCN(Cc2ccccc2)CC1
Reactant: Clc1ccccc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: OC(CC1CCN(Cc2ccccc2)CC1)c1ccccc1Cl
Temperature: -78 °C
Reaction time: 1 h

Procedure:
After dissolving 1.75 ml of 1-bromo-2-chlorobenzene in 30 ml of tetrahydrofuran, the solution was cooled to −78° C. Next, 5.31 ml of n-butyllithium (2.6 M, n-hexane solution) was added dropwise thereto while stirring and after 1 hour, a solution of 2.50 g of 1-benzylpiperidine-4-acetaldehyde in tetrahydrofuran (10 ml) was added and stirring was continued for 1 hour. After adding water to the reaction solution, the temperature was raised to room temperature and extraction was performed with ethyl acetate. The organic layer was washed with water and saturated brine in that order and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure to obtain 2-(1-benzylpiperidin-4-yl)-1-(2-chlorophenyl)ethanol.
Reaction SMILES: O.[OH-].[Li+].[CH3:4][C:5]([Si:8]([CH3:41])([CH3:40])[O:9][CH2:10][C@@H:11]([O:13][C:14]1[CH:15]=[C:16]([O:29][C:30]2[N:35]=[CH:34][C:33]([C:36]([O:38]C)=[O:37])=[CH:32][CH:31]=2)[CH:17]=[C:18]([C:20]([NH:22][C:23]2[CH:27]=[CH:26][N:25]([CH3:28])[N:24]=2)=[O:21])[CH:19]=1)[CH3:12])([CH3:7])[CH3:6]>O.C1COCC1>[CH3:4][C:5]([Si:8]([CH3:41])([CH3:40])[O:9][CH2:10][C@@H:11]([O:13][C:14]1[CH:15]=[C:16]([O:29][C:30]2[N:35]=[CH:34][C:33]([C:36]([OH:38])=[O:37])=[CH:32][CH:31]=2)[CH:17]=[C:18]([C:20]([NH:22][C:23]2[CH:27]=[CH:26][N:25]([CH3:28])[N:24]=2)=[O:21])[CH:19]=1)[CH3:12])([CH3:6])[CH3:7]
Reactant: COC(=O)c1ccc(Oc2cc(O[C@@H](C)CO[Si](C)(C)C(C)(C)C)cc(C(=O)Nc3ccn(C)n3)c2)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](CO[Si](C)(C)C(C)(C)C)Oc1cc(Oc2ccc(C(=O)O)cn2)cc(C(=O)Nc2ccn(C)n2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.5 %

Procedure:
A solution of lithium hydroxide monohydrate (0.10 g, 4.17 mmol) in water (15 mL) was added to a solution of methyl 6-[(3-[((1S)-2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-1-methylethyl)oxy]-5-{[(1-methyl-1H-pyrazol-3-yl)amino]carbonyl}phenyl)oxy]pyridine-3-carboxylate (0.90 g, 1.67 mmol) in THF (30 mL). The mixture was allowed to stir at RT overnight. The THF was removed in vacuo and the resulting solution was partitioned between water (50 mL) and ethyl acetate (75 mL), then the ethyl acetate layer separated, washed with brine and dried (MgSO4). The aqueous layer was then taken to pH 7 by addition of 1N hydrochloric acid (5.2 mL) and extracted with ethyl acetate (75 mL). The ethyl acetate layer was separated, washed with brine and dried (MgSO4). The ethyl acetate layers were combined and evaporated to give the required product (0.84 g).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([O-:3])=[O:2].CN1CCOCC1.[C:18](Cl)(=[O:22])[CH2:19][CH2:20][CH3:21]>C(Cl)Cl>[N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH:8][C:18](=[O:22])[CH2:19][CH2:20][CH3:21])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: Nc1ccc([N+](=O)[O-])cc1
Reactant: CCCC(=O)Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CCCC(=O)Nc1ccc([N+](=O)[O-])cc1
Reaction time: 0.5 h
Yield: 99.6 %

Procedure:
To a solution of 4-nitro aniline (1.01 g, 7.23 mmol) in anhydrous CH2Cl2 (20 mL) was added NMM (0.95 mL, 8.68 mmol). To the reaction mixture was added dropwise butyryl chloride (1.00 mL, 8.68 mmol) at 0° C. After stirring for 0.5 h, the reaction was extracted with CH2Cl2 (20 mL), washed with H2O (30 mL), dried over Na2SO4, and evaporated in vacuo to give N-(4-Nitrophenyl)butyramide (1.50 g, 100%) as a white solid.
Reaction SMILES: [I:1][CH2:2][C:3]1[N:4]=C(C2C=CC(C)=CC=2)O[C:7]=1[C:8]1C=CC=CC=1.C/C(/C(C)=O)=N\O.[CH:28]([C:31]1[CH:38]=[CH:37][C:34]([CH:35]=[O:36])=[CH:33][CH:32]=1)([CH3:30])[CH3:29]>>[I:1][CH2:2][C:3]1[N:4]=[C:35]([C:34]2[CH:33]=[CH:32][C:31]([CH:28]([CH3:30])[CH3:29])=[CH:38][CH:37]=2)[O:36][C:7]=1[CH3:8]
Reactant: CC(C)c1ccc(C=O)cc1
Reactant: Cc1ccc(-c2nc(CI)c(-c3ccccc3)o2)cc1
Agent: CC(=O)/C(C)=N/O
Product: Cc1oc(-c2ccc(C(C)C)cc2)nc1CI

Procedure:
Analogously to the building block synthesis of 4-iodomethyl-5-phenyl-2-p-tolyloxazole, diacetylmonoxime and 4-isopropylbenzaldehyde gave 4-iodomethyl-2-(4-isopropylphenyl)-5-methyloxazole.
Reaction SMILES: [CH2:1]([N:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:10]([CH:22]=[CH2:23])[C:9]1=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>CCO.CCOC(C)=O.[Pd]>[CH2:1]([N:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:10]([CH2:22][CH3:23])[C:9]1=[O:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: C=Cc1c(OCc2ccccc2)ccn(Cc2ccccc2)c1=O
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCc1c(OCc2ccccc2)ccn(Cc2ccccc2)c1=O
Yield: 62.6 %

Procedure:
To a solution of 1-benzyl-4-(benzyloxy)-3-vinylpyridin-2(1H)-one (0.5 g, 1.6 mmol) in EtOH (10.0 mL) and EtOAc (10.0 mL) was added Pd/C (10%, 0.25 g) and stirred in an atmosphere of hydrogen gas at 30 psi for 16 h. The catalyst was removed by filtration, the filtrate was concentrated to dryness and the resulting residue was purified by silica gel flash chromatography using EtOAc/hexanes (1:1, v/v) to afford the title compound (0.32 g, 64%) as a pale yellow powder: 1H-NMR (CD3OD) δ: 7.52 (d, 1H, J=7.6 Hz), 7.39-7.2 (m, 10H), 6.41 (d, 1 h, J=7.6 Hz), 5.18 (s, 2H), 5.15 (s, 2H), 2.58 (q, 2H, J=7.2 Hz), 1.03 (t, 3H, J=7.2 Hz), ER-MS m/z=320 (MH+) HR-MS m/z calcd C21H22NO2 320.1651, found 320.1648.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:9][S:10]([CH3:13])(=[O:12])=[O:11])=[C:6]([NH2:8])[CH:7]=1.C([O-])(=O)C.[K+].C(OC(=O)C)(=O)C.C1OCCOCCOCCOCCOCCOC1.C(O[N:49]=O)(C)(C)C>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]2[C:5]([C:9]([S:10]([CH3:13])(=[O:12])=[O:11])=[N:49][NH:8]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)ON=O
Reactant: CS(=O)(=O)Cc1ccc(Br)cc1N
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)OC(C)=O
Product: CS(=O)(=O)c1n[nH]c2cc(Br)ccc12

Procedure:
To a suspension of {5-bromo-2-[(methylsulfonyl)methyl]phenyl}amine (Intermediate 74) (0.26 g) in chloroform (8 ml) was added potassium acetate (0.11 g) and acetic anhydride (0.195 ml). The mixture was heated under nitrogen at reflux for 18 h. 18-Crown-6 (0.26 g) and tert-butylnitrite (0.35 ml) were added and the mixture was stirred at reflux for a further 88 h. The mixture was concentrated under vacuum and the residue was purified by column chromatography on silica eluting with cyclohexane:ethylacetate (4:1 to 1:1) to give the title compound (0.14 g).