Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C@@H:5]1[O:22][C@H:21]([CH2:23][O:24][C:25](=[O:27])[CH3:26])[C@@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:6]1[O:7][C:8](=[O:10])[CH3:9])(=O)[CH3:2].[CH3:28][C:29]([CH2:34][CH2:35][CH2:36][CH:37]([CH3:44])[CH2:38][CH2:39][CH2:40][CH:41]([CH3:43])[CH3:42])=[CH:30]CCO.C(N(CC)CC)C>C(#N)C.C(OCC)(=O)C>[C:8]([O:7][C@@H:6]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@@H:21]([CH2:23][O:24][C:25](=[O:27])[CH3:26])[O:22][CH:5]1[O:4][CH2:1][CH2:2][CH:28]=[C:29]([CH3:30])[CH2:34][CH2:35][CH2:36][CH:37]([CH3:44])[CH2:38][CH2:39][CH2:40][CH:41]([CH3:42])[CH3:43])(=[O:10])[CH3:9]
Reactant: CC(=CCCO)CCCC(C)CCCC(C)C
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(=O)OC[C@H]1OC(OCCC=C(C)CCCC(C)CCCC(C)C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C

Procedure:
2.11 g (5.41 mmol) of β-D-glucose pentaacetate and 1.0 g (4.2 mmol) of 4,8,12-trimethyltridec-3-en-1-ol were dissolved in dry acetonitrile (4 mL). 1.0 mL (8.3 mmol) of boron trifluoride diethyl etherate complex was added to the solution with cooling on ice. The reaction mixture was allowed to warm up slowly to room temperature while being stirred for 24 hours before addition of 1.7 mL (12 mmol) of triethylamine at 0° C. The resulting solution was diluted with ethyl acetate, and washed with water, 1M hydrochloric acid, saturated sodium bicarbonate aqueous solution, and saturated brine, successively, and dried over sodium sulfate. After filtration, the filtrate was concentrated to obtain 1-O-(4,8,12-trimethyltridec-3-enyl)-D-glucopyranoside tetraacetate as a crude product.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][CH:11]=1.C([Li])(C)(C)C.[C:23](=[O:25])=[O:24].Cl>CN(C)C=O.CCOCC.O>[C:23]([C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][CH:11]=1)([OH:25])=[O:24]
Reactant: COc1cccc(-c2cc(OC)ccc2Br)c1
Reactant: O=C=O
Agent: Cl
Agent: [Li]C(C)(C)C
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COc1cccc(-c2cc(OC)ccc2C(=O)O)c1
Temperature: -60 °C

Procedure:
12.1 g of 2-bromo-5,5'-dimethoxybiphenyl was dissolved in 100 mL of dry dimethylformamide and the resulting solution was cooled to -60° C. under nitrogen. 55 mL of 1.7 M t-butyllithium in hexanes was added over a 20-minute period. The resulting solution was transferred to another flask containing a mixture of 275 mL of ether and dry ice which effected a lot of gas evolution. The mixture was allowed to warm to room temperature over a 3-hour period during which time a white precipitate had formed. The mixture was diluted with ether and treated with dilute hydrochloric acid and water. The organic layer was separated and the solvents were removed under reduced pressure to yield a yellow oil. Hexanes were added to the oil causing a solid to precipitate out. The solids were filtered and stirred in a 60:40% ether-hexane mixture to remove impurities. The solid was filtered and dried in vacuo to yield 7.82 g of 2-carboxy-5,5'-dimethoxybiphenyl as an off-white solid. The structure was confirmed by NMR and infrared spectroscopy.
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[CH:8][CH:9]=[C:10]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[C:5]2=[N:4][C:3]=1[CH2:17][CH2:18][C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=1.CC1(C)C(C)(C)OB([C:37]2[CH:42]=[CH:41][C:40]([N:43]3[C:47](=[O:48])[N:46]([CH2:49][O:50][CH2:51][CH2:52][Si:53]([CH3:56])([CH3:55])[CH3:54])[N:45]=[N:44]3)=[CH:39][CH:38]=2)O1>>[O:14]1[CH2:15][CH2:16][N:11]([C:10]2[C:5]3[N:6]([C:2]([C:37]4[CH:42]=[CH:41][C:40]([N:43]5[C:47](=[O:48])[N:46]([CH2:49][O:50][CH2:51][CH2:52][Si:53]([CH3:56])([CH3:55])[CH3:54])[N:45]=[N:44]5)=[CH:39][CH:38]=4)=[C:3]([CH2:17][CH2:18][C:19]4[CH:28]=[CH:27][C:26]5[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=5)[N:20]=4)[N:4]=3)[N:7]=[CH:8][CH:9]=2)[CH2:12][CH2:13]1
Reactant: CC1(C)OB(c2ccc(-n3nnn(COCC[Si](C)(C)C)c3=O)cc2)OC1(C)C
Reactant: Brc1c(CCc2ccc3ccccc3n2)nc2c(N3CCOCC3)ccnn12
Product: C[Si](C)(C)CCOCn1nnn(-c2ccc(-c3c(CCc4ccc5ccccc5n4)nc4c(N5CCOCC5)ccnn34)cc2)c1=O

Procedure:
Compound 46a (0.30 g, 0.68 mmol) was subjected to Suzuki coupling conditions with compound 53c using the procedures described in Example 38, Step A to obtain compound 53d as a white solid. Mass Spectrum (LCMS, ESI pos.): Calcd. for C34H39N9O3Si: 650.3 (M+H). Found: 650.2.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][NH:24][CH2:25][CH3:26])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.C(N(C(C)C)CC)(C)C.Cl[C:38]([O:40][CH2:41][C:42]1[CH:47]=[C:46]([Cl:48])[CH:45]=[C:44]([Cl:49])[CH:43]=1)=[O:39]>C(Cl)Cl.O>[CH3:1][O:2][C:3](=[O:27])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:20])[F:22])=[CH:15][C:14]=2[CH2:23][N:24]([C:38]([O:40][CH2:41][C:42]2[CH:43]=[C:44]([Cl:49])[CH:45]=[C:46]([Cl:48])[CH:47]=2)=[O:39])[CH2:25][CH3:26])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: O=C(Cl)OCc1cc(Cl)cc(Cl)c1
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1OC
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1OC)C(=O)OCc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To (2′-ethylaminomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester (0.101 g, 0.26 mmol) and diisopropylethylamine (0.23 mL, 1.32 mmol) in CH2Cl2 (1 mL) was added 3,5-dichlorobenzyl chloroformate (1.06 mmol) in CH2Cl2, and the reaction was stirred at room temperature for 5 minutes. The mixture was diluted with H2O and extracted with CH2Cl2. The combined organic layers were dried over Na2SO4, decanted, and concentrated, and the residue was purified by silica gel chromatography to give the title compound.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:10][CH:9]([CH3:11])[C:8](=[O:12])[NH:7]1)=[O:5])C.Cl>[OH-].[Na+]>[CH3:11][CH:9]1[C:8](=[O:12])[NH:7][C@H:6]([C:4]([OH:5])=[O:3])[CH2:10]1
Reactant: CCOC(=O)C1CC(C)C(=O)N1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC1C[C@@H](C(=O)O)NC1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The crystals (2.0 g) of 2-ethoxycarbonyl-4-methyl-5-oxopyrrolidine in the above-mentioned stage B were dissolved in a 2N sodium hydroxide solution (6 ml), and the solution was stirred at room temperature overnight. The mixture was neutralized with dilute hydrochloric acid, followed by concentration under reduced pressure. The residue was crystallized from water to give 4-methylpyroglutamic acid isomer A (900 mg) as crystals.
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:24][N:25]([CH3:33])[C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:4][N:5]([S:14]([C:17]2[O:18][C:19]([CH:22]=[O:23])=[CH:20][CH:21]=2)(=[O:16])=[O:15])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1.[CH3:34][Mg]Br.Cl>O1CCCC1>[F:1][C:2]1[C:3]([CH2:24][N:25]([CH3:33])[C:26](=[O:32])[O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[CH:4][N:5]([S:14]([C:17]2[O:18][C:19]([CH:22]([OH:23])[CH3:34])=[CH:20][CH:21]=2)(=[O:15])=[O:16])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: CN(Cc1cn(S(=O)(=O)c2ccc(C=O)o2)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Reactant: C[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Product: CC(O)c1ccc(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)c(F)c2-c2cccnc2F)o1
Reaction time: 2 h
Yield: 86 %

Procedure:
To a solution of tert-butyl ({4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(5-formyl-2-furyl)sulfonyl]-1H-pyrrol-3-yl}methyl)methylcarbamate (464 mg) in tetrahydrofuran (5 mL) was added a 1.0 mol/L solution (1.3 mL) of methylmagnesium bromide in tetrahydrofuran under ice-cooling and the mixture was stirred for 2 hr. 1 mol/L Hydrochloric acid was added to the reaction mixture and the mixture was further stirred for 1 hr and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=9:1→3:2) to give the title compound as a pale-yellow oil (yield 410 mg, 86%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([O:20][CH2:21][CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[CH:17]=[C:16](Br)[CH:15]=2)=[CH:9][C:8]=1[Cl:31])[CH3:2].[CH3:33][O:34][CH2:35][C:36]#[CH:37]>C(N(CC)CC)C.CN(C=O)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu](I)I>[CH2:1]([O:3][C:4](=[O:32])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([O:20][CH2:21][CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[CH:17]=[C:16]([C:37]#[C:36][CH2:35][O:34][CH3:33])[CH:15]=2)=[CH:9][C:8]=1[Cl:31])[CH3:2]
Reactant: CCOC(=O)COc1ccc(Sc2cc(Br)cc(OCCCN3CCOCC3)c2)cc1Cl
Reactant: C#CCOC
Agent: Cl[Pd]Cl
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(Sc2cc(C#CCOC)cc(OCCCN3CCOCC3)c2)cc1Cl

Procedure:
{4-[3-Bromo-5-(3-morpholin-4-yl-propoxy)-phenylsulfanyl]-2-chloro-phenoxy}-acetic acid ethyl ester (0.2 g; 0.37 mmol), 3-methoxy-propyne (0.10 g; 1.47 mmol), bis(triphenylphosphine) palladium (II) chloride (21 mg; 0.029 mmol) and copper iodide (4.2 mg; 0.022 mmol) were dissolved in a mixture of triethylamine (2 mL) and DMF (2 mL) under an atmosphere of nitrogen. The reaction mixture was reacted in a microwave oven at 150° C. for 1 h. The reaction mixture was evaporated to dryness and extracted with ethyl acetate from a aqueous 5% citric acid solution. The crude product was dried, evaporated to dryness and purified by preparative HPLC (method B). Yield: 160 mg. HPLC-MS: m/z: 534.1 (M+); Rt: 1.79 min.
Reaction SMILES: [CH:1]1([CH2:4][N:5]([C:10]2[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[C:12]([C:18]#[N:19])[CH:11]=2)[CH2:6][C:7]([OH:9])=O)[CH2:3][CH2:2]1.[CH2:20]([NH2:22])[CH3:21]>>[CH:1]1([CH2:4][N:5]([C:10]2[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[C:12]([C:18]#[N:19])[CH:11]=2)[CH2:6][C:7]([NH:22][CH2:20][CH3:21])=[O:9])[CH2:2][CH2:3]1
Reactant: N#Cc1ccc(N(CC(=O)O)CC2CC2)cc1C#N
Reactant: CCN
Product: CCNC(=O)CN(CC1CC1)c1ccc(C#N)c(C#N)c1

Procedure:
Synthesized in a manner similar to example 3 using N-(cyclopropylmethyl)-N-(3,4-dicyanophenyl)glycine and ethylamine: MS (ES) m/z 283 (M+1).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][C:9]2[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][CH:10]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(O)C.[CH2:23]1[CH2:29][S:26](=[O:28])(=[O:27])[O:25][CH2:24]1>C(OCC)C>[CH2:16]([O:15][C:13]([C:12]1[CH:18]=[CH:19][C:9]([CH2:8][CH2:7][N:1]2[CH2:6][CH2:5][N:4]([CH2:24][CH2:23][CH2:29][S:26]([OH:28])(=[O:27])=[O:25])[CH2:3][CH2:2]2)=[CH:10][CH:11]=1)=[O:14])[CH3:17]
Reactant: O=S1(=O)CCCO1
Reactant: CCOC(=O)c1ccc(CCN2CCNCC2)cc1
Solvent: CCOCC
Solvent: CCO
Product: CCOC(=O)c1ccc(CCN2CCN(CCCS(=O)(=O)O)CC2)cc1
Temperature: 20 °C
Reaction time: 8 h

Procedure:
To a solution of 10.25 g. (39 mmole) ethyl 4-[2-(piperazin-1-yl)-ethyl]-benzoate and 70 ml. anhydrous ethanol, there are added 4.76 g. (39 mmole) 1,3-propanesultone, followed by stirring at 20° C. After standing overnight, the ethanol is stripped off and the residue is treated with diethyl ether and ligroin. After suction filtration, it is recrystallised from ethanol to give 11.2 g. (75% of theory) of the desired compound; m.p. 235°-236° C.
Reaction SMILES: [Cl-:1].[NH2:2][N+:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](Cl)=[O:13]>C1(C)C(C)=CC=CC=1>[Cl-:9].[Cl:1][C:17]1[CH:16]=[CH:15][C:11]([C:12]([NH:2][N+:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[O:13])=[CH:10][CH:18]=1
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: N[n+]1ccccc1
Agent: [Cl-]
Solvent: Cc1ccccc1C
Product: O=C(N[n+]1ccccc1)c1ccc(Cl)cc1
Yield: 97 %

Procedure:
1-Aminopyridinium chloride (104 parts) and -chlorobenzoyl chloride (150 parts) were heated in xylene (750 parts) at 140° C for 4 hours. The solid product was filtered off and recrystallised from n-butanol to give 1-(p-chlorobenzamido)pyridinium chloride (209 parts, 97% yeild), melting point 241° C.
Reaction SMILES: [OH-].[K+].[OH:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([N:14]=CC2C=CC=CC=2)[C:6](=[O:22])[C:5]=1C(OCC)=O>O1CCOCC1>[NH2:14][N:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:4]([OH:3])=[CH:5][C:6]1=[O:22]
Reactant: CCOC(=O)c1c(O)c2ccccc2n(N=Cc2ccccc2)c1=O
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Nn1c(=O)cc(O)c2ccccc21
Yield: 91 %

Procedure:
To a solution of 25% by weight aqueous potassium hydroxide (200 mL) and 1,4-dioxane (50 mL) heated to 90-100° C. was added portion wise ethyl 4-hydroxy-2-oxo-1-{[phenylmethylene]amino}-1,2-dihydroquinoline-3-carboxylate (6.72 g, 20.0 mmol). The reaction mixture was heated at reflux for 90 minutes allowing distillation to occur and additional water and dioxane (30 mL each) were added to the reaction vessel to reach the original volume. The mixture was refluxed for an additional 90 minutes with distillation, cooled, washed with 200 mL of 1:1 diethyl ether/ethyl acetate, acidified with concentrated hydrochloric acid to pH 2 and the resulting solid was collected by filtration, washed with water and dried to constant mass to give 1-amino-4-hydroxyquinolin-2(1H)-one as a tan sold (3.22 g, 91% yield). MS (DCI) m/z 177 (M+H)+. 1H NMR (300 MHz, DMSO-d6) δ 5.56 (s, 2 H) 5.94 (s, 1 H) 7.20 (t, J=7.54 Hz, 1 H) 7.62 (m, 1 H) 7.85 (m, 2 H) 11.33 (s, 1 H).
Reaction SMILES: [C:1]([O:7][CH2:8]/[CH:9]=[CH:10]/[C:11]([F:14])([F:13])[F:12])(=[O:6])[CH2:2]C(C)=O.C(N(CC)CC)C.C(NC1C=CC(S([N:35]=[N+:36]=[N-])(=O)=O)=CC=1)(=O)C.[Li]>C(#N)C.O.C(OCC)C>[N+:35](=[CH:2][C:1]([O:7][CH2:8]/[CH:9]=[CH:10]/[C:11]([F:14])([F:13])[F:12])=[O:6])=[N-:36]
Reactant: CC(=O)Nc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Reactant: CC(=O)CC(=O)OC/C=C/C(F)(F)F
Agent: [Li]
Solvent: CCOCC
Solvent: O
Solvent: CCN(CC)CC
Product: [N-]=[N+]=CC(=O)OC/C=C/C(F)(F)F
Reaction time: 0.29 h
Yield: 74.4 %

Procedure:
To a solution of trans-4,4,4-trifluoro-2-buten-1-yl acetoacetate (13.7 g, 65.1 mmol) and triethylamine (11.7 mL, 84 mmol) in anhydrous acetonitrile (60 mL), a solution of p-acetamidobenzenesulfonyl azide (20.1 g, 84 mmol) in anhydrous acetonitrile (60 mL) was added dropwise over a period of 30 minutes. A white precipitate was observed after 15-20 minutes and additional acetonitrile (100 mL) was added to facilitate stirring. The resulting mixture was stirred at room temperature for one additional hour. Then, a solution of lithium hydroxyde (9.0 g, 214 mmol) in water (75 mL) was added to the reaction mixture. After stirring for one hour, the resulting mixture was poured onto 2:1 diethylether:ethyl acetate (150 mL) and layers were separated. Aqueous layer was extracted with 2:1 diethylether:ethyl acetate (150 mL) and the combined organic phases were washed with a saturated aqueous sodium chloride solution (50 mL). The resulting organic solution was dried over sodium sulfate, filtered and the solvent removed under reduced pressure. The residue was purified by column chromatography using a mixture 4:1 of hexane and ethyl acetate as eluent to afford 9.4 g (75% yield) of trans-4,4,4-trifluoro-2-buten-1-yl diazoacetate as a yellow oil.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]=2[C:21]([F:24])([F:23])[F:22])[O:11][CH2:10][C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B.C1COCC1.Cl>C1COCC1>[CH2:1]([N:8]1[CH2:9][CH2:10][O:11][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]=2[C:21]([F:24])([F:22])[F:23])[CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1COC(c2ccc(O)cc2C(F)(F)F)CN1Cc1ccccc1
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: Oc1ccc(C2CN(Cc3ccccc3)CCO2)c(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 4-benzyl-6-(4-hydroxy-2-trifluoromethyl-phenyl)-morpholin-3-one (26.18 g; 67.3 mmol) in THF (600 mL) was added dropwise BH3-THF in THF (235.4 mL; 1.00 mol/l; 235.4 mmol), at 0° C. The resulting mixture was stirred for 1 hour at 0° C. and thereafter 18 hours at RT. Subsequently, 1M aqueous HCl (550 mL) was added and the mixture stirred overnight at RT. The resulting mixture was partitioned between EtOAc and 2M aqueous NaOH (350 mL), the organic layers was dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO2, CH2Cl2/MeOH 98:2) to afford 4-(4-benzyl-morpholin-2-yl)-3-trifluoromethyl-phenol
Reaction SMILES: CCN(C1C=CC=CC=1)CC.O[CH:13]([C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18]([NH2:20])=[O:19])[CH3:14].S(Cl)([Cl:26])=O.O>C(Cl)Cl>[Cl:26][CH:13]([C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18]([NH2:20])=[O:19])[CH3:14]
Reactant: O=S(Cl)Cl
Reactant: CC(O)c1cccc(C(N)=O)c1
Solvent: CCN(CC)c1ccccc1
Solvent: ClCCl
Solvent: O
Product: CC(Cl)c1cccc(C(N)=O)c1
Yield: 75 %

Procedure:
Diethylaniline (390 μL, 2.45 mmol) was added 3-(1-hydroxyethyl)benzamide (400 mg, 2.45 mmol) slurried in DCM (20 mL) and the reaction mixture was cooled with an ice-bath. Thionyl chloride ((255 μL, 2.47 mmol) was added dropwise and the reaction was put in the refrigerator overnight. Water was added, the reaction mixture was extracted twice with DCM, washed with a 10% HCl solution, neutralized with a saturated bicarbonate solution, treated with brine, dried (MgSO4), filtered and evaporated to dryness. The crude product was recrystallized from diethylether/hexane to give 335 mg (75%) of the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][C:9]2[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:16])=[NH:7])=[CH:4][CH:3]=1.C([Li])CCC.Cl[P:25]([CH:29]([CH3:31])[CH3:30])[CH:26]([CH3:28])[CH3:27]>>[CH:26]([P:25]([CH:29]([CH3:31])[CH3:30])[N:7]=[C:6]([NH:8][C:9]1[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:16])[C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:18][CH:17]=1)([CH3:28])[CH3:27]
Reactant: Cc1ccc(C(=N)Nc2c(C)cccc2C)cc1
Reactant: CC(C)P(Cl)C(C)C
Agent: [Li]CCCC
Product: Cc1ccc(C(=NP(C(C)C)C(C)C)Nc2c(C)cccc2C)cc1

Procedure:
Procedure as described for NP Amidine I using the following amounts: 1.19 g of 4-methyl-N1-(2,6-dimethylphenyl)benzamidine (Amidine III, 5.0 mmol), 2.50 mL of 2.0 M butyllithium (5.0 mmol), 0.80 mL chlorodiisopropylphosphine (5.0 mmol). After filtration to remove lithium chloride and removal of solvent, a yellow oil was isolated (1.76 g).
Reaction SMILES: [H-].[Na+].[CH3:3][OH:4].Cl[C:6]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[C:8]([Cl:15])[N:7]=1.O>C1(C)C(C)=CC=CC=1>[Cl:15][C:8]1[N:7]=[C:6]([O:4][CH3:3])[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Reactant: CO
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Solvent: O
Product: COc1nc(Cl)ccc1[N+](=O)[O-]
Reaction time: 0.33 h

Procedure:
To a suspension of sodium hydride (684 mg, 28.49 mmol) in xylene (100 ml), methanol (0.98 ml, 25.9 mmol) in xylene (30 ml) was added under nitrogen. The mixture was stirred for 20 min. A solution of 2,6-dichloro-3-nitropyridine (5.0 g, 25.9 mmol) in xylene (100 ml) was added to the reaction mixture and stirred at room temperature overnight. Water (50 ml) was added and the organic layer was separated. The organics was washed with water (1×50 ml) and brine (2×50 ml), dried, and concentrated in vacuo. The crude product was purified by flash chromatography (10:1 methylene chloride and acetone) to provide the desired compound, 6-chloro-2-methoxy-3-nitro-pyridine, as the only isomer as light yellow solid (90%).
Reaction SMILES: [CH:1]([N:4]([CH2:8][C:9]1[CH:37]=[CH:36][C:12]([C:13]([N:15]2[CH2:20][CH2:19][N:18]([S:21]([C:24]3[CH:33]=[CH:32][C:31]4[C:26](=[CH:27][C:28]([O:34]C)=[CH:29][CH:30]=4)[CH:25]=3)(=[O:23])=[O:22])[CH2:17][CH2:16]2)=[O:14])=[CH:11][CH:10]=1)[CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].B(Br)(Br)Br.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH:1]([N:4]([CH2:8][C:9]1[CH:37]=[CH:36][C:12]([C:13]([N:15]2[CH2:16][CH2:17][N:18]([S:21]([C:24]3[CH:33]=[CH:32][C:31]4[C:26](=[CH:27][C:28]([OH:34])=[CH:29][CH:30]=4)[CH:25]=3)(=[O:23])=[O:22])[CH2:19][CH2:20]2)=[O:14])=[CH:11][CH:10]=1)[CH:5]([CH3:7])[CH3:6])([CH3:2])[CH3:3]
Reactant: COc1ccc2ccc(S(=O)(=O)N3CCN(C(=O)c4ccc(CN(C(C)C)C(C)C)cc4)CC3)cc2c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)N(Cc1ccc(C(=O)N2CCN(S(=O)(=O)c3ccc4ccc(O)cc4c3)CC2)cc1)C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.5 %

Procedure:
According to a similar method described in Working Example 36, to a solution of 1-(4-diisopropylaminomethylbenzoyl)-4-(7-methoxynaphthalene-2-sulfonyl)piperazine (150 mg) in CH2Cl2 (6 ml) was added dropwise at 0° C. a solution of 3.5 M BBr3 in CH2Cl2 (0.18 ml), and the solution was stirred at room temperature for 1 hour. To the reaction solution was added sodium bicarbonate solution and the organic layer was separated, dried and concentrated to give a colorless solid of the title compound (119 mg).
Reaction SMILES: Br[CH2:2][C:3]1[CH:28]=[CH:27][C:6]2[N:7]3[C:24]([C:25]#[N:26])=[CH:23][CH:22]=[C:8]3[C:9]3([CH2:15][CH2:14][N:13](C(=O)C(F)(F)F)[CH2:12][CH2:11]3)[O:10][C:5]=2[CH:4]=1.[CH3:29][O-:30].[Na+]>>[CH3:29][O:30][CH2:2][C:3]1[CH:28]=[CH:27][C:6]2[N:7]3[C:24]([C:25]#[N:26])=[CH:23][CH:22]=[C:8]3[C:9]3([CH2:11][CH2:12][NH:13][CH2:14][CH2:15]3)[O:10][C:5]=2[CH:4]=1
Reactant: C[O-]
Reactant: N#Cc1ccc2n1-c1ccc(CBr)cc1OC21CCN(C(=O)C(F)(F)F)CC1
Agent: [Na+]
Product: COCc1ccc2c(c1)OC1(CCNCC1)c1ccc(C#N)n1-2
Temperature: 25 °C
Reaction time: 5 h
Yield: 24.9 %

Procedure:
7′-(Bromomethyl)-1-(2,2,2-trifluoroacetyl)spiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]-benzoxazine]-1′-carbonitrile (53.2 mg, 0.117 mmol) was treated with sodium methoxide (36 mg, 0.67 mmol) at room temperature. The mixture was allowed to stir for 5 h at room temperature before it was concentrated under reduced pressure. The residue was taken up in ethyl acetate, filtered, and concentrated to give 7′-(methoxymethyl)spiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1′-carbonitrile (9.0 mg, 4%). ESI-MS m/z calc. 309.2, found 310.3 (M+1)+; Retention time 0.97 minutes (3 min run).
Reaction SMILES: [CH3:1]/[C:2](=[CH:6]\[CH2:7][CH2:8][CH3:9])/[C:3](O)=[O:4].C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.[Cl-].[Li+].[C:26]1([C@H:32]2[C@@H:36]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[O:35][C:34](=[O:43])[NH:33]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1COCC1>[CH3:1]/[C:2](=[CH:6]\[CH2:7][CH2:8][CH3:9])/[C:3]([N:33]1[C@@H:32]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C@@H:36]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[O:35][C:34]1=[O:43])=[O:4]
Reactant: O=C1N[C@@H](c2ccccc2)[C@@H](c2ccccc2)O1
Reactant: CCC/C=C(\C)C(=O)O
Agent: CC(C)(C)C(=O)Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCC/C=C(\C)C(=O)N1C(=O)O[C@H](c2ccccc2)[C@@H]1c1ccccc1
Reaction time: 1 h
Yield: 71.5 %

Procedure:
To a solution of (E)-2-methyl-2-hexenoic acid (6.0 g, 47 mmol) in 250 mL of THF at 0° C. was added 16.3 mL (117 mmol) of triethylamine, then 5.8 mL (47 mmol) of pivaloyl chloride resulting in a thick suspension. The mixture was stirred for 1 hour at 0° C. at which time 2.0 g (47 mmol) of lithium chloride was added in one portion, followed by 10.0 g (42 mmol) of (4S,5R)-4,5-diphenyl-2-oxazolidinone in four batches. Stirring was maintained throughout the solid additions. The resulting mixture was stirred for 1 hour at 0° C., then for 1 hour at ambient temperature, and was vacuum filtered through a coarse frit and concentrated. The residue was partitioned between EtOAc/water, and the organics were dried over MgSO4 and concentrated. To the residue was added 100 mL of MTBE and the mixture warmed cautiously with swirling. The warm slurry was filtered to provide 10.5 g (64% yield) of the titled compound as a colorless solid: 1H NMR (CDCl3) δ 7.12 (m, 3H), 7.07 (m, 3H), 6.94 (m, 2H), 6.84 (m, 2H), 6.17 (m, 1H), 5.89 (d, J=7.8 Hz, 1H), 5.68 (d, J=7.8 Hz, 1H), 2.18 (m, 2H), 1.92 (s, 3H), 1.50 (m, 2H), 0.96 (t, J=7.6 Hz, 3H).