Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([OH:10])[CH3:9].[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17](Cl)(=[O:19])=[O:18]>ClCCl>[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17]([C:8](=[O:10])[CH3:9])(=[O:19])=[O:18]
Reactant: O=S(=O)(Cl)c1ccccn1
Reactant: CCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)S(=O)(=O)c1ccccn1
Temperature: 0 °C
Reaction time: 4 h
Yield: 95 %

Procedure:
To a solution of triethylamine (0.86 g, 8.51 mmol, 2.2 equiv.) in dichloromethane (3 mL) at 0° C. was added ethanol (0.18 g, 3.87 mmol, 1 equiv.) followed by the addition of 2-pyridylsulfonyl chloride (0.83 g, 4.65 mmol, 1.2 equiv.). After stirring for 4 hours at 0° C., the solution was concentrated under reduced pressure. The concentrate was dissolved in aqueous NaHCO3 solution (50 mL) and extracted with diethyl ether (3×50 mL). The ether extracts were combined and washed with aqueous NaCl (50 mL), dried (MgSO4), and concentrated under reduced pressure. Column chromatography (5% EtOAc/Hex) afforded 16 (95%): 1H NMR (CDCl3, 400 MHz) δ 8.70 (d, J=4.7 Hz, 1H, ArH), 7.95 (p, J=6.4 Hz, 2H, ArH), 7.56 (t, J=5.3 Hz, 1H, ArH), 4.37 (q, J=7.0 Hz, 2H, CH2OSO2R), 1.29 (t, J=7.0 Hz, 3H); MALDI-FTMS 188.0000 (C6H9NOS+H30 requires 188.0376).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH2:12](O)[CH3:13].S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[N:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([O:6][CH2:12][CH3:13])=[O:5]
Reactant: CCO
Reactant: O=C(O)c1cc(Cl)cnc1Cl
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc(Cl)cnc1Cl
Temperature: 130 °C

Procedure:
To a solution of 2,5-dichloronicotinic acid (30 g, 0.16 mol) in toluene (100 ml) was added ethanol (50 ml) and cone, sulfuric acid (1 ml). The reaction mixture was heated at 130° C. for 3 days with stirring. Then the reaction mixture was cooled and poured into sat. sodium bicarbonate solution. The whole mixture was extracted with ethyl acetate. The organic phase was washed with brine, dried (sodium sulfate), and concentrated to afford 34 g (quant.) of title compound:
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].[N:11]1([CH2:17][CH2:18][CH2:19][NH:20][C:21]2[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=2)[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.N[C:29]1C=CC=CC=1>>[N:11]1([CH2:17][CH2:18][CH2:19][NH:20][C:21]2[CH:26]=[CH:25][C:24]([NH:27][CH:29]=[C:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[NH:1][C:2]3=[O:10])=[CH:23][CH:22]=2)[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1
Reactant: Nc1ccc(NCCCN2CCOCC2)cc1
Reactant: O=C1Cc2ccccc2N1
Reactant: Nc1ccccc1
Product: O=C1Nc2ccccc2C1=CNc1ccc(NCCCN2CCOCC2)cc1

Procedure:
Example 298–301 are prepared by substituting the appropriate 6′-fluoro or 5′-chloro or 5′-fluoro or 4′-fluoro substituted 1,3-dihydro-indol-2-one for the 1,3-dihydro-indol-2-one and N-(3-morpholin-4-yl-propyl)-benzene-1,4-diamine (used in the preparation of Example 297) for aniline in the reaction of Example 1.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][N+:7]([O-])=[CH:6][CH:5]=1)(=O)[CH3:2].[CH:11]1([C:17]([NH:19][NH2:20])=[O:18])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.C([OH:23])C>>[N:7]1[CH:8]=[CH:9][C:4]([C:1](=[N:20][NH+:19]([O-:23])[C:17]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[O:18])[CH3:2])=[CH:5][CH:6]=1
Reactant: CCO
Reactant: CC(=O)c1cc[n+]([O-])cc1
Reactant: NNC(=O)C1CCCCC1
Product: CC(=N[NH+]([O-])C(=O)C1CCCCC1)c1ccncc1
Yield: 79 %

Procedure:
A mixture of 5.48 gm (0.04 mole) of 4-acetylpyridine 1-oxide, 5.68 gm (0.04 mole) of cyclohexanecarboxylic acid hydrazide and 100 ml of absolute ethanol is refluxed 4 hours. The reaction mixture is concentrated in vacuo to dryness to give a solid. The solid is crystallized from isopropanol to furnish 8.20 gm (79%) of the title compound; mp 245.3°.
Reaction SMILES: [C:1]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([OH:15])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:16]([NH:23][CH2:24][CH2:25][CH2:26]Br)([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].[I-].[K+]>CN(C=O)C>[C:19]([O:18][C:16]([NH:23][CH2:24][CH2:25][CH2:26][O:15][C:7]1[CH:6]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:14]=[CH:13][C:8]=1[C:9]([O:11][CH3:12])=[O:10])=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)NCCCBr
Reactant: COC(=O)c1ccc(C(C)(C)C)cc1O
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C(C)(C)C)cc1OCCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 45.1 %

Procedure:
Methyl 4-tert-butyl-2-hydroxybenzoate (2.41 g, 11.6 mmol) was dissolved in DMF (15 mL) and K2 CO3 (2.39 g, 17.4 mmol) and N-Boc-3-bromopropylamine (4.14 g, 17.4 mmol) was added using DMF (10 mL) to aid the transfer. Potassium iodide (0.30 g) was added, and the reaction stirred at room temperature under nitrogen for 18 hr. The DMF was removed in vacuo and the residue taken up in ethyl acetate and washed with water and brine, dried, and the solvent removed in vacuo to give a viscous brown oil. Purification by chromaotgraphy over silica on a preparative scale apparatus, eluting with a gradient of hexane to hexane:ethyl acetate (70:30) gave 1.91 g (45.2%) of a viscous yellow oil.
Reaction SMILES: B(Br)(Br)[Br:2].[Cl:5][C:6]12O[CH:11]1[CH2:10][CH2:9][C:8]([Cl:14])([F:13])[CH2:7]2.[OH2:15]>ClCCl>[Br:2][C:6]1([Cl:5])[CH2:11][CH2:10][CH2:9][C:8]([Cl:14])([F:13])[CH:7]1[OH:15]
Reactant: FC1(Cl)CCC2OC2(Cl)C1
Reactant: BrB(Br)Br
Reactant: O
Solvent: ClCCl
Product: OC1C(F)(Cl)CCCC1(Cl)Br

Procedure:
2.91 cm3 (2.91 mmol) of BBr3 in molar solution in dichloromethane were introduced at 4° C. under argon atmosphere into 0.98 (5.3 mmol) of epoxide 2e in solution in 6.5 cm3 dichloromethane. The reaction mixture was then allowed to return to room temperature and stirring was continued (1 h 30 min). 5 cm3 of distilled water were then added and the mixture was extracted with dichloromethane (4×10 cm3). The extract was dried over MgSO4, filtered and evaporated down. The crude product was purified by flash chromatography on silica (eluent ether/petroleum ether=5/95): 1.03 g of alcohol 1i were obtained (macrobore GC purity>97%); the yield of product 1i was 73%.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[CH:16]=[CH:17][NH:18]3)[CH2:10][CH2:9]1)(OC(C)(C)C)=O.[C:23]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:28]=[CH:27][C:26]([S:29]([Cl:32])(=[O:31])=[O:30])=[CH:25][CH:24]=1>>[ClH:32].[C:23]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:28]=[CH:27][C:26]([S:29]([N:18]2[C:19]3[C:15](=[C:14]([N:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)[CH:22]=[CH:21][CH:20]=3)[CH:16]=[CH:17]2)(=[O:31])=[O:30])=[CH:25][CH:24]=1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc3[nH]ccc23)CC1
Product: Cl
Product: O=S(=O)(c1ccc(-c2ccccc2)cc1)n1ccc2c(N3CCNCC3)cccc21

Procedure:
The title compound was prepared from 4-(4-boc-piperazinyl)-indole and 1,1′-biphenyl-4-ylsulfonyl chloride according to Method 3: 1H NMR (270 MHz, DMSO-d6) δ 9.26 (br, 1H), 8.04 (m, 2H), 7.88 (m, 3H), 7.67 (m, 3H), 7.46 (m, 3H), 7.27 (t, J=8 Hz, 1H), 6.96 (d, J=5 Hz, 1H), 6.80 (d, J=8 Hz, H), 3.25 (m 8H); MS (ESI+) for m/z 418 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]([S:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=3)=[CH:11][C:12]=2[C:13]#[N:14])=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].[CH2:30]([O:32][CH2:33]Cl)[CH3:31]>O1CCCC1.O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]([CH2:33][O:32][CH2:30][CH3:31])[C:10]([S:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=3)=[CH:11][C:12]=2[C:13]#[N:14])=[CH:6][CH:7]=1
Reactant: CCOCCl
Reactant: N#Cc1cc(Sc2ccc(Cl)c(Cl)c2)[nH]c1-c1ccc(Cl)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CCOCn1c(Sc2ccc(Cl)c(Cl)c2)cc(C#N)c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.5 %

Procedure:
A mixture of 2-(p-chlorophenyl)-5-[(3,4-dichlorophenyl)thio]pyrrole-3-carbonitrile (820 mg, 2.16 mmol) and potassium tert-butoxide (266 mg, 2.37 mmol) in tetrahydrofuran is stirred at room temperature for 30 minutes, treated with chloromethyl ethyl ether (225 mg, 2.37 mmol), stirred at room temperature for 4 hours, and diluted with water and ethyl acetate. The phases are separated and the aqueous phase is extracted with ethyl acetate. The organic phase and extracts are combined, washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo to obtain a syrup. The syrup is crystallized from an ethyl acetate/hexanes solution to give the title product as a solid (780 mg, mp 95°-97° C.).
Reaction SMILES: I[CH2:2][C@@H:3]([CH3:18])[CH2:4][N:5]1[C:10]2[CH:11]=[C:12]([O:15][CH3:16])[CH:13]=[CH:14][C:9]=2[O:8][CH2:7][C:6]1=[O:17].[CH2:19]([CH:23]1[CH2:29][CH:28]2[NH:30][CH:25]([CH2:26][CH2:27]2)[CH2:24]1)[CH2:20][CH2:21][CH3:22]>CCCCCCC.CCOC(C)=O>[CH2:19]([CH:23]1[CH2:24][CH:25]2[N:30]([CH2:2][C@@H:3]([CH3:18])[CH2:4][N:5]3[C:10]4[CH:11]=[C:12]([O:15][CH3:16])[CH:13]=[CH:14][C:9]=4[O:8][CH2:7][C:6]3=[O:17])[CH:28]([CH2:27][CH2:26]2)[CH2:29]1)[CH2:20][CH2:21][CH3:22]
Reactant: CCCCC1CC2CCC(C1)N2
Reactant: COc1ccc2c(c1)N(C[C@H](C)CI)C(=O)CO2
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CCCCC1CC2CCC(C1)N2C[C@@H](C)CN1C(=O)COc2ccc(OC)cc21
Yield: 67.8 %

Procedure:
The compound (S)-4-(3-Iodo-2-methylpropyl)-6-methoxy-4H-benzo[1,4]oxazin-3-one (111MF36) (0.239 g, 0.66 mmol) and 3-Butyl-8-aza-bicyclo[3.2.1]octane (0.100 g, 0.60 mmol) were mixed according to GP16. CC (SiO2; Heptane/EtOAc 4:1-4) gave the title compound (111MF40) (0.163 g, 61%). 1H NMR (CDCl3) δ 6.88 (d, J=8.8 Hz, 1H), 6.85 (d, J=2.8 Hz, 1H), 6.49 (dd, J=8.8 Hz, J=2.8 Hz, 1H), 4.61-4.47 (m, 2H), 4.01-3.99 (m, 2H), 3.77 (s, 3H), 3.17-3.04 (m, 2H), 2.35-2.29 (m, 1H), 2.14-1.79 (m, 3H), 1.57-1.13 (m, 6H), 0.88 (m, 3H); 13C NMR (CDCl3) δ 165.4, 155.6, 139.8, 129.8, 117.1, 107.0, 103.8, 68.0, 61.6, 60.2, 58.1, 56.0, 45.4, 38.5, 38.4, 36.9, 31.6, 29.4, 28.2, 27.3, 26.5, 23.9, 14.3; HPLC-MS (ammonium acetate) [M+H]+=401.3.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][C:3]=1[CH:12]=[O:13].C1N2[CH2:20][CH2:21]N(CC2)C1>C(OCC)C>[CH3:11][O:10][C:8]([C:6]1[CH:5]=[CH:4][C:3]([CH:12]([OH:13])[C:6]([C:8]([O:10][CH2:20][CH3:21])=[O:9])=[CH2:5])=[C:2]([Cl:1])[N:7]=1)=[O:9]
Reactant: COC(=O)c1ccc(C=O)c(Cl)n1
Reactant: C1CN2CCN1CC2
Solvent: CCOCC
Product: C=C(C(=O)OCC)C(O)c1ccc(C(=O)OC)nc1Cl

Procedure:
To a mixture of Methyl 6-chloro-5-formyl-2-pyridincarboxylate (10 mmol, 1.99 g) and DABCO (10 mmol. 1.12 g) was added an methyl/ethyl acrylate (60 mmol.) under neat conditions [solvent free conditions] at room temperature and the reaction progress was monitored by TLC. Upon completion of the reaction mixture (˜5 min.) was diluted with diethyl ether (300 ml) and washed with water 3×50 ml. The organic layer was dried over Na2SO4 and concentrated, the residue was subjected to column chromatography over silica gel, eluting with ethyl acetate and hexane (2:8, v/v) to give the desired product in almost quantitative (2.98 g.).
Reaction SMILES: Cl[C:2]1[C:7]([S:8](Cl)(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:12][O:13][C:14]1[CH:19]=[C:18]([NH2:20])[CH:17]=[C:16]([O:21][CH3:22])[N:15]=1.N.[C:24](N1C=CN=C1)([N:26]1C=CN=C1)=[O:25]>N1C=CC=CC=1.ClCCCl>[CH3:22][O:21][C:16]1[CH:17]=[C:18]([N:20]2[C:24](=[O:25])[NH:26][C:2]3[N:3]=[CH:4][CH:5]=[CH:6][C:7]=3[S:8]2(=[O:10])=[O:9])[CH:19]=[C:14]([O:13][CH3:12])[N:15]=1
Reactant: COc1cc(N)cc(OC)n1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=S(=O)(Cl)c1cccnc1Cl
Agent: N
Solvent: ClCCCl
Solvent: c1ccncc1
Product: COc1cc(N2C(=O)Nc3ncccc3S2(=O)=O)cc(OC)n1
Yield: 20.2 %

Procedure:
The title compound (2.6 g, 7.73 mmol) was prepared in three steps from 2-chloropyridine-3-sulfonyl chloride (8.24 g, 38.9 mmol) and 2,6-dimethoxypyridin-4-amine (6.0 g, 38.9 mmol) in pyridine (25 mL) at rt; followed by ammonia in an autoclave at 100° C. for 16 h; followed by 1,1′-carbonyldiimidazole (6.2 g, 38.2 mmol) in 1,2-dichloroethane (100 mL) at 90° C. for 16 h using the methods of (IntF1), steps 1 and 2, and (IntA14), step 3.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][C:9](=[O:12])[CH2:10]Br)=[C:6]([Cl:13])[CH:5]=[C:4]([CH3:14])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[OH:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>C(#N)C>[Cl:1][C:2]1[C:7]([NH:8][C:9](=[O:12])[CH2:10][N:27]2[CH2:28][CH2:29][N:24]([CH2:23][CH2:22][OH:21])[CH2:25][CH2:26]2)=[C:6]([Cl:13])[CH:5]=[C:4]([CH3:14])[N:3]=1
Reactant: OCCN1CCNCC1
Reactant: Cc1cc(Cl)c(NC(=O)CBr)c(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1cc(Cl)c(NC(=O)CN2CCN(CCO)CC2)c(Cl)n1
Temperature: 5 °C
Yield: 90.2 %

Procedure:
N-(2,4-Dichloro-6-methylpyridin-3-yl)-2-bromoacetamide (70.0 g, 234.9 mmol) was dissolved in acetonitrile (105 mL), and potassium carbonate (39.0 g, 282.2 mmol) was added to the solution under stirring and under cooling with ice. While the inner temperature was maintained at 5° C. or lower, a solution of 1-(2-hydroxyethyl)piperazine (36.7 g, 281.9 mmol) in acetonitrile (140 mL) was added dropwise to the resultant mixture. Thereafter, the temperature of the mixture was elevated to room temperature, and the mixture was stirred for 4 hours. The reaction mixture was extracted with chloroform-water, and the aqueous layer was further extracted twice with chloroform. The combined organic layer was washed with saturated brine and dried over sodium sulfate anhydrate, followed by condensation under reduced pressure. The residue was recrystallized from isopropanol and diisopropyl ether, to thereby yield 73.57 g of N-(2,4-dichloro-6-methylpyridin-3-yl)-2-[4-(2-hydroxyethyl)piperazin-1-yl]acetamide (yield: 90%) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1([CH2:13][CH:14]([C:17]([F:20])([F:19])[F:18])[CH:15]=O)[CH2:12][CH2:11][CH2:10]1.[NH2:21][C:22]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:23]=1[CH:24]=[CH:25][C:26]([CH3:32])=[N:27]2.[BH4-].[Na+].CCCCCC.C(OCC)(=[O:43])C>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1([CH2:13][C:14]([C:17]([F:20])([F:19])[F:18])([OH:43])[CH2:15][NH:21][C:22]2[CH:31]=[CH:30][CH:29]=[C:28]3[C:23]=2[CH:24]=[CH:25][C:26]([CH3:32])=[N:27]3)[CH2:12][CH2:11][CH2:10]1
Reactant: Cc1ccc2c(N)cccc2n1
Reactant: CCOC(C)=O
Reactant: O=CC(CC1(c2cc(F)ccc2Cl)CCC1)C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CCCCCC
Product: Cc1ccc2c(NCC(O)(CC3(c4cc(F)ccc4Cl)CCC3)C(F)(F)F)cccc2n1

Procedure:
Analogously to Example 79, 200 mg (0.64 mmol) of 3-[1-(2-chloro-5-fluorophenyl)cyclobut-1-yl]-2-(trifluoromethyl)-propanal and 126 mg (0.80 mmol) of 5-amino-2-methylquinoline are reacted, and the isolated crude product is reduced with 102 mg (2.70 mmol) of NaBH4. After chromatography on silica gel with hexane-ethyl acetate, 165 mg of product is obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[F:8][C:9]1[C:14]([CH:15]=[O:16])=[CH:13][CH:12]=[CH:11][C:10]=1B(O)O.C([O-])([O-])=O.[K+].[K+]>CC#N.O>[F:8][C:9]1[C:10]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:11][CH:12]=[CH:13][C:14]=1[CH:15]=[O:16]
Reactant: Brc1ccccn1
Reactant: O=Cc1cccc(B(O)O)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: O=Cc1cccc(-c2ccccn2)c1F
Temperature: 80 °C

Procedure:
A mixture of commercially available 2-bromopyridine (200 mg; 1.26 mmol), (2-fluoro-3-formylphenyl)boronic acid (212 mg; 1.26 mmol), K2CO3 (699 mg; 5.06 mmol), and PdCl2(dbpf) (11 mg; 0.017 mmol) in MeCN (5 ml) and water (5 ml) was heated to 80° C., under nitrogen, for 2 h. After cooling to rt, MeCN was removed under reduced pressure, and the aq. layer was extracted with AcOEt (2×). The mixed organic layers were washed with brine, dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (toluene/AcOEt=8/2) afforded 2-fluoro-3-(pyridin-2-yl)benzaldehyde as a yellow solid. LC-MS (conditions C): tR=0.78 min.; [M+H]+: 202.20 g/mol.
Reaction SMILES: [CH:1]1[CH2:2][CH:3]([CH:6]([CH2:10][CH3:11])CC=O)[CH2:4][CH:5]=1.C1CCC([CH:17](CC)[CH2:18][CH:19]=[O:20])C=1.[CH2:23]([Mg]Br)C.S(=O)(=O)(O)O>O1CCCC1.O>[OH:20][CH:19]([CH2:18][CH3:17])[CH2:23][CH2:11][CH2:10][CH2:6][CH:3]1[CH2:2][CH2:1][CH:5]=[CH:4]1
Reactant: CCC(CC=O)C1C=CCC1
Reactant: CCC(CC=O)C1CC=CC1
Reactant: CC[Mg]Br
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Solvent: O
Product: CCC(O)CCCCC1C=CCC1
Temperature: -30 °C

Procedure:
All work is performed in an inert atmosphere using anhydrous tetrahydrofuran. The starting material, 3-(5-cyclopenten-3-yl) valeraldehyde {2-cyclopentene-1-pentanal} (75 g, 0.493 moles) is dissolved in tetrahydrofuran (750 ml) and cooled in a -30° C. ethanol/dry ice bath. Ethyl magnesium bromide (0.493 moles) is added dropwise to the stirring reaction mixture for a period of over 2 hours. The reaction is warmed to 0° C. and water (100 ml), followed by 15% sulfuric acid (200 ml), is added. The aqueous layer is extracted with ether (2×300 ml) and the organic extracts are combined, reduced in volume and washed with brine (400 ml). The product is dried over anhydrous sodium sulfate and the remaining solvent removed under vacuum leaving a clear yellow oil. The crude product is chromatographed on silica gel and subsequently kugelrohred under vacuum leaving clear, colorless oil (10.2 g, 0.056 moles).
Reaction SMILES: [O:1]=[C:2]1[C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][N:3]1[CH2:20][C:21](O)=[O:22].[F:24][C:25]1[CH:26]=[C:27]([CH:35]=[CH:36][C:37]=1[F:38])[O:28][CH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.C(N=C=NCCCN(C)C)C.CCOCC>CN(C)C1C=CN=CC=1.C(Cl)Cl>[F:24][C:25]1[CH:26]=[C:27]([CH:35]=[CH:36][C:37]=1[F:38])[O:28][CH:29]1[CH2:34][CH2:33][N:32]([C:21](=[O:22])[CH2:20][N:3]2[CH2:4][CH2:5][CH2:6][C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:2]2=[O:1])[CH2:31][CH2:30]1
Reactant: O=C(O)CN1CCCC(c2ccccc2)(c2ccccc2)C1=O
Reactant: Fc1ccc(OC2CCNCC2)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CCOCC
Solvent: ClCCl
Product: O=C(CN1CCCC(c2ccccc2)(c2ccccc2)C1=O)N1CCC(Oc2ccc(F)c(F)c2)CC1
Reaction time: 18 h

Procedure:
To a mixture of the product of Example 68E (225 mg, 0.73 mmol), 4-(3,4-difluorophenoxy)piperidine (155 mg, 0.73 mmol), and 4-(dimethylamino)pyridine (8.9 mg, 0.07 mmol) in CH2Cl2 (3 mL) at ambient temperature was added N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine (0.129 mL, 0.727 mmol) via syringe. The reaction was stirred for 18 hours, then diluted with 50 mL CH2Cl2 and washed with 1 N aqueous HCl, saturated aqueous NaHCO3 solution and brine, dried with Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by chromatography on silica gel (Analogix® Intelliflash™ 280; SF15-24 g column; 50% ethyl acetate/hexanes). Hexanes (20 mL) were added and the flask was placed in an ultrasonic bath for 10 minutes resulting in a milky mixture. Ether (6 mL) was added to help precipitate the solid, which was collected by vacuum filtration and air-dried to give the titled compound. 1H NMR (300 MHz, CDCl3) δ ppm 7.39-7.15 (m, 10H), 7.06 (dd, J=19.1, 9.1, 1H), 6.72 (ddd, J=11.9, 6.6, 3.0, 1H), 6.64-6.55 (m, 1H), 4.49-4.32 (m, 2H), 4.11 (d, J=15.6, 1H), 3.80-3.33 (m, 6H), 2.73-2.56 (m, 2H), 2.01-1.72 (m, 6H); MS (ESI+) m/z 505 (M+H)+.
Reaction SMILES: [S:1](=[O:5])(=[O:4])([OH:3])[OH:2].[NH2:6][CH2:7][C:8]([O-:10])=[O:9].[Na+:11]>>[NH2:6][CH2:7][C:8]([OH:10])=[O:9].[S:1]([O-:5])([O-:4])(=[O:3])=[O:2].[Na+:11].[Na+:11]
Reactant: NCC(=O)[O-]
Reactant: O=S(=O)(O)O
Agent: [Na+]
Product: NCC(=O)O
Product: O=S(=O)([O-])[O-]

Procedure:
An aqueous ammoniacal solution of glycinonitrile containing 2804 g (50 moles) of glycinonitrile is fed into an aqueous sodium hydroxide solution (20% sodium hydroxide) containing 2,040 g (51 moles) of sodium hydroxide at 50°-60° C. The resulting mixture is then boiled until free of ammonia. The resulting ammonia free sodium glycinate solution is cooled to 80° C, bleached with hydrogen peroxide (5 ml of 36% H2O2), treated with charcoal and filtered to remove color bodies, cooled to room temperature (ca. 25° C), and diluted to 12.13 Kg with water. The resulting aqueous solution consists essentially of 40% sodium glycinate and 0.3% sodium hydroxide. Said solution is substantially free of disodium iminodiacetate and it contains only trace quantities of color bodies and other undesired side products. A starting aqueous solution having a pH of 6 and consisting essentially of water, sodium sulfate and glycine is formed by adding 93% sulfuric acid (2,662 g) to the aforesaid 12.13 Kg of sodium glycinate solution. Said starting aqueous solution is designated "Starting Solution 1."
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C([O:9][C:10](=O)[C:11]([CH2:24][O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:17]1[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][CH:18]=1)[C:12](OCC)=[O:13])C>C(OCC)C>[CH2:26]([O:25][CH2:24][C:11]([C:17]1[CH:18]=[CH:19][C:20]([Br:23])=[CH:21][CH:22]=1)([CH2:10][OH:9])[CH2:12][OH:13])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CCOC(=O)C(COCc1ccccc1)(C(=O)OCC)c1ccc(Br)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: OCC(CO)(COCc1ccccc1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 22 h
Yield: 35.7 %

Procedure:
To a 0° C. suspension of LAH (444 mg, 11.1 mmol) in diethyl ether (10 mL) was added a solution of 2-Benzyloxymethyl-2-(4-bromo-phenyl)-malonic acid diethyl ester (1.67 g, 3.84 mmol) in diethyl ether (10 mL) dropwise via addition funnel. The reaction mixture was warmed to room temperature and stirred for 22 hours. The reaction was quenched with water (1.5 mL), 15% NaOH (1.5 mL), and water (3 mL) added sequentially. The white slurry was stirred for 30 minutes, diluted with ethyl acetate and filtered to remove the aluminum salts. The filtrate was concentrated in vacuo to afford a green semisolid, which was purified by flash chromatography (40 g silica, 30-82% ethyl acetate/heptane, 10 column volumes). Product fractions were combined and concentrated in vacuo to afford the title compound as a colorless oil (482 mg, 36% yield). 1H NMR (500 MHz, CD3OD) δ ppm 7.45 (d, J=8.54 Hz, 2H), 7.35 (d, J=8.78 Hz, 2H), 7.22-7.33 (m, 5H), 4.51 (s, 2H), 3.92 (s, 4H), 3.82 (s, 2H).
Reaction SMILES: [Cl-:1].[Al+3].[Cl-].[Cl-].[C:5]([N:8]1[CH2:16][CH2:15][CH:11]([C:12](Cl)=[O:13])[CH2:10][CH2:9]1)(=[O:7])[CH3:6].[CH2:17]([Cl:19])Cl>C1C(Cl)=CC=C(Cl)C=1>[Cl:1][C:9]1[CH:10]=[C:11]([C:12]([CH:11]2[CH2:15][CH2:16][N:8]([C:5](=[O:7])[CH3:6])[CH2:9][CH2:10]2)=[O:13])[CH:15]=[CH:16][C:17]=1[Cl:19]
Reactant: CC(=O)N1CCC(C(=O)Cl)CC1
Reactant: [Cl-]
Reactant: ClCCl
Agent: [Al+3]
Solvent: Clc1ccc(Cl)cc1
Product: CC(=O)N1CCC(C(=O)c2ccc(Cl)c(Cl)c2)CC1
Reaction time: 48 h
Yield: 36.5 %

Procedure:
To a slurry of 53.2 g (0.4 mol) of aluminum chloride in 80 mL of diclorobenzene was added portionwise 38.0 g (0.2 mol) of N-acetylisonipecotic acid chloride (by closed addition method) so as to maintain at 5°-10°. During the addition a total of 50 mL of methylene chloride was added as needed. After the addition was complete the mixture was allowed to come to room temperature and stirred for two days. The mixture was poured onto an excess of crushed ice. The aqueous mixture was extracted several times with chloroform. The collected extracts were dried over anhydrous sodium sulfate and the mixture was filtered. The filtrate was concentrated under reduced pressure and the residue was triturated in isopropyl ether. The residue crystallized and 22 g (36.5%) of crude product was obtained. A 5-g sample was recrystallized from acetone-water after treatment with charcoal. After air-drying the off-white solid was recrystallized from isopropyl ether-methanol, mp 134°-136°.