Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:33]=[CH:34][CH:35]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([NH:15][C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][C:24]=4[O:26][C@H:27]([CH3:32])[C:28](OC)=[O:29])[N:19]=[CH:18][N:17]=3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[NH:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1>>[F:1][C:2]1[CH:3]=[C:4]([CH:33]=[CH:34][CH:35]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([NH:15][C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][C:24]=4[O:26][C@H:27]([CH3:32])[C:28](=[O:29])[N:36]4[CH2:40][CH2:39][CH2:38][CH2:37]4)[N:19]=[CH:18][N:17]=3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: C1CCNC1
Reactant: COC(=O)[C@@H](C)Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4cccc(F)c4)c3)c12
Product: C[C@@H](Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4cccc(F)c4)c3)c12)C(=O)N1CCCC1
Yield: 77.6 %

Procedure:
Using the same procedure as in Example 26, methyl (2R)-2-[(4-{[1-(3-fluorobenzyl)-1H-indazol-5-yl]amino}quinazolin-5-yl)oxy]propanoate (250 mg, 0.53 mmol) was reacted with pyrrolidine (0.44 ml, 5.3 mmol) to give the title compound as a white solid (210 mg, 77%), except that the mixture was heated at 55° C. for 20 hours and purified by chromatography on silica gel (eluant: 3% methanol in DCM); NMR Spectrum 1.60 (d, 3H), 1.82 (m, 2H), 1.94 (m, 2H), 3.5-3.3 (m, 3H), 3.76 (m, 1H), 5.62 (q, 1H), 5.70 (s, 2H), 7.07 (m, 3H), 7.27 (d, 1H), 7.36 (m, 2H), 7.74 (m, 2H), 7.85 (m, 1H), 8.16 (s, 1H), 8.51 (s, 1H), 8.56 (s, 1H), 11.08 (br s, 1H); Mass spectrum 511.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:12])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].N1C=CC=CC=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=1[S:27](Cl)(=[O:29])=[O:28]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[F:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=1[S:27]([NH:1][C:2]1[C:3]([F:12])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])(=[O:29])=[O:28]
Reactant: COC(=O)c1cccc(N)c1F
Reactant: O=S(=O)(Cl)c1cc(F)ccc1F
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1cccc(NS(=O)(=O)c2cc(F)ccc2F)c1F
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 3-amino-2-fluorobenzoate (21.8 g, 129 mmol) in DCM (300 mL) were added pyridine (30.6 g, 387.6 mmol) and a catalytic amount of DMAP. The mixture was cooled to 0° C. 2,5-Difluorobenzene-1-sulfonyl chloride (28.8 g, 136 mmol) in DCM (20 mL) was added dropwise to the mixture. The reaction was stirred at rt overnight. The reaction mixture was washed with water (300 mL), and extracted with DCM (2×200 mL). The organic layer was washed with brine, dried over anhydrous NaSO4, filtered and concentrated under reduced pressure to give the crude product, which was washed with petroleum ether to afford the title compound of Step A. (16 g, 35.9%). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.71-10.91 (br, 1H), 7.65-7.73 (m, 1H), 7.48-7.62 (m, 4H), 7.20-7.28 (m, 1H), 3.77 (s, 3H).
Reaction SMILES: [O:1]=[C:2]1[C:10]2([C:22]3[C:13](=[CH:14][C:15]4[O:20][CH2:19][CH2:18][O:17][C:16]=4[CH:21]=3)[O:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:23][C:24]1[O:28][C:27]([C:29]([O:31]C)=[O:30])=[CH:26][CH:25]=1.[OH-].[Li+].Cl>O1CCCC1.O>[O:1]=[C:2]1[C:10]2([C:22]3[C:13](=[CH:14][C:15]4[O:20][CH2:19][CH2:18][O:17][C:16]=4[CH:21]=3)[O:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:23][C:24]1[O:28][C:27]([C:29]([OH:31])=[O:30])=[CH:26][CH:25]=1
Reactant: COC(=O)c1ccc(CN2C(=O)C3(COc4cc5c(cc43)OCCO5)c3ccccc32)o1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(CN2C(=O)C3(COc4cc5c(cc43)OCCO5)c3ccccc32)o1
Temperature: 60 °C
Reaction time: 2 h
Yield: 102.3 %

Procedure:
A mixture of methyl 5-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]furan-2-carboxylate (1.38 g, 3.17 mmol) and lithium hydroxide (0.76 g, 31.7 mmol) in tetrahydrofuran (10 mL) and water (10 mL) was stirred at 60° C. for 2 h. The reaction mixture was acidified with 1 M hydrochloric acid (50 mL) and extracted with dichloromethane (3×30 mL). The combined organic solution was washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to afford 5-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]furan-2-carboxylic acid (1.36 g, quantitative) as a colorless solid: mp 192-195° C. (diethyl ether); 1H NMR (300 MHz, CDCl3) δ8.40 (br s, 1H), 7.27 (dd, J=7.8, 7.8 Hz, 1H), 7.25 (d, J=3.3 Hz, 1H), 7.18 (d, J=7.5 Hz, 1H), 7.06 (dd, J=7.5, 7.5 Hz, 1H), 6.94 (d, J=7.8 Hz, 1H), 6.50 (s, 1H), 6.45 (d, J=3.3 Hz, 1H), 6.31 (s, 1H), 5.19 (d, J=16.5 Hz, 1H), 4.92 (d, J=9.3 Hz, 1H), 4.87 (d, J=16.5 Hz, 1H), 4.66 (d, J=9.3 Hz, 1H), 4.21-4.07 (m, 4H); 13C NMR (75 MHz, CDCl3) δ177.4, 162.8, 155.2, 154.4, 144.8, 143.7, 141.3, 138.6, 132.3, 129.1, 124.2, 124.0, 121.1, 120.9, 111.8, 110.7, 109.0, 99.5, 80.0, 64.7, 64.0, 58.2, 37.5; MS (ES+) m/z 419.9 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.C([Li])CCC.[Br:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[CH3:36])[CH2:23][C:24](N(OC)C)=[O:25])=[CH:18][CH:17]=1>>[Br:15][C:16]1[CH:17]=[CH:18][C:19]([CH:22]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[CH3:36])[CH2:23][C:24]([C:2]2[CH:7]=[N:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=2)=[O:25])=[CH:20][CH:21]=1
Reactant: COc1ccc(Br)cn1
Reactant: CON(C)C(=O)CC(c1ccc(Br)cc1)c1ccccc1C
Agent: [Li]CCCC
Product: COc1ccc(C(=O)CC(c2ccc(Br)cc2)c2ccccc2C)cn1

Procedure:
In analogy to example 151, step 1, 5-bromo-2-methoxypyridine was reacted first with n-butyllithium and later with 3-(4-bromo-phenyl)-N-methoxy-N-methyl-3-o-tolyl-propionamide (example 74, step 4) to give the title compound as a colorless oil, MS (ESI+): m/z=410.2 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[S:10][C:11]2[C:12]([Cl:18])=[N:13][CH:14]=[CH:15][C:16]=2[N:17]=1.[Cu][C:20]#[N:21].O>CN1C(=O)CCC1>[Cl:8][C:4]1[C:3]([C:9]2[S:10][C:11]3[C:12]([Cl:18])=[N:13][CH:14]=[CH:15][C:16]=3[N:17]=2)=[C:2]([CH:7]=[CH:6][CH:5]=1)[C:20]#[N:21]
Reactant: Clc1cccc(Br)c1-c1nc2ccnc(Cl)c2s1
Reactant: N#C[Cu]
Solvent: CN1CCCC1=O
Solvent: O
Product: N#Cc1cccc(Cl)c1-c1nc2ccnc(Cl)c2s1
Temperature: 150 °C
Yield: 28.9 %

Procedure:
A stirred mixture of 2-(2-bromo-6-chlorophenyl)-4-chlorothiazolo[5,4-c]pyridine (1.48 g, 4.11 mmol) and copper(I) cyanide (0.45 g, 5.0 mmol) in NMP (20 mL) was heated at 150° C. for 20 minutes. After cooling to room temperature, the mixture was poured into water (250 mL) and the insoluble material was collected by filtration. The solid was then suspended in EtOAc (300 mL) and, after vigorous stirring, was collected by filtration. The filtrate was concentrated under reduced pressure and the resultant residue was purified by column chromatography on silica gel eluting with 25-33% diethyl ether in pentane followed by 0-10% MeOH in DCM to afford the title compound as a pale yellow solid (0.364 g, 29% yield). LCMS (Method E): RT=3.59 min, m/z: 306 [M+H+].
Reaction SMILES: [C:1]([OH:12])(=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH2:13]([N:15]([CH2:18][CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)[CH2:16][CH3:17])[CH3:14]>>[C:1]([N:22]1[CH2:23][CH2:24][CH:19]([CH2:18][N:15]([CH2:16][CH3:17])[CH2:13][CH3:14])[CH2:20][CH2:21]1)(=[O:12])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCN(CC)CC1CCNCC1
Reactant: CCCCCCC/C=C/C(=O)O
Product: CCCCCCC/C=C/C(=O)N1CCC(CN(CC)CC)CC1

Procedure:
The same procedures as in Example 2 were carried out using (E)-2-decenoic acid and 4-(diethylaminomethyl)piperidine as starting raw materials, to produce an intended compound.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][N:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)=[CH:21][CH:20]=1)[C:13]([C:35]1[CH:40]=[CH:39][C:38]([O:41]CC3C=CC=CC=3)=[CH:37][CH:36]=1)=[C:12]2[CH3:49])C1C=CC=CC=1>O1CCCC1.C(O)C>[OH:41][C:38]1[CH:39]=[CH:40][C:35]([C:13]2[N:14]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][N:29]4[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]4)=[CH:21][CH:20]=3)[C:15]3[C:11]([C:12]=2[CH3:49])=[CH:10][C:9]([OH:8])=[CH:17][CH:16]=3)=[CH:36][CH:37]=1
Reactant: Cc1c(-c2ccc(OCc3ccccc3)cc2)n(Cc2ccc(OCCCN3CCCCC3)cc2)c2ccc(OCc3ccccc3)cc12
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1c(-c2ccc(O)cc2)n(Cc2ccc(OCCCN3CCCCC3)cc2)c2ccc(O)cc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 5-Benzyloxy-2-(4-benzyloxy-phenyl)-1-[4-(3-piperidin-1-yl-propoxy)-benzyl]-3methyl-1H-indole No. 165 (2.35 g) in tetrahydrofuran (25 mL) and ethanol (25 mL) was added to 2.3 g of 10% palladium on carbon Cyclohexadiene (10 mL) was added and the reaction allowed to stir at room temperature for 18 hours. The catalyst was filtered through celite and the reaction mixture was concentrated and chromatographed on silica gel using dichlomaethane/methanol (4:1) to elute the product (0.8 g) as a white foam: Mp=125-130° C., 1H NMR 9.68 (s, 1H), 8.70 (s, 1H), 7.15 (d, 2H, J=8.6 Hz), 7.05 (d, 1H, J=8.8 Hz), 6.85 (d, 2H, J=8.6 Hz), 6.80 (d, 1H, J=2.4 Hz), 6.74 (d, 4H, J=2.6 Hz), 6.57 (dd, 1H, J=8.6, 2.2 Hz), 5.09 (s, 2H), 3.88 (t, 2H, J=6.4 Hz), 3.60-3.15 (m, 2H), 2.62-2.38 (m, 4H), 2.09 (s, 3H), 1.92-1.78 (m, 2H), 1.55-1.43 (m, 4H), 1.42-1.30 (m, 2H); IR (KBr) 3400 (br), 2900, 1620, 1515 cm−1; MS eI m/z 470.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[Cl:22])[O:5][CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH:13]2[O:18][CH2:17][CH2:16][NH:15][CH2:14]2)[CH2:8][CH2:7]1.C(N(CC)CC)C.[F:30][C:31]1[CH:32]=[CH:33][C:34]2[N:35]([CH:37]=[C:38]([C:40](Cl)=[O:41])[N:39]=2)[CH:36]=1.C([O-])(O)=O.[Na+]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[Cl:22])[O:5][CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH:13]2[O:18][CH2:17][CH2:16][N:15]([C:40]([C:38]3[N:39]=[C:34]4[CH:33]=[CH:32][C:31]([F:30])=[CH:36][N:35]4[CH:37]=3)=[O:41])[CH2:14]2)[CH2:8][CH2:7]1
Reactant: Clc1ccc(OC2CCN(CC3CNCCO3)CC2)cc1Cl
Reactant: O=C(Cl)c1cn2cc(F)ccc2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1cn2cc(F)ccc2n1)N1CCOC(CN2CCC(Oc3ccc(Cl)c(Cl)c3)CC2)C1
Reaction time: 2 h
Yield: 8.2 %

Procedure:
The product of Example 2, Step (c) (0.2 g) was dissolved in dichloromethane (4 ml) and triethylamine (0.16 ml) added. The product of Step (c) (0.12 g) was then added and the reaction stirred for 2 hrs. Saturated aqueous NaHCO3 solution was added and the product was extracted with dichloromethane. The combined organic extracts were dried with MgSO4 and concentrated. Purification by reverse phase HPLC (with a gradient eluent system (25% MeCN/NH3(aq) (0.1%) to 95% MeCN/NH3(aq) (0.1%)) gave the title compound (0.024 g).
Reaction SMILES: [C:1]1(=O)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:12][CH:13]=[C:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C(C)=CC=CC=1>[C:1]1([NH:12][CH:13]=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: CCOC(=O)C(=CN)C(=O)OCC
Reactant: O=C1CCCCCCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1C
Product: CCOC(=O)C(=CNC1=CCCCCCCCC1)C(=O)OCC

Procedure:
A mixture of 25.0 g of cyclodecanone, 60.7 g of diethyl aminomethylenemalonate, 1.54 g of p-toluenesulfonic acid monohydrate in 500 ml xylene is refluxed 2 weeks under argon, collecting the distillate in a Dean-Stark trap. The solution is then decanted and solvent is removed. The residual oil is triturated twice with hexane and the combined hexane extract is concentrated to yield an oil which is flash chromatographed on 600 g of silica gel using 99:1 methylene chloride ethyl acetate as eluent. A forerun containing cyclodecanone is discarded and the fractions containing the product are combined and concentrated to dryness to give diethyl N-(1-cyclodecenyl)-aminomethylenemalonate as an oil.
Reaction SMILES: [C:1]([O:4][CH2:5][C@H:6]([N:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH:21]3[CH2:23][CH2:22]3)[C:14]=2[N+:18]([O-])=O)[C:9]1=[O:24])[CH3:7])(=[O:3])[CH3:2].C(O)C>[Pd]>[C:1]([O:4][CH2:5][C@H:6]([N:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH:21]3[CH2:22][CH2:23]3)[C:14]=2[NH2:18])[C:9]1=[O:24])[CH3:7])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@@H](C)n1ccc2c([N+](=O)[O-])c(C3CC3)ccc2c1=O
Agent: [Pd]
Solvent: CCO
Product: CC(=O)OC[C@@H](C)n1ccc2c(N)c(C3CC3)ccc2c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A round bottom flask was charged with (R)-2-(6-cyclopropyl-5-nitro-1-oxoisoquinolin-2(1H)-yl)propyl acetate (28 mg, 0.000085 mol), ethanol (10 mL, 0.2 mol) and palladium, 10% weight on charcoal (1.0 mg, 0.0000085 mol) was added and the flask was evacuated of any air and flushed with hydrogen two times and the reaction was stirred at room temperature under hydrogen (1 atm) for 2 hours. The reaction was filtered over celite and the solvent removed to obtain the product. MS m/z=301.2 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](F)=[C:6]([CH:19]=1)[C:7]([C:9](=[CH:15][N:16]([CH3:18])C)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:8].N[C@@H:22]1[CH2:27]C[CH2:25][N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:23]1.C(=O)([O-])[O-].[K+].[K+].Cl>C1COCC1.CN(C=O)C>[Br:1][C:2]1[CH:19]=[C:6]2[C:5](=[N:4][CH:3]=1)[N:16]([C@@H:18]1[CH2:27][CH2:22][CH2:23][N:24]([C:28]([O:30][C:31]([CH3:32])([CH3:34])[CH3:33])=[O:29])[CH2:25]1)[CH:15]=[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:7]2=[O:8]
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1cc(Br)cnc1F
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](N)C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn([C@@H]2CCCN(C(=O)OC(C)(C)C)C2)c2ncc(Br)cc2c1=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 75.5 %

Procedure:
Ethyl 2-(5-bromo-2-fluoronicotinoyl)-3-(dimethylamino)acrylate (Intermediate 3, 2.0 g, 5.79 mmol), (R)-tert-butyl 3-aminopiperidine-1-carboxylate (1.160 g, 5.79 mmol, CNH technologies), and potassium carbonate (2.042 g, 7.38 mmol, Aldrich) were combined in THF (10.0 mL). The reaction was heated at 60° C. for 2 hrs. After 2 h, DMF (5.0 mL) was added. The reaction was heated at 90° C. for 14 h. The reaction mixture was cooled to 0° C. and 1N HCl was slowly added until pH was around 4. The resulting precipitate was filtered, washed with water and dried overnight to yield a light yellow solid (2.10 g, 75%).
Reaction SMILES: [F:1][C:2]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[N+:14]([O-:16])=[O:15])[C:8](Cl)=[O:9].[CH3:22][NH2:23]>CCOCC.O>[CH3:22][NH:23][C:8](=[O:9])[C:7]1[CH:11]=[CH:12][C:13]([N+:14]([O-:16])=[O:15])=[C:5]([O:4][C:3]2[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:2]=2[F:1])[CH:6]=1
Reactant: CN
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])c(Oc2ccc(F)cc2F)c1
Solvent: CCOCC
Solvent: O
Product: CNC(=O)c1ccc([N+](=O)[O-])c(Oc2ccc(F)cc2F)c1
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
A solution of 3-(2,4-difluorophenoxy)-4-nitrobenzoyl chloride (1.1 g) in dry ether (15 ml) was added dropwise to a stirred mixture of methylamine (40% in water; 2 ml) in water (8 ml) and ether (5 ml) at 5° to 8° C. The mixture was stirred for 30 minutes at 5° C. and for 30 minutes at room temperature. Precipitates in the mixture were filtered and washed with water and ether successively to give pale brown crystals of N-methyl-3-(2,4-difluorophenoxy)-4-nitrobenzamide (0.88 g).
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[C:13]1([S:19]([CH2:22][CH2:23][S:24][C:25]2[N:33]=[CH:32][CH:31]=[CH:30][C:26]=2[C:27]([OH:29])=O)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH2:34]([NH2:38])[CH:35]([CH3:37])[CH3:36]>C(Cl)Cl.C(OCC)(=O)C>[CH2:34]([NH:38][C:27](=[O:29])[C:26]1[CH:30]=[CH:31][CH:32]=[N:33][C:25]=1[S:24][CH2:23][CH2:22][S:19]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)(=[O:20])=[O:21])[CH:35]([CH3:37])[CH3:36]
Reactant: CC(C)CN
Reactant: O=C(O)c1cccnc1SCCS(=O)(=O)c1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)CNC(=O)c1cccnc1SCCS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
171 mg (1.05 mmol) of CDI were added to a solution of 323 mg (1.00 mmol) of 2-(2-(phenylsulfonyl)ethylthio)nicotinic acid in DCM (16 ml), and the mixture was stirred for 1 hour at RT. 99 μl (1.00 mmol) of isobutylamine were then added, and stirring was continued for a further 5 days at RT. The reaction solution was then washed in each case twice with a 4 M aq. ammonium chloride solution and a 1 M aq. sodium hydrogen carbonate solution. The organic phase was dried over MgSO4, filtered and concentrated in vacuo. The residue obtained was taken up in ethyl acetate (30 ml) and washed with 0.4 M hydrochloric acid (5 ml). The organic phase was again dried over MgSO4, filtered and concentrated in vacuo. 160 mg (0.42 mmol, 42 of N-(isobutyl)-2-(2-(phenylsulfonyl)ethylthio)nicotinamide were obtained as residue. MS: m/z 379.1 [M+H]+
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[C:5]#[N:6])[CH3:2].[N+:10]([CH2:12][C:13]([O:15][CH3:16])=[O:14])#[C-:11].[NH4+].[Cl-].C(Cl)Cl>COCCOCCOC>[CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[C:5]1[N:6]=[CH:11][NH:10][C:12]=1[C:13]([O:15][CH3:16])=[O:14])[CH3:2]
Reactant: CCOC(C#N)OCC
Reactant: [C-]#[N+]CC(=O)OC
Agent: [Cl-]
Agent: [NH4+]
Solvent: COCCOCCOC
Solvent: ClCCl
Product: CCOC(OCC)c1nc[nH]c1C(=O)OC
Temperature: 75 °C
Yield: 26 %

Procedure:
A mixture of diethoxyacetonitrile (38.72 mmol, 1 equiv.) and methyl isocyanoacetate (99.1 mmol, 1.4 equiv.) in dry bis(2-methoxyethyl)ether (20 ml) was added to a suspension of 30-35% KH (54.2 mmol, 1.4 equiv.) in dry bis(2-methoxyethyl)ether (30 ml). The resulting mixture was heated overnight at 70-80° C. The reaction mixture was then cooled to 25° C., and sat. NH4Cl solution (20 ml) was added. DCM (100 ml) was added, and the phases were separated. The aqueous phase was extracted with DCM (2×75 ml) and the combined organic phases were dried over Na2SO4 and filtered, and the solvent was removed in vacuo. Cold ether (10 ml) was added to the brown oil so obtained, and the resulting solid was filtered out and washed with ether. The desired product was thus obtained in the form of a yellow solid. Yield: 26%
Reaction SMILES: [CH2:1]([Li])CCC.CCCCCC.[C:12]([C:16]1[CH:36]=[CH:35][C:19]([CH2:20][N:21]([CH2:25][C:26]2[CH:27]=[C:28]([C:32](=O)[CH3:33])[CH:29]=[CH:30][CH:31]=2)[CH:22]2[CH2:24][CH2:23]2)=[CH:18][CH:17]=1)([CH3:15])([CH3:14])[CH3:13]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:12]([C:16]1[CH:36]=[CH:35][C:19]([CH2:20][N:21]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([CH3:1])=[CH2:33])[CH:27]=2)[CH:22]2[CH2:24][CH2:23]2)=[CH:18][CH:17]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(=O)c1cccc(CN(Cc2ccc(C(C)(C)C)cc2)C2CC2)c1
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CCCCCC
Product: C=C(C)c1cccc(CN(Cc2ccc(C(C)(C)C)cc2)C2CC2)c1
Yield: 35.2 %

Procedure:
The procedure described in Example 60 was repeated, except that methyl triphenylphosphonium bromide (0.32 g; 8.94×10−1 mmol), n-butyl lithium in n-hexane (1.56 M: 0.6 ml; 8.9×10−1 mmol), and Compound 82 (0.20 g; 5.96×10−1 mmol) were used, to thereby yield 0.07 g of the target compound (yield: 35.2%).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[C:8]([Br:13])[CH:9]=[CH:10][CH:11]=2)[C:6](C=O)=[CH:5]1)(=[O:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:24])C=1>C(Cl)Cl>[C:1]([N:4]1[C:12]2[C:7](=[C:8]([Br:13])[CH:9]=[CH:10][CH:11]=2)[C:6](=[O:24])[CH2:5]1)(=[O:3])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(=O)n1cc(C=O)c2c(Br)cccc21
Solvent: ClCCl
Product: CC(=O)N1CC(=O)c2c(Br)cccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1-Acetyl-4-bromo-1H-indole-3-carbaldehyde (3.5 g, 13.2 mmol) was dissolved in CH2Cl2 (50 mL). 3-Chloroperbenzoic acid (3.9 g, 15.8 mmol) was added, and the reaction stirred 16 h at r.t. The solution was washed with sat. NaHCO3 and brine, dried (MgSO4), and concentrated. The residue was stirred with K2CO3 (100 mg) in MeOH (50 mL) for 2 min. The solution was concentrated and purified by silica gel chromatography (100% CH2Cl2) to provide the title compound as a faintly blue solid (880 mg, 26%). MS (ES) [m+H] calc'd for C10H8BrNO2, 254, 256; found 254, 256.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][C:6]2[C:8]([O:13][CH3:14])=[CH:9][CH:10]=[C:11]([F:12])[C:5]=2[O:4][CH2:3]1.[C:15]1(=O)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.CC(O)=O.[BH3-]C#N.[Na+]>CO>[CH:15]1([NH:1][C@@H:2]2[CH2:7][C:6]3[C:8]([O:13][CH3:14])=[CH:9][CH:10]=[C:11]([F:12])[C:5]=3[O:4][CH2:3]2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: O=C1CCCCC1
Reactant: COc1ccc(F)c2c1C[C@@H](N)CO2
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COc1ccc(F)c2c1C[C@@H](NC1CCCCC1)CO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (R)-3-amino-8fluoro-5-methoxy-3,4-dihydro-2H-1-benzopyran (0.45 g, 2.2 mmol), cyclohexanone (0.7 g, 7.2 mmol) and HOAc (0.14 g, 2.3 mmol) in methanol (25 mL) was NaCNBH3 (0.5 g, 8 mmol) added in portions at room temperature. The solution was stirred at room temperature overnight to give a quantitative yield of the title compound. GC/MS (70 eV) M=279 (30%).
Reaction SMILES: Br[CH2:2][CH2:3][F:4].[OH:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH:9]=[O:10].C([O-])([O-])=O.[K+].[K+]>CC(=O)CC>[F:4][CH2:3][CH2:2][O:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH:9]=[O:10]
Reactant: O=Cc1cccc(O)c1
Reactant: FCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: O=Cc1cccc(OCCF)c1
Temperature: 25 °C

Procedure:
Combine 1-bromo-2-fluoroethane (4.575 g; 36.0 mmol), 3-hydroxybenzaldehyde (4.103 gm; 33.60 mmol), and K2CO3 (7.05 gm; 51.0 mmol) in 2-butanone (100 mL) and reflux. After 18 hour cool the mixture to ambient temperature, concentrate, and partition between 100 mL of water and 100 mL of dichloromethane. Separate the layers and extract the aqueous layer with dichloromethane (2×75 mL). Combine the organic layers and wash sequentially with brine (2×150 mL), 1 M NaOH (2×100 mL), NaHCO3 (saturated, 100 mL), and brine (150 mL), dried (MgSO4), concentrate, and chromatograph on silica gel (0–25% diethyl ether in hexanes) to give the title compound.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C[O:8][C:9]([C:11]1[N:12]([CH3:23])[C:13]2[C:18]([CH:19]=1)=[C:17]([NH2:20])[C:16]([O:21][CH3:22])=[CH:15][CH:14]=2)=O>C1COCC1>[NH2:20][C:17]1[C:16]([O:21][CH3:22])=[CH:15][CH:14]=[C:13]2[C:18]=1[CH:19]=[C:11]([CH2:9][OH:8])[N:12]2[CH3:23]
Reactant: COC(=O)c1cc2c(N)c(OC)ccc2n1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc2c(cc(CO)n2C)c1N
Yield: 91.7 %

Procedure:
Lithium aluminum hydride (5.84 mL, 5.84 mmol, 1.0 M solution in Et2O) was added to a solution of 10 (595 mg, 2.59 mmol) in THF (12 mL) under argon. The reaction was then heated at reflux for 15 min, quenched by careful addition of H2O followed by 1 M NaOH, then extracted with CH2Cl2 (3×). The combined organic layers were dried over Na2SO4 and evaporated to afford 11 (490 mg, 94%) as a brown oil which was used without further purification; 1H NMR (CDCl3): δ 6.95 (1H, d), 6.71 (1H, d), 6.34 (1H, s), 4.77 (2H, s), 3.87 (3H, s), 3.74 (3H, s).