Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([O:12][CH2:13][CH3:14])=[O:11].[H-].[Na+].[Cl:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Cl)=[CH:20][CH:19]=1>CN(C=O)C>[Cl:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=[C:2]2[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:20][CH:19]=1
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Reactant: ClCc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2ccccc2n1Cc1ccc(Cl)cc1
Reaction time: 1 h
Yield: 73.6 %

Procedure:
Ethyl indole-2-carboxylate (0.5 g) was dissolved in DMF and sodium hydride (0.116 g) was added in a single portion. The reaction was stirred for 1 hour, then 4-chlorobenzyl chloride (0.468 g) was added dropwise. Stirring was continued for a further 2 hours and then the reaction was quenched by the addition of water. The reaction mixture was partitioned between water and ethyl acetate. Combined organic extracts were dried (MgSO4) and concentrated in vacuo and the residue purified by column chromatography using isohexane-5% ethyl acetate as eluent to give the desired end product as a white solid (0.61 g, 74%), mp 107-108°; NMR δ(CD3SOCD3) 1.25 (t, 3H), 4.3 (q, 2H), 5.8 (s, 2H), 7.1 (t, 1H), 7.3 (m, 4H), 7.55 (d, 1H), 7.7 (d, 1H); M/z (+) 314 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([NH:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[F:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[C:21](Cl)=[O:22].N1C=CC=CC=1>C1COCC1>[F:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[C:21]([N:6]([C:5]1[CH:15]=[CH:16][C:2]([F:1])=[CH:3][CH:4]=1)[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)=[O:22]
Reactant: COc1ccc(Nc2ccc(F)cc2)cc1
Reactant: COc1ccc(C(=O)Cl)cc1F
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COc1ccc(N(C(=O)c2ccc(OC)c(F)c2)c2ccc(F)cc2)cc1
Temperature: 25 °C

Procedure:
4-Fluoro-N-(4-methoxyphenyl)aniline (1c) (90.78 g, 0.418 mol) and 3-fluoro-4-methoxybenzoyl chloride (94.55 g, 0.501 mol) were mixed together and dissolved in anhydrous THF (200 mL) in a dry 1 L three-necked round-bottomed flask fitted with a stifling bar, a reflux condenser and an argon inlet. Anhydrous pyridine (132.22 g, 1.672 mol) was added via a syringe at room temperature under argon. The reaction mixture was stirred and heated to reflux overnight. Then, the reaction mixture was cooled to room temperature and filtered to remove pyridine salt. The solution was concentrated to remove THF solvent. The residue oil was washed with 200 mL of 2N HCl solution and extracted with ethyl acetate (2×200 mL). The combined organic layer was washed with a saturated aqueous Na2CO3 solution (150 mL) to remove excess benzoyl chloride and acid, dried over MgSO4 (50 g), filtered, and concentrated under reduced pressure to give an oil. The residue was purified by flash column chromatography using silica-gel with CH2Cl2/acetone (50/1 v/v) to afford the pure corresponding benzamide compound as a yellow solid. M.p. 54-56° C. MS (ESI) m/z 370.1 [M+H]+, 1H NMR (CDCl3/TMS) δ 7.24-7.11 (m, 4H), 7.05-6.97 (m, 4H), 6.85-6.78 (m, 3H), 3.86 (s, 3H), 3.79 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:16]2[C@H:20]([CH2:21][O:22][CH3:23])[CH2:19][O:18][C:17]2=[O:24])[CH:5]=[CH:6][C:7]=1[C:8]([N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)=[O:9].[Cl:25][C:26]1[C:31]([Cl:32])=[CH:30][C:29]([Cl:33])=[C:28](Cl)[N:27]=1>>[F:1][C:2]1[CH:3]=[C:4]([N:16]2[C@H:20]([CH2:21][O:22][CH3:23])[CH2:19][O:18][C:17]2=[O:24])[CH:5]=[CH:6][C:7]=1[C:8]([N:10]1[CH2:15][CH2:14][N:13]([C:28]2[C:29]([Cl:33])=[CH:30][C:31]([Cl:32])=[C:26]([Cl:25])[N:27]=2)[CH2:12][CH2:11]1)=[O:9]
Reactant: COC[C@@H]1COC(=O)N1c1ccc(C(=O)N2CCNCC2)c(F)c1
Reactant: Clc1cc(Cl)c(Cl)nc1Cl
Product: COC[C@@H]1COC(=O)N1c1ccc(C(=O)N2CCN(c3nc(Cl)c(Cl)cc3Cl)CC2)c(F)c1
Yield: 72.7 %

Procedure:
By reaction and treatment in the same manner as in Example 147 and using (R)-3-[3-fluoro-4-(piperazine-1-carbonyl)phenyl]-4-methoxymethyloxazolidin-2-one (405 mg) described in Preparation Example 158 and 2,3,5,6-tetrachloropyridine (390 mg), the title compound (452 mg) was obtained.
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[CH2:7]([S:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH:24]1[C:33]2[C:28](=[CH:29][C:30]([OH:34])=[CH:31][CH:32]=2)[CH2:27][CH2:26][CH:25]1[C:35]1[CH:40]=[CH:39][C:38]([OH:41])=[CH:37][CH:36]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]>O.CO>[CH2:7]([S:14]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH:24]1[C:33]2[C:28](=[CH:29][C:30]([OH:34])=[CH:31][CH:32]=2)[CH2:27][CH2:26][CH:25]1[C:35]1[CH:40]=[CH:39][C:38]([OH:41])=[CH:37][CH:36]=1)=[O:2])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCCSCCCCCCCCCC1c2ccc(O)cc2CCC1c1ccc(O)cc1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCCCCCCS(=O)CCCCCCCCCC1c2ccc(O)cc2CCC1c1ccc(O)cc1
Reaction time: 16 h

Procedure:
A solution of sodium metaperiodate (0.026 g.) in water (2 ml.) was added to a stirred solution of (1RS, 2RS)-1-(9-n-heptylthiononyl)-2-p-hydroxyphenyl-1,2,3,4-tetrahydronaphth-6-ol (Example 7; 0.052 g.) in methanol (20 ml.) and the mixture was stirred for 16 hours. The methanol was removed by evaporation, the residue was extracted three times with ethyl acetate (10 ml. each time) and the combined extracts were washed with water, dried and evaporated to dryness. The residue was purified by chromatography on a silica gel column using a 2:1 v/v mixture of toluene and ethyl acetate as eluant, and there was thus obtained as an oil (1RS, 2RS)-1-(9-n-heptylsulphinylnonyl)-2-p-hydroxyphenyl-1,2,3,4- tetrahydronaphth-6-ol, the structure of which was confirmed by proton magnetic resonance and mass spectroscopy.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl[C:10]1[CH:18]=[CH:17][C:13]([C:14]([NH2:16])=[O:15])=[CH:12][N:11]=1.C(=O)([O-])[O-].[K+].[K+].CC(N(C)C)=O>O>[I:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:10]2[CH:18]=[CH:17][C:13]([C:14]([NH2:16])=[O:15])=[CH:12][N:11]=2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(I)cc1
Reactant: NC(=O)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: NC(=O)c1ccc(Oc2ccc(I)cc2)nc1
Temperature: 200 °C
Reaction time: 3 h
Yield: 84.7 %

Procedure:
Combine 4-iodophenol (6.31 g, 28.7 mmol), 6-chloro-nicotinamide (4.51 g, 28.8 mmol), potassium carbonate (10.0 g, 72.4 mmol), and dimethylacetamide (145 mL), stir and heat at 200° C. After 3 h, cool to ambient temperature and dilute with water (600 mL), filter, and dry in vacuo to provide 8.27 g (85%) of the title compound as a white/brown solid: mass spectrum (electrospray): m/z=341.0 (M+1); 1H NMR (methanol-d4): 8.67 (d, 1H, J=2.4 Hz), 8.31 (dd, 1H, J=2.4, 8.3 Hz), 7.82-7.79 (m, 2H). 7.09 (d, 1H, J=8.8 Hz), 7.03-6.99 (m, 2H).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([C:9](=O)[CH3:10])[CH:6]=[CH:7][CH:8]=1.Cl.[NH2:15][OH:16].O.O.O.C([O-])(=O)C.[Na+]>CO>[F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([C:9](=[N:15][OH:16])[CH3:10])[CH:6]=[CH:7][CH:8]=1
Reactant: CC(=O)c1cccc(C(F)(F)F)c1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(=NO)c1cccc(C(F)(F)F)c1
Yield: 90.1 %

Procedure:
7.5 g of 3'-trifluoromethylacetophenone, 6.25 g of hydroxylamine hydrochloride, and 8.8 g of sodium acetate trihydrate were heated in 125 ml of methanol under reflux for one hour. After completion of the reaction, the methanol was distilled off under reduced pressure. 190 ml of water was added to the resulting residue, followed by extraction with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate and stripped of the solvent by distillation under reduced pressure to obtain 7.3 g of 3'-trifluoromethylacetophenone oxime having a melting point of 63° to 65° C.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([N:12]1[CH2:15][CH:14]([O:16][C:17]2[C:22](Cl)=[N:21][CH:20]=[CH:19][N:18]=2)[CH2:13]1)=[O:11].[C:24]([Si:28]([CH3:46])([CH3:45])[O:29][CH:30]1[CH2:35][CH2:34][C:33](B2OC(C)(C)C(C)(C)O2)=[CH:32][CH2:31]1)([CH3:27])([CH3:26])[CH3:25].C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1.O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([N:12]1[CH2:15][CH:14]([O:16][C:17]2[C:22]([C:33]3[CH2:34][CH2:35][CH:30]([O:29][Si:28]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:45])[CH3:46])[CH2:31][CH:32]=3)=[N:21][CH:20]=[CH:19][N:18]=2)[CH2:13]1)=[O:11]
Reactant: O=C(c1nc2ccccc2[nH]1)N1CC(Oc2nccnc2Cl)C1
Reactant: CC1(C)OB(C2=CCC(O[Si](C)(C)C(C)(C)C)CC2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)[Si](C)(C)OC1CC=C(c2nccnc2OC2CN(C(=O)c3nc4ccccc4[nH]3)C2)CC1
Temperature: 120 °C
Yield: 163.8 %

Procedure:
A glass microwave vessel was charged with (1H-benzo[d]imidazol-2-yl)(3-(3-chloropyrazin-2-yloxy)azetidin-1-yl)methanone (see PREPARATION P23.1; 219 mg, 0.664 mmol), tert-butyldimethyl(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-enyloxy)silane (366 mg, 1.082 mmol, purchased from Small Molecules Inc.), sodium carbonate (211 mg, 1.992 mmol), and dioxane:water (10:1, 15 mL). The solution was purged with N2 for 5 minutes, then palladium tetrakis (153 mg, 0.133 mmol) was added. The reaction mixture was stirred and heated in a Biotage Initiator at 120° C. for 60 minutes. The reaction was poured into water (30 mL) and extracted with EtOAc (2×20 mL). The combined EtOAc layers were eluted through a plug of silica gel. The filtrate was concentrated in vacuo to give crude (1H-benzo[d]imidazol-2-yl)(3-(3-(4-(tert-butyldimethylsilyloxy)cyclohex-1-enyl)pyrazin-2-yloxy)azetidin-1-yl)methanone (550 mg, 164% yield), as a yellow solid. The product was carried forward in the next step without further purification. MS (ESI) m/z 506.3 (MH+).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:8]=[C:7]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[N:6]=1)=O.[NH2:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][C:31]([CH3:36])=[C:30]2[CH3:37].C[Al](C)C>C1(C)C=CC=CC=1>[CH3:36][C:31]1[NH:32][C:33]2[C:29]([C:30]=1[CH3:37])=[CH:28][C:27]([NH:26][C:3]([C:5]1[CH:10]=[C:9]([O:11][CH2:12][CH2:13][N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:8]=[C:7]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:6]=1)=[O:2])=[CH:35][CH:34]=2
Reactant: COC(=O)c1cc(OCCN2CCOCC2)nc(N2CCOCC2)n1
Reactant: Cc1[nH]c2ccc(N)cc2c1C
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: Cc1[nH]c2ccc(NC(=O)c3cc(OCCN4CCOCC4)nc(N4CCOCC4)n3)cc2c1C
Temperature: 25 °C

Procedure:
To a stirred mixture of compound (I) (1.02 g, 2.9 mmol) and 5-amino-2,3-dimethyl indole (488 mg, 3.04 mmol) in toluene (6.9 mL) that was heated briefly until components partly dissolved and cooled to ambient temperature, was added 2 M solution of trimethylaluminum in toluene (2.32 mL, 1.6 eq) drop-wise under nitrogen purge. Reaction mixture was stirred until bubbling (gas evolution) completed, and then heated at 115° C. (oil bath) for 15 minutes. To a cooled reaction mixture chloroform and 1 N NaOH were added, chloroform layer was separated, washed twice with water, brine and dried over anhydrous sodium sulfate. Flash column chromatography on silica gel (eluent dichloromethane-acetone-methanol (3:1:01)) and recrystallization from chloroform-ethyl acetate mixture afforded target amide, 2-Morpholin-4-yl-6-(2-morpholin-4-yl-ethoxy)-pyrimidine-4-carboxylic acid (2,3-dimethyl-1H-indol-5-yl)-amide, as a pale yellow solid (1.1 g, 79%).
Reaction SMILES: [C:1]([N:8]([CH3:28])[CH:9]1[CH2:14][CH2:13][CH:12]([NH:15][CH2:16][C:17]2[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][C:22]=2[O:23][CH3:24])[CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Br[C:30]1[CH:31]=[CH:32][C:33]([CH3:36])=[N:34][CH:35]=1>>[C:4]([O:3][C:1](=[O:2])[N:8]([CH:9]1[CH2:14][CH2:13][CH:12]([NH:15][CH2:16][C:17]2[CH:18]=[C:19]([C:30]3[CH:35]=[N:34][C:33]([CH3:36])=[CH:32][CH:31]=3)[CH:20]=[CH:21][C:22]=2[O:23][CH3:24])[CH2:11][CH2:10]1)[CH3:28])([CH3:7])([CH3:6])[CH3:5]
Reactant: COc1ccc(B(O)O)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Reactant: Cc1ccc(Br)cn1
Product: COc1ccc(-c2ccc(C)nc2)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
The title compound was prepared from boronic acid 4 (400 mg, 1.05 mmol) and 5-bromo-2-methylpyridine (181 mg, 1.05 mmol) in accordance with Method B.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]3)[C:8]2=[O:11])=[CH:4][CH:3]=1.[F:18][C:19]([F:23])([F:22])[CH2:20][NH2:21].CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:16][CH2:15][CH:14]([NH:21][CH2:20][C:19]([F:23])([F:22])[F:18])[CH2:13][CH2:12]3)[C:8]2=[O:11])=[CH:4][CH:3]=1
Reactant: NCC(F)(F)F
Reactant: O=C1CCC2(CC1)Cc1ccc(Br)cc1C2=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: O=C1c2cc(Br)ccc2CC12CCC(NCC(F)(F)F)CC2
Temperature: 25 °C
Yield: 16.8 %

Procedure:
In a 25 mL round bottom flask was placed 6′-bromospiro[cyclohexane-1,2′-indene]-1′,4(3′H)-dione (501 mg, 1.716 mmol) and it was dissolved in dichloroethane (5.7 mL). To this solution was added the trifluoro ethylamine (162 μL, 2.059 mmol), AcOH (124 μL, 2.059 mmol), and NaBH(OAc)3 (582 mg, 2.746 mmol) at last. The reaction was stirred at room temperature. When the reaction was completed it was quenched with saturated NaHCO3 (aq) (20 mL) and diluted with ethyl acetate (20 mL). The phases were separated and the aqueous phase was back-extracted with ethyl acetate twice (5 mL/each). The combined organic phases were dried over Na2SO4, filtered and concentrated under reduce pressure. The crude material was purified by flash chromatography (ISCO, 40 g SiO2 cartridge, ethyl acetate/hexanes as the eluents). At the end, two isomers were obtained and their corresponding fractions were combined separately and concentrated under reduce pressure yielding 6′-bromo-4-(2,2,2-trifluoroethylamino)spiro[cyclohexane-1,2′-inden]-1′(3′H)-one (axial, 97b) (420 mg, 1.120 mmol) and 6′-bromo-4-(2,2,2-trifluoroethylamino)spiro[cyclohexane-1,2′-inden]-1′(3′H)-one (equatorial, 98b) (108 mg, 0.288 mmol) (82% yield). Compound 97b: M+H=375.9, 1H NMR=(CDCl3, 400 MHz) δ 7.85 (d, J=1.6 Hz, 1H), 7.67 (dd, J=8.0, 1.6 Hz, 1H), 7.29 (d, J=8.0 Hz, 1H), 3.21 (q, J=9.2 Hz, 2H), 2.93 (s, 2H), 2.90 (m, 1H), 2.01-1.94 (m, 2H), 1.87-1.81 (m, 2H), 1.75-1.68 (m, 2H), 1.38-1.29 (m, 2H). Compound 98b: M+H=375.8, 1H NMR=(CDCl3, 400 MHz) δ 7.86 (d, J=1.6 Hz, 1H), 7.68 (dd, J=8.0, 1.6 Hz, 1H), 7.32 (d, J=8.0 Hz, 1H), 3.24 (q, J=9.6 Hz, 2H), 2.95 (s, 2H), 2.68 (m, 1H), 2.03-1.97 (m, 2H), 1.81-1.74 (ddd, J=14.0, 14.0, 3.6 Hz, 2H), 1.46 (m, 2H), 1.31-1.21 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][CH3:9])[CH:3]=1.[Cl:10]N1C(=O)CCC1=O.O>CN(C)C=O>[Cl:1][C:2]1[C:7]([Cl:10])=[CH:6][N:5]=[C:4]([O:8][CH3:9])[CH:3]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1cc(Cl)ccn1
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(Cl)c(Cl)cn1
Temperature: 25 °C
Reaction time: 12 h
Yield: 73.1 %

Procedure:
10.0 g (69.9 mmol) of crude 4-chloro-2-methoxypyridine obtained in Step (d) was dissolved in 100 ml of dimethylformamide, and 37.2 g (279 mmol) of N-chlorosuccinimide was added, followed by stirring at room temperature for 12 hours. 400 ml of water was added to terminate the reaction, followed by extraction with ethyl ether. The organic layer was washed with a saturated sodium chloride solution, dried over sodium sulfate and subjected to filtration, and the solvent was distilled off under reduced pressure to obtain 9.10 g (crude yield: 73%) of crude 4,5-dichloro-2-methoxypyridine.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.C1COCC1.O1CCCCC1[O:32][CH2:33][CH2:34][CH2:35][C:36]1[CH:37]=[C:38]2[C:42](=[CH:43][CH:44]=1)[C:41](=O)[O:40][CH2:39]2.Cl>C(COC)OC.C1COCC1>[OH:32][CH2:33][CH2:34][CH2:35][C:36]1[CH:37]=[C:38]2[C:42](=[CH:43][CH:44]=1)[C:41](=[C:3]1[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][C:2]1=[O:10])[O:40][CH2:39]2
Reactant: O=C1OCc2cc(CCCOC3CCCCO3)ccc21
Reactant: O=C1Cc2ccccc2N1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: COCCOC
Solvent: C1CCOC1
Product: O=C1Nc2ccccc2C1=C1OCc2cc(CCCO)ccc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 82.7 %

Procedure:
To a stirred solution of oxindole (401 mg, 3.0 mmol) in anhydrous dimethoxyethane (20 ml) under nitrogen was added 1.0M LiHMDS/THF solution (6.3 ml, 6.3 mmol). The mixture was stirred at room temperature for 10 minutes, and 5-[3-(tetrahydro-pyran-2-yloxy)-propyl]-3H-isobenzofuran-1-one (500 mg, 1.81 mmol) was added. After stirred at room temperature for 2.5 hours, the mixture was poured into a mixture of THF (30 ml) and 2M HCl aqueous solution (30 ml) and heated at 65° C. for 1 hour. The mixture was cooled to room temperature, and then poured into an ice water (300 ml). The resulting solid was separated, rinsed with water, and dried to give 3-[5-(3-hydroxy-propyl)-3H-isobenzofuran-1-ylidene]-1,3-dihydro-indol-2-one as a yellow solid (460 mg, 83%).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[C:11]1[N:16]=[C:15]([CH3:17])[C:14]([CH2:18]O)=[C:13]([O:20][CH2:21][CH3:22])[CH:12]=1)[CH3:2].O=S(Cl)[Cl:25]>C(Cl)Cl>[Cl:25][CH2:18][C:14]1[C:15]([CH3:17])=[N:16][C:11]([C:4]2[C:3]([CH2:1][CH3:2])=[CH:8][CH:7]=[CH:6][C:5]=2[CH2:9][CH3:10])=[CH:12][C:13]=1[O:20][CH2:21][CH3:22]
Reactant: CCOc1cc(-c2c(CC)cccc2CC)nc(C)c1CO
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CCOc1cc(-c2c(CC)cccc2CC)nc(C)c1CCl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of [6-(2,6-diethyl-phenyl)-4-ethoxy-2-methyl-pyridin-3-yl]-methanol (1.8 g) and SOCl2 (2 mL) in CH2Cl2 (10 mL) is stirred at room temperature for one hour. The volatile materials are removed in vacuo to give 3-chloromethyl-6-(2,6-diethyl-phenyl)-4-ethoxy-2-methyl-pyridine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([CH:17]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[CH3:35])[CH2:18][C:19]([C:21]3[CH:26]=[CH:25][C:24](=[O:27])[N:23]([CH3:28])[CH:22]=3)=O)=[CH:13][CH:12]=2)[CH:5]=[CH:6][C:7]=1[C:8]([OH:10])=[O:9].Cl.[NH2:37][OH:38].C([O-])(O)=O.[Na+]>>[F:1][C:2]1[CH:3]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([CH:17]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[CH3:35])[CH2:18]/[C:19](=[N:37]\[OH:38])/[C:21]3[CH:26]=[CH:25][C:24](=[O:27])[N:23]([CH3:28])[CH:22]=3)=[CH:13][CH:12]=2)[CH:5]=[CH:6][C:7]=1[C:8]([OH:10])=[O:9]
Reactant: NO
Reactant: Cc1ccccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(-c2ccc(C(=O)O)c(F)c2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1ccccc1C(C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(-c2ccc(C(=O)O)c(F)c2)cc1

Procedure:
In analogy to example 151, step 3, 3-fluoro-4′-[3-(1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-3-oxo-1-o-tolyl-propyl]-biphenyl-4-carboxylic acid was reacted with hydroxylamine hydrochloride in the presence of NaHCO3 to give the title compound containing less than 10% of the corresponding Z isomer as a colorless solid, MS (ESI+): m/z=485.3 [M+H]+.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12](O)=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.B#B>O1CCCC1>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)CCCCCc1ccccc1
Agent: B#B
Solvent: C1CCOC1
Product: OCCCCCCc1ccccc1

Procedure:
A solution of 6-phenylhexanoic acid (19.8 mmol) in sieve dried tetrahydrofuran (5 ml) was reduced with diborane in tetrahydrofuran (30 ml, 29.1 mmol) at 0° C. for 4 hours to give 6-phenylhexanol. To an ice cold solution of the hexanol (ca. 19.8 mmol) and carbon tetrabromide (21.98 mmol) in methylene chloride (50 ml) was added triphenylphosphine (22.30 mmol) in methylene chloride (50 ml) and the resulting solution was stirred for 2.5 hours. The volatiles were evaporated and the residue was taken up in either (100 ml), cooled in ice, and filtered. The filtrate was evaporated and distilled to afford 6-phenylhexyl bromide as an oil. A mixture of the bromide (8.00 mmol), salicylaldehyde (8.19 mmol) and potassium carbonate (9.33 mmol) in dimethylformamide (10 ml) was heated to 100° C. and maintained at that temperature for one hour. The cooled reaction mixture was taken up in hexane (50 ml) and washed with 5% sodium hydroxide (50 ml) and saturated sodium chloride (50 ml). The organic phase was dried over anhydrous magnesium sulfate and charcoal. Evaporation yielded a colorless oil which was purified by flash chromatography over silica gel with 5% ethyl acetate in hexane as eluant to afford the desired product as an oil.
Reaction SMILES: [C:1]([C:3]1[N:11]=[CH:10][C:9]2[NH:8][C:7]3[N:12]=[CH:13][C:14]([C:16]4[CH:21]=[CH:20][C:19]([CH2:22][N:23]5[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]5)=[CH:18][CH:17]=4)=[CH:15][C:6]=3[C:5]=2[CH:4]=1)#[N:2].C1(C2[O:37]N2S(C2C=CC=CC=2)(=O)=O)C=CC=CC=1>C(Cl)Cl>[C:1]([C:3]1[N:11]=[CH:10][C:9]2[NH:8][C:7]3=[N+:12]([O-:37])[CH:13]=[C:14]([C:16]4[CH:17]=[CH:18][C:19]([CH2:22][N:23]5[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]5)=[CH:20][CH:21]=4)[CH:15]=[C:6]3[C:5]=2[CH:4]=1)#[N:2]
Reactant: N#Cc1cc2c(cn1)[nH]c1ncc(-c3ccc(CN4CCCCC4)cc3)cc12
Reactant: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Solvent: ClCCl
Product: N#Cc1cc2c(cn1)[nH]c1c2cc(-c2ccc(CN3CCCCC3)cc2)c[n+]1[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.9 %

Procedure:
A mixture of 6-cyano-3-(4-piperidin-1-ylmethyl-phenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole (110 mg, 0.30 mmol) and 3-phenyl-2-(phenylsulfonyl)oxaziridine (102 mg, 0.39 mmol) in DCM (5.8 mL) was stirred at room temperature for 2 h. The solid was collected by filtration and washed with DCM (3×20 mL) to afford a bright yellow solid (100 mg, 90%). NMR (400 MHz, DMSO-D6): 8.98 (s, 1H), 8.91 (s, 1H), 8.90 (s, 1H), 8.83 (s, 1H), 7.66 (m, 4H), 4.43 (s, 2H), 3.13 (m, 2H), 2.14 (m, 2H), 1.59 (m, 4H), 1.34 (m, 2H). LCMS (method D): RT=8.82 min, M+H+=384.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[N:8]([CH2:12][CH2:13]OS(C)(=O)=O)[CH:7]=[C:6]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:5]2=[O:24].[CH3:25][N:26](C)[CH2:27]CN>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[N:8]([CH2:12][CH2:13][N:26]([CH3:27])[CH3:25])[CH:7]=[C:6]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:5]2=[O:24]
Reactant: CCOC(=O)c1cn(CCOS(C)(=O)=O)c2ncc(Br)cc2c1=O
Reactant: CN(C)CCN
Solvent: ClCCl
Product: CCOC(=O)c1cn(CCN(C)C)c2ncc(Br)cc2c1=O
Yield: 49 %

Procedure:
A solution of ethyl 6-bromo-1-{2-[(methylsulfonyl)oxy]ethyl}-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate (Intermediate 20, 700 mg, 1.67 mmol) in dichloromethane was purged with N,N-dimethylethane-1,2-diamine gas until the starting material disappeared. The reaction mixture was washed with water, and the organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford ethyl 6-bromo-1-[2-(dimethylamino)ethyl]-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate 300 mg, (49%).