Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:15][CH2:14][CH:13]2[CH:10]([N:11]([C:16]([C:18]3[C:19]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:20][CH:21]=[CH:22][CH:23]=3)=[O:17])[CH2:12]2)[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>O1CCOCC1>[C:19]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:16]([N:11]1[CH:10]2[CH:13]([CH2:14][CH2:15][NH:8][CH2:9]2)[CH2:12]1)=[O:17]
Reactant: CC(C)(C)OC(=O)N1CCC2CN(C(=O)c3ccccc3-c3ccccc3)C2C1
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Product: O=C(c1ccccc1-c1ccccc1)N1CC2CCNCC21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 8-(biphenyl-2-carbonyl)-3,8-diaza-bicyclo[4.2.0]octane-3-carboxylic acid tert-butyl ester in dioxane (8.0 mL) was added trifluoro acetic acid (3 mL), the reaction mixture was stirred for 16 h at room temperature. The solvent and the excess of trifluoro acetic acid were removed under reduced pressure. The resulting trifluoro acetic acid salt of the title compound (388.0 mg was used crude without further purification. MS (ESI) mass calcd. for C19H20N2O, 292.37; m/z found, 293.2 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH2:10][C@H:9]1[C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:17][C:18]1[CH:19]=[C:20]2[C:28](=[C:29]([NH2:31])[CH:30]=1)[NH:27][C:26]1[CH:25]=[N:24][CH:23]=[CH:22][C:21]2=1.CCN=C=NCCCN(C)C.CCOC(C)=O>N1C=CC=CC=1.O.[Cl-].[Na+].O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH2:10][C@H:9]1[C:14](=[O:16])[NH:31][C:29]1[CH:30]=[C:18]([Cl:17])[CH:19]=[C:20]2[C:28]=1[NH:27][C:26]1[CH:25]=[N:24][CH:23]=[CH:22][C:21]2=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCOC[C@H]1C(=O)O
Reactant: Nc1cc(Cl)cc2c1[nH]c1cnccc12
Agent: CCN=C=NCCCN(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCOC[C@H]1C(=O)Nc1cc(Cl)cc2c1[nH]c1cnccc12
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A solution of morpholine-3(S),4-dicarboxylic acid 4-tert-butyl ester (2.83 g, 12.7 mmol) in pyridine (106 ml) was stirred at RT. 6-chloro-9H-β-carbolin-8-ylamine (2.30 g, 10.6 mmol) was added, followed by EDCI (4.06 g, 21.2 mmol). The clear orange-to-brown solution was stirred at RT for 14 hr. The solution was diluted with H2O (120 ml) and poured into a separatory funnel containing EtOAc (200 ml), H2O (100 ml) and brine (100 ml). The mixture was shaken and the layers were separated. The aqueous layer was extracted with EtOAc (2×50 ml) and the combined organic layers were washed with brine. The organic layer was dried, filtered and concentrated to a reduced volume, then added drop-wise to a stirring solution of 1:1 Et2O/hexanes (500 ml). The precipitate which formed was filtered and washed with 1:1 Et2O/Hexanes. The filtrate was concentrated to a reduced volume and a second crop of precipitate was collected. The solid product was placed under high vacuum for 2 hr to yield 3(S)-(6-chloro-9H-β-carbolin-8-ylcarbamoyl)-morpholine-4-carboxylic acid tert-butyl ester as a pale yellow to pale brown solid (4.36 g).
Reaction SMILES: C(OC(=O)[CH:5]([C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][N:12]=1)C(OCC)=O)C.[OH-].[Na+]>S(=O)(=O)(O)O>[CH3:5][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][N:12]=1
Reactant: CCOC(=O)C(C(=O)OCC)c1ccc([N+](=O)[O-])cn1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccc([N+](=O)[O-])cn1
Temperature: 100 °C
Yield: 85.2 %

Procedure:
To 2-(5-nitro-pyridin-2-yl)-malonic acid diethyl ester (12.0 g, 42.5 mmol) was added cold aq. 20% sulfuric acid (120 mL) and the mixture was heated to 100° C. for 2 h. The cooled reaction was added to cold dilute sodium hydroxide solution and the pH adjusted to pH ˜10. The organics were extracted with dichloromethane (×4), then the combined organic phases were dried over sodium sulfate. The filtrate was concentrated to afford 2-methyl-5-nitro pyridine (5.0 g, 83%) as a brown solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:24])[CH2:15][S:16][C:17]2[CH:18]=[C:19]([CH3:23])[CH:20]=[CH:21][CH:22]=2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:33]2[CH:38]=[CH:37][C:36]([C:39]3([C:42]([NH:44][S:45]([CH3:48])(=[O:47])=[O:46])=[O:43])[CH2:41][CH2:40]3)=[CH:35][CH:34]=2)O1>>[OH:24][CH:14]([C:9]1[C:10]([CH3:13])=[N:11][O:12][C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([C:33]2[CH:34]=[CH:35][C:36]([C:39]3([C:42]([NH:44][S:45]([CH3:48])(=[O:47])=[O:46])=[O:43])[CH2:41][CH2:40]3)=[CH:37][CH:38]=2)=[CH:3][CH:4]=1)[CH2:15][S:16][C:17]1[CH:18]=[C:19]([CH3:23])[CH:20]=[CH:21][CH:22]=1
Reactant: CC1(C)OB(c2ccc(C3(C(=O)NS(C)(=O)=O)CC3)cc2)OC1(C)C
Reactant: Cc1cccc(SCC(O)c2c(C)noc2-c2ccc(Br)cc2)c1
Product: Cc1cccc(SCC(O)c2c(C)noc2-c2ccc(-c3ccc(C4(C(=O)NS(C)(=O)=O)CC4)cc3)cc2)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 7, using 1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-2-m-tolylsulfanyl-ethanol and N-{1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarbonyl}-methanesulfonamide.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([N:8]=[CH:9][C:10]=2[C:11]([NH:13][C:14]2[C:15]([CH3:24])=[N:16][CH:17]=[C:18]([CH:23]=2)[C:19]([O:21]C)=[O:20])=[O:12])[CH:7]=1.[CH3:25][N:26]1[CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:28]=[N:27]1.C(=O)([O-])[O-].[Cs+].[Cs+].C(Cl)Cl>COCCOC.O>[CH3:24][C:15]1[C:14]([NH:13][C:11]([C:10]2[CH:9]=[N:8][N:6]3[CH:7]=[C:2]([C:29]4[CH:28]=[N:27][N:26]([CH3:25])[CH:30]=4)[CH:3]=[CH:4][C:5]=23)=[O:12])=[CH:23][C:18]([C:19]([OH:21])=[O:20])=[CH:17][N:16]=1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: COC(=O)c1cnc(C)c(NC(=O)c2cnn3cc(Br)ccc23)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: O
Solvent: COCCOC
Product: Cc1ncc(C(=O)O)cc1NC(=O)c1cnn2cc(-c3cnn(C)c3)ccc12
Temperature: 100 °C
Reaction time: 7 h

Procedure:
Methyl 5-(6-bromopyrazolo[1,5-a]pyridine-3-carboxamido)-6-methylnicotinate (step 1) (7 g, 17.99 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (4.49 g, 21.58 mmol) and cesium carbonate (23.44 g, 71.9 mmol) were stirred in 1,2-dimethoxyethane (60 ml) and water (25.00 ml). The mixture was degassed thoroughly refilling with nitrogen. PdCl2(dppf).CH2Cl2 adduct (0.350 g, 0.429 mmol) was added and the mixture was degassed thoroughly refilling with nitrogen, The mixture was stirred at 100° C. for 7 hrs and then cooled to 50° C. and filtered through glass-fiber paper. The filtrate was acidified to pH 5 by the addition of 2M HCl and filtered. The foam residue was dissolved in DCM/MeOH (1:1) and azeotroped with toluene (×2). The resulting solid was dried in a vacuum oven to afford the title compound;
Reaction SMILES: C[O:2][C:3]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([C:18]([NH2:20])=[O:19])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.C(O)(=O)C(O)=O.C(O)(C)C>O>[CH:7]1[CH:8]=[CH:9][C:10]2[N:11]([C:18]([NH2:20])=[O:19])[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=3[C:3](=[O:2])[CH2:4][C:5]=2[CH:6]=1
Reactant: COC1=Cc2ccccc2N(C(N)=O)c2ccccc21
Agent: O=C(O)C(=O)O
Solvent: O
Solvent: CC(C)O
Product: NC(=O)N1c2ccccc2CC(=O)c2ccccc21
Temperature: 25 °C
Yield: 95 %

Procedure:
100 g of 10-methoxycarbamazepine in 1000 ml water and 69.24 g of oxalic acid solution were heated to 90° C. and maintained for about 17 hrs. After completion of the reaction the reaction mixture was cooled to room temperature (RT). The resulting reaction mass was filtered and washed with 1000 ml of DM water. The wet material obtained was charged with isopropyl alcohol and DM water. The obtained reaction mixture was heated to reflux for about 2 h. The reaction mixture was cooled to 15-25° C., filtered and washed with 100 ml of IPA-water mixture. The resulting compound is dried at 60° C. for 6 h to produce 90 g of Oxcarbazepine.
Reaction SMILES: ClC1C=CC=CC=1C=O.CC1C=CN=CC=1.C(OC(=O)C)(=O)C.[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH:31]=[CH:32][C:33]1[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=1>>[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH2:31][CH2:32][C:33]1[CH:34]=[CH:35][N:36]=[CH:37][CH:38]=1
Reactant: Clc1ccccc1C=Cc1ccncc1
Agent: O=Cc1ccccc1Cl
Solvent: Cc1ccncc1
Solvent: CC(=O)OC(C)=O
Product: Clc1ccccc1CCc1ccncc1

Procedure:
14.1 g. (0.1 mole) of 2-chlorobenzaldehyde and 9.4 g. (0.1 mole) or 4-methylpyridine are refluxed for six hours in 40ml. of acetic anhydride. The reaction mixture is concentrated in vacuo and then dissolved in 200 ml. of chloroform. The chloroform solution is washed with aqueous sodium bicarbonate, dried with MgSO4, filtered and concentrated in vacuo. The oily residue is dissolved in isopropanol and treated with HCl in isopropanol until acidic. The crystalline hydrochloride salt is filtered, dissolved in 150 ml. of water and neutralized with aqueous sodium bicarbonate. The product is extracted with chloroform to yield 12.6 g. of oil 4-[2-(2-chlorophenyl)ethenyl]pyridine.
Reaction SMILES: [OH:1][CH2:2][CH:3]([N:15]1[C:21](=[O:22])[CH2:20][CH2:19][N:18]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=2)[CH2:17][CH2:16]1)[CH2:4][CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][C:10]([OH:14])([CH3:13])[CH2:9][CH2:8]1.I[CH3:34].[H-].[Na+]>>[OH:14][C:10]1([CH3:13])[CH2:9][CH2:8][N:7]([CH2:6][CH2:5][CH2:4][CH:3]([N:15]2[C:21](=[O:22])[CH2:20][CH2:19][N:18]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:31])([F:30])[F:32])[CH:24]=3)[CH2:17][CH2:16]2)[CH2:2][O:1][CH3:34])[CH2:12][CH2:11]1
Reactant: CC1(O)CCN(CCCC(CO)N2CCN(c3cccc(C(F)(F)F)c3)CCC2=O)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Product: COCC(CCCN1CCC(C)(O)CC1)N1CCN(c2cccc(C(F)(F)F)c2)CCC1=O
Yield: 25 %

Procedure:
In analogy to the procedure described in example 23B, (rac)-4-[1-hydroxymethyl-4-(4-hydroxy-4-methyl-piperidin-1-yl)-butyl]-1-(3-trifluoromethyl-phenyl)-[1,4]diazepan-5-one was treated with iodomethane and NaH to give the title compound in 25% yield as colorless oil. MS: 472.4 (MH+).
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=1[F:20])[C:14]([OH:16])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH3:43][C@@H:44]([CH2:54][CH3:55])[C@H:45]([NH:52][CH3:53])[CH2:46][N:47]1[CH2:50][CH:49]([OH:51])[CH2:48]1>C(Cl)Cl>[F:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=1[F:20])[C:14]([N:52]([C@@H:45]([C@@H:44]([CH3:43])[CH2:54][CH3:55])[CH2:46][N:47]1[CH2:48][CH:49]([OH:51])[CH2:50]1)[CH3:53])=[O:16]
Reactant: CC[C@H](C)[C@@H](CN1CC(O)C1)NC
Reactant: O=C(O)c1ccc(F)c(F)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC[C@H](C)[C@@H](CN1CC(O)C1)N(C)C(=O)c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.7 %

Procedure:
DIPEA (0.224 mL, 1.29 mmol) was added to 3,4-difluorobenzoic acid (0.068 g, 0.43 mmol) and TBTU (0.138 g, 0.43 mmol) in DCM (2 mL). The mixture was stirred at rt for 30 min. 1-((2S,3S)-3-Methyl-2-(methylamino)pentyl)azetidin-3-ol (Compound G2.1) (0.1 g, 0.43 mmol) in DCM (1 mL) was added and the resultant mixture was stirred at rt overnight. The mixture was washed with NaHCO3, filtered through a phase separator and concentrated under reduced pressure. The residue was purified by preparative HPLC to give the title compound (95 mg, 68%). Mixture of rotamers: 1H NMR (600 MHz, DMSO-d6) δ 0.61-0.74, 0.75-0.92, 0.97-1.09, 1.20-1.63, 2.33-2.45, 2.48-2.83, 3.11-3.23, 3.32-3.38, 3.39-3.53, 4.04-4.23, 5.14-5.31, 7.10-7.22, 7.28-7.41, 7.42-7.56, 7.56-7.70. Total number of protons: 24. HRMS (M+H)+: calculated 327.1884. found 327.1878. The compounds according to Examples 29.2-29.9 were prepared, from appropriate intermediates, by analogy with the method described for Example 29.1 hereinbefore.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH:18]([CH:21]([CH3:23])[CH3:22])[C:19]#[N:20].Br[CH2:25][CH2:26][CH2:27][Cl:28]>O1CCCC1>[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]([CH:21]([CH3:23])[CH3:22])([CH2:25][CH2:26][CH2:27][Cl:28])[C:19]#[N:20]
Reactant: CC(C)C(C#N)c1ccccc1F
Reactant: ClCCCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)C(C#N)(CCCCl)c1ccccc1F
Temperature: 25 °C
Yield: 83.8 %

Procedure:
To a mixture of a 0.5 M solution of potassium bis(trimethylsilyl)amide (12.4 mL and tetrahydrofuran (44 mL) stirring at −78° under argon was added dropwise a solution of the title product of Example 8, Step (a) (1.00 g) in tetrahydrofuran (2 mL). After stirring at −78° for 0.5 hour, 1-bromo-3-chloropropane (1.3 g) was added, and the mixture was stirred while being permitted to warm to room temperature. The mixture was partitioned between diethyl ether and saturated aqueous ammonium chloride, the aqueous layer was extracted with two portions of ether, the combined organic extracts washed with brine, dried over magnesium sulfate, filtered and evaporated to give a compound (1.20 g) which was characterized by NMR, as follows: 1H NMR(CDCl3) d 7.64-7.00(m, 4H), 3.50(t, 2H), 1.24(d, 3H), 0.82(d, 3H).
Reaction SMILES: C(O)C.Cl.[CH3:5][C:6]1[CH:21]=[CH:20][C:9]([NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[C:8]([N+:22]([O-])=O)[CH:7]=1.[OH-].[Na+]>[Fe].O>[CH3:5][C:6]1[CH:21]=[CH:20][C:9]([NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[C:8]([NH2:22])[CH:7]=1
Reactant: CCCCCCCCCNc1ccc(C)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCCCCCCCCNc1ccc(C)cc1N
Reaction time: 1 h

Procedure:
A mixture of ethanol (1685 parts), water (210 parts), hydrochloric acid (density 1.18 g. ml.) (20 parts) and iron powder (820 parts) was stirred vigorously and boiled for 1 hour when an ethanolic (420 parts) solution of 4-methyl-2-nitro-N-nonylaniline (575 parts) was added during 30 minutes. The mixture was boiled for 15 hours when sodium hydroxide solution (density 1.35 g. ml.) (20 parts) were added and the mixture was filtered while still hot and the residue was washed with boiling ethanol. After removal of the solvent from the combined filtrate and washings the residual oil was distilled under reduced pressure to give 4-methyl-2-amino-N-nonylaniline (390 parts) as a pale yellow oil, boiling point 176° C. at 0.7 mm, which solidified on cooling.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([F:23])[CH:21]=3)[NH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].C[N:27](C=O)C>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]=[C:11]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([F:23])[CH:21]=3)[N:16]([NH2:27])[CH:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)N1CC=C(c2c[nH]c3ccc(F)cc23)CC1
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CC=C(c2cn(N)c3ccc(F)cc23)CC1
Temperature: 25 °C
Yield: 94 %

Procedure:
A solution of 4-(5-fluoro-1H-indol-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (730 mg, 2.31 mmol) in anhydrous DMF is added slowly to a stirred solution of 60% NaH (1108 mg, 27.72 mmol) in anhydrous DMF (20 mL) at 0° C. under N2 and stirred at rt for an hour. HOSA (1305 mg, 11.55 mmol) is added portion-wise at 0° C., stirred at 0° C. for 5 hours, poured into ice/water (350 mL) and extracted with ether (3×35 mL). The combined organic extract is washed with water (2×20 mL) and brine (20 mL), dried (Na2SO4), filtered and concentrated in vacuo. The residue is washed with heptane (3×5 mL) to afford 4-(1-Amino-5-fluoro-1H-indol-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (715 mg, 94%) as a solid. MS: 332 (M+H); 1H NMR (300 MHz, CDCl3): δ 7.52 (d, H), 7.36 (m, H), 7.20 (s, H), 7.04 (t, H), 6.06 (s, H), 4.78 (s, 2H), 4.15(m, 2H), 3.69 (t, 2H), 2.54 (s, 2H), 1.55 (s, 9H).
Reaction SMILES: [Li]CCCC.[C:6](#[N:8])[CH3:7].[CH:9]1([C:13](OCC)=[O:14])[CH2:12][CH2:11][CH2:10]1.C(#N)C.C(=O)=O>C1COCC1>[CH:9]1([C:13](=[O:14])[CH2:7][C:6]#[N:8])[CH2:12][CH2:11][CH2:10]1
Reactant: CCOC(=O)C1CCC1
Reactant: CC#N
Agent: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: N#CCC(=O)C1CCC1
Reaction time: 2 h

Procedure:
To 800 mL of THF at −78° C. was added n-BuLi (312.0 mL, 780.0 mmol, 2.5 M in hexanes). After the reaction temperature equilibrated (˜15 min), a solution of acetonitrile (40.7 mL, 780.0 mmol in 100 mL of THF) was added dropwise via addition funnel over a 20 min period. The resulting slurry (milky white) was allowed to stir for one hr before a solution of ethyl cyclobutanecarboxylate (53.9 mL, 390.1 mmol in 150 mL of THF) was added down the side of the flask over a 20 min period. After one hr the reaction was warmed to −45° C. (acetonitrile/CO2) and allowed to stir for two hr. The reaction was quenched cold by the dropwise addition of 2 N HCl (˜390 mL, pH=7) and then diluted with EtOAc (1 L). The layers were separated and the aqueous layer was extracted with CH2Cl2 (2×600 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure to yield 3-cyclobutyl-3-oxo-propionitrile (quantitative yield) as a yellow oil that was used without further purification. Rf 0.32 (40% EtOAc/hexanes); m/z (APCI+) 138 (M−1).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][O:7][CH2:8]Cl)(=[O:3])[CH3:2].[CH2:10]([O:12][P:13]([O:17]CC)[O:14][CH2:15][CH3:16])[CH3:11]>>[C:1]([O:4][CH2:5][CH2:6][O:7][CH2:8][P:13]([O:14][CH2:15][CH3:16])([O:12][CH2:10][CH3:11])=[O:17])(=[O:3])[CH3:2]
Reactant: CC(=O)OCCOCCl
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(COCCOC(C)=O)OCC
Temperature: 25 °C
Yield: 68.1 %

Procedure:
A mixture of 1-acetoxy-2-(chloromethoxy)ethane (67.8 g, 444 mmol) and triethylphosphite (81.3 g, 490 mmol) was heated at 105°-110° C. for 12 hours. Vigorous gas evolution was noted initially. The reaction mixture was next cooled to room temperature and the crude material purified by distillation (0.9 mmHg, 130°-134° C.) to afford 76.9 g (68%) of 1-acetoxy-2-(diethylphosphonomethoxy)ethane as a colorless liquid.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([CH:10]=[O:11])[C:4]=2[CH:3]=[CH:2]1.[F:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH2:15]Br>>[F:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH2:15][N:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([CH:10]=[O:11])[C:4]=2[CH:3]=[CH:2]1
Reactant: Fc1ccccc1CBr
Reactant: O=Cc1cccc2[nH]ccc12
Product: O=Cc1cccc2c1ccn2Cc1ccccc1F

Procedure:
The same procedures used in Example 1 were repeated except for using 725 mg of indole-4-carbaldehyde and 2-fluorobenzyl bromide instead of the benzyl bromide used in Example 1 to give 1.22 g of 1-(2-fluorobenzyl)indole-4-carbaldehyde as yellow crystals. The yield thereof was found to be 96%.
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:7]=[CH:8][C:9]2[O:13][CH:12]([OH:14])[C:11]([CH3:16])([CH3:15])[C:10]=2[CH:17]=1)(=[O:4])=[O:3].O>C(O)(=O)C>[CH3:1][S:2]([O:5][CH:6]1[CH2:17][C:10]2[C:11]([CH3:15])([CH3:16])[C:12](=[O:14])[O:13][C:9]=2[CH:8]=[CH:7]1)(=[O:3])=[O:4]
Reactant: CC1(C)c2cc(OS(C)(=O)=O)ccc2OC1O
Solvent: O
Solvent: CC(=O)O
Product: CC1(C)C(=O)OC2=C1CC(OS(C)(=O)=O)C=C2
Yield: 70 %

Procedure:
A solution of 2-hydroxy-2,3-dihydro-3,3-dimethylbenzofuran-5-yl methanesulphonate (20 parts) in warm acetic acid (200 parts) was treated with 200 parts of a 20% aqueous solution of chromic oxide. After about 15 seconds the mixture was poured into water and the solution extracted with ether. The extracts were thoroughly washed with aqueous sodium bicarbonate, then dried and the solvent evaporated to give 2-oxo-2,5-dihydro-3,3-dimethyl-benzofuran-5-yl methanesulphonate (14 parts, 70% yield), melting point 120°-121° C. after recrystallisation from benzene-petroleum.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14]([OH:16])=[O:15].[OH-].[Na+].[CH2:19](Br)[CH2:20][CH2:21][CH3:22].Cl>O.CS(C)=O>[CH2:19]([N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[CH:7]=2)[C:2](=[O:1])[C:3]([C:14]([OH:16])=[O:15])=[CH:4]1)[CH2:20][CH2:21][CH3:22]
Reactant: COc1ccc2c(O)c(C(=O)O)cnc2c1
Reactant: CCCCBr
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CCCCn1cc(C(=O)O)c(=O)c2ccc(OC)cc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
11.0 g. (50 millimoles) of 4-hydroxy-7-methoxyquinoline-3-carboxylic acid is introduced into a suspension of 14.0 g. (351 millimoles) of pulverized sodium hydroxide in 200 ml. of dimethyl sulfoxide. The mixture is stirred for 10 minutes at room temperature, and then 16.1 ml. (150 mmol) of butyl bromide is added dropwise thereto so that the temperature does not exceed 25° C. Thereafter, the mixture is stirred for 2 hours at room temperature, poured into water, and acidified with hydrochloric acid. The thus-precipitated product is filtered off, washed with water, dried, and recrystallized from dimethylformamide.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([OH:15])[CH2:11][CH2:10]2)[CH:5]=[C:4]([CH3:16])[N:3]=1.[Br:17]NC(=O)CCC(N)=O>C(Cl)(Cl)Cl>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([OH:15])[CH2:11][CH2:10]2)[C:5]([Br:17])=[C:4]([CH3:16])[N:3]=1
Reactant: NC(=O)CCC(=O)NBr
Reactant: Cc1cc(N[C@H]2CC[C@H](O)CC2)nc(N)n1
Solvent: ClC(Cl)Cl
Product: Cc1nc(N)nc(N[C@H]2CC[C@H](O)CC2)c1Br
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of (trans-4-(2-amino-6-methylpyrimidin-4-ylamino)cyclohexanol (1.33 g, 5.98 mmol) in chloroform (15 mL) was added N-bromosuccinamide (1.08 g, 6.04 mmol). After stirring at room temperature for 1.5 hr, the solution was concentrated. The residue was purified by flash chromatography eluting with chloroform/7 N ammonia in methanol (0.5-5%) to afford the title compound (1.14 g, 63%).
Reaction SMILES: C([CH:3]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][N:12]=1)[C:4]([O:6]C(C)(C)C)=[O:5])#N>O.Cl>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:3][C:4]([OH:6])=[O:5])=[N:12][CH:13]=1
Reactant: COc1ccc(C(C#N)C(=O)OC(C)(C)C)nc1
Agent: Cl
Solvent: O
Product: COc1ccc(CC(=O)O)nc1
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 53.7 %

Procedure:
The crude tert-butyl cyano(5-methoxypyridin-2-yl)acetate (3.46 g) was suspended in a mixture of 45 mL of water and 45 mL of concentrated HCl. The mixture was heated at 60° C. for 1 hour and at reflux overnight. The reaction was cooled and the water was removed under vacuum. The oily solid residue was redissolved in a minimal amount of water (˜50-70 mL) and 2N NaOH was added to adjust the pH to approximately 14. The solution was washed with diethyl ether and was reacidified to pH 4 with 2N HCl and concentrated to dryness to give a white solid. This solid was triturated in hot THF (3×) and the combined supernatants were cooled in an icebath to initiate crystallization. After 20 minutes, the solid was collected by filtration washing with heptanes to give (5-methoxypyridin-2-yl)acetic acid (1.25 g). A second crop of product precipitated from the filtrate (0.39 g). The filtrate was concentrated, and the material was triturated with hot ethyl acetate and heptanes to provide a third crop of product as a brown solid (0.11 g of lower purity). The total yield of SM-1aa was 1.75 g (98%). MS (ES+) 168.1 (M+H)+. 1H NMR (DMSO-d6) δ 3.66 (s, 2H), 3.81 (s, 3H), 7.27 (d, 1H), 7.33-7.36 (m, 1H), 8.18 (d, 1H).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[F:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH3:13].[C:14](Cl)(=[O:20])[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].Cl>>[F:5][C:6]1[CH:11]=[C:10]([C:14](=[O:20])[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH:9]=[CH:8][C:7]=1[O:12][CH3:13]
Reactant: CCCCCC(=O)Cl
Reactant: COc1ccccc1F
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CCCCCC(=O)c1ccc(OC)c(F)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 90.4 %

Procedure:
Aluminum chloride (6.5 g, 48.8 mmol) was added to a stirred mixture of 1-fluoro-2-methoxybenzene (5.0 mL, 44.4 mmol) and hexanoyl chloride (7.5 mL, 53.3 mmol) at room temperature. The mixture warmed and HCl evolution occurred. The resulting mixture was stirred at room temperature for 45 minutes and then partitioned between EtOAc (100 mL) and water (100 mL). The EtOAc layer was washed with water (100 mL), aqueous K2CO3 (100 mL) and brine (50 mL), dried over MgSO4, filtered, and evaporated under vacuum to yield crude 1-(3-fluoro-4-methoxyphenyl)-1-hexanone (9 g) as a solid.