Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][CH2:3][C@@H:4]([C@H:6]([C@@H:8]([C@@H:10]([CH2:12][OH:13])[OH:11])[OH:9])[OH:7])[OH:5].C(=O)([O-])O.[Na+].Cl[C:20]([O:22][CH2:23][CH:24]([CH2:29][CH3:30])[CH2:25][CH2:26][CH2:27][CH3:28])=[O:21]>O.O1CCCC1.CC(C)=O>[CH2:29]([CH:24]([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:23][O:22][C:20]([N:2]([CH3:1])[CH2:3][C@@H:4]([C@H:6]([C@@H:8]([C@@H:10]([CH2:12][OH:13])[OH:11])[OH:9])[OH:7])[OH:5])=[O:21])[CH3:30]
Reactant: CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: CCCCC(CC)COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: CCCCC(CC)COC(=O)N(C)C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Temperature: 5 °C
Reaction time: 8 h
Yield: 49.8 %

Procedure:
In a reactor, 117 g (0.6 mol) of N-methyl-D-glucamine were dissolved in a mixture of 800 ml of water and 400 ml of tetrahydrofuran, and 201.6 g (2.4 mol) of sodium hydrogen carbonate were then dispersed. While the temperature of the reaction mixture was maintained at 5° C., 115.6 g (0.6 mol) of 2-ethylhexyl chloroformate were added dropwise, and the mixture was then allowed to react for 3 hours with stirring at 5° C. and left standing overnight at room temperature. The reaction mixture was then filtered and concentrated; the pasty residue obtained was dissolved in 2 liters of acetone and then filtered after cooling to 5° C. The crystallized product collected was dried. 105 g (50% yield) of N-(2-ethylhexyloxycarbonyl)-N-methyl-D-glucamine, the melting point of which is 74° C., were obtained.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][CH:18]([N:21]([CH2:29][CH2:30][CH2:31][O:32][C:33]2[CH:34]=[C:35]3[C:40](=[CH:41][CH:42]=2)[N:39]([CH3:43])[C:38](=[O:44])[CH:37]=[CH:36]3)[CH2:22][C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)[CH2:17][CH2:16]1)=O)(C)(C)C>ClCCl>[CH3:43][N:39]1[C:40]2[C:35](=[CH:34][C:33]([O:32][CH2:31][CH2:30][CH2:29][N:21]([CH:18]3[CH2:17][CH2:16][NH:15][CH2:20][CH2:19]3)[CH2:22][C:23]3[CH:24]=[CH:25][N:26]=[CH:27][CH:28]=3)=[CH:42][CH:41]=2)[CH:36]=[CH:37][C:38]1=[O:44]
Reactant: Cn1c(=O)ccc2cc(OCCCN(Cc3ccncc3)C3CCN(C(=O)OC(C)(C)C)CC3)ccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1c(=O)ccc2cc(OCCCN(Cc3ccncc3)C3CCNCC3)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.5 %

Procedure:
Trifluoroacetic acid (30 ml) was added to a dichloromethane solution (10 ml) of 4-{[3-(1-methyl-2-oxo-1,2-dihydro-quinolin-6-yloxy)-propyl]-pyridin-4-ylmethyl-amino}-piperidine-1-carboxylic acid tert-butyl ester (1.08 g), and the mixture was stirred at room temperature overnight. The reaction mixture was condensed under reduced pressure. PL-HCO3(40 g) was added to the dichloromethane solution of the residue and followed by celite filtration. The filtrate was condensed under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate: methanol=4:1). The purified product was condensed under reduced pressure to give the title compound(758 mg) as an orange oil.
Reaction SMILES: C([Mg]Cl)CCC.C([Li])CCC.Br[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=1.CN(C)[CH:22]=[O:23]>O1CCCC1.CCCCCC.C(O)(=O)C.C1(C)C=CC=CC=1>[Br:19][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[CH:22]=[O:23]
Reactant: Brc1cccc(Br)c1
Reactant: CN(C)C=O
Agent: CCCC[Mg]Cl
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=Cc1cccc(Br)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 78.2 %

Procedure:
n-Butylmagnesium chloride (4.00 mmol) in 2.00M tetrahydrofuran solution (2.00 mL) was added to ice-cooled n-butyllithium (8.06 mmol) in 1.55M hexane (5.20 mL). The mixture was stirred at 0° C. for 15 minutes to give a suspension. To the suspension was added dropwise a toluene solution (25 mL) containing 1,3-dibromobenzene (2.36 g, 10.0 mmol), while keeping the temperature below 5° C., over a period of 15 minutes, thereby to give a suspension. The suspension was stirred at 0° C. for 5 hours, and then N,N-dimethylformamide (1.0 mL, 13 mmol) was added thereto. The resultant mixture was stirred at 0° C. for 30 minutes, and 10% aqueous acetic acid (20 mL) was added. The reaction mixture was extracted twice with toluene (20 mL). The organic extracts were combined, washed with water (20 mL), and dried over magnesium sulfate. Toluene was added to the solution to a volume of 85 mL. The solution (83 ml) was purified by flash column chromatography on silica gel in a developing solvent system of hexane-ethyl acetate (25:1, v/v) to give the title compound (1.446 g, 78% yield) as a pale yellowish crystalline solid.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH:12]=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl.[NH2:18][C@@H:19]([CH2:24][OH:25])[C:20]([O:22][CH3:23])=[O:21].[O-]S([O-])(=O)=O.[Mg+2].[BH4-].[Na+]>C(Cl)Cl.C(N(CC)CC)C>[Si:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH2:12][NH:18][C@@H:19]([CH2:24][OH:25])[C:20]([O:22][CH3:23])=[O:21])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(C=O)c1
Reactant: COC(=O)[C@@H](N)CO
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](CO)NCc1cccc(O[Si](C)(C)C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 36 h
Yield: 96.2 %

Procedure:
To a solution of 3-(tert-butyldimethylsilyloxy)benzaldehyde (Example 12-1c) 1.52 g (6.43 mmol), triethyl amine (5 mL) and (S)-methyl 2-amino-3-hydroxypropanoate hydrochloride (1.00 g, 6.43 mmol) in DCM (30 mL) was added MgSO4 and the solution was stirred at RT for 36 h. MgSO4 was then filtered off and DCM was removed under vacuum. The residue was dissolved in dry MeOH (40 mL), cooled to 0° C. and treated in small portions with NaBH4 (1.2 equiv.). The mixture was stirred at 0° C. for 3 h, quenched with water (10 mL) and concentrated by removing MeOH. The residue was extracted with Ethyl acetate to provide (S)-methyl 2-(3-(tert-butyldimethylsilyloxy)benzylamino)-3-hydroxypropanoate as yellowish oil (2.10 g, 96%). MS 340 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C@@H:8]([NH:17][C:18]([C@@H:20]2[CH2:25][CH2:24][CH2:23][N:22]([C:26](=[O:42])[CH2:27][CH2:28][CH:29]3[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]3)[CH2:21]2)=[O:19])[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:5]=[N:6][CH:7]=1.[F:43][CH2:44][CH2:45][O:46][C:47]1[CH:52]=[CH:51][C:50]([C:53]#[C:54][Si](C)(C)C)=[CH:49][CH:48]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>COCCOC.C(N)CCC.C1COCC1.O.[Cu](I)I.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:13]([O:12][C:10](=[O:11])[CH2:9][C@H:8]([NH:17][C:18]([C@@H:20]1[CH2:25][CH2:24][CH2:23][N:22]([C:26](=[O:42])[CH2:27][CH2:28][CH:29]2[CH2:30][CH2:31][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:33][CH2:34]2)[CH2:21]1)=[O:19])[C:4]1[C:5]([C:54]#[C:53][C:50]2[CH:51]=[CH:52][C:47]([O:46][CH2:45][CH2:44][F:43])=[CH:48][CH:49]=2)=[N:6][CH:7]=[CH:2][CH:3]=1)([CH3:14])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)C[C@H](NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cncc(Br)c1
Reactant: C[Si](C)(C)C#Cc1ccc(OCCF)cc1
Agent: I[Cu]I
Agent: [Pd]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: COCCOC
Solvent: O
Solvent: CCCCN
Product: CC(C)(C)OC(=O)C[C@H](NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cccnc1C#Cc1ccc(OCCF)cc1
Yield: 39 %

Procedure:
To a degassed solution of tert-butyl 4-[3-((3R)-3-{[(1S)-1-(5-bromopyridin-3-yl)-3-tert-butoxy-3-oxopropyl]carbamoyl}piperidin-1-yl)-3-oxopropyl]piperidine-1-carboxylate (example 27c, 100 mg, 150 μmol), copper iodide (3.5 mg, 20 μmol), tetrakis(triphenylphosphine) palladium(0) (17.7 mg, 20 μmol) and {[4-(2-fluoroethoxy)phenyl]ethynyl}(trimethyl)silane (73 mg, 310 μmol) in 1,2-dimethoxyethan (0.9 mL) and n-butyl amine (0.23 mL) was added a 1 M tetra-n-butyl ammonium fluoride solution in THF (200 μL) over 15 minutes at 80° C. After 20 additional minutes at 80° C. (36 mg, mmol) was added, the mixture was diluted with water after 20 minutes and extracted with ethyl acetate. The organic phase was dried over sodium sulfate and concentrated in vacuum. The residue was purified by preparative HPLC to yield 43 mg of tert-butyl 4-{3-[(3R)-3-{[(1S)-3-tert-butoxy-1-({[4-(2-fluoroethoxy)phenyl]ethynyl}pyridin-3-yl)-3-oxopropyl]carbamoyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:21]1([C:24]([NH:26][NH2:27])=[O:25])[CH2:23][CH2:22]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@@H:10]1[CH2:11][CH2:12][C@@H:13]2[C:18]([NH:27][NH:26][C:24]([CH:21]1[CH2:23][CH2:22]1)=[O:25])=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: NNC(=O)C1CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(NNC(=O)[C@H]1CC[C@H]2CN1C(=O)N2OCc1ccccc1)C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.7 %

Procedure:
To a solution of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid 1 (0.25 g, 0.90 mmol) in dry DCM (30 mL) were added cyclopropanecarbohydrazide 196 (0.135 g, 1.35 mmol), 1-hydroxybenzotriazole (0.19 g, 1.35 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.26 g, 1.35 mmol) and 4-(dimethylamino)pyridine (0.16 g, 1.35 mmol) at room temperature. The reaction mixture was stirred at room temperature overnight, and concentrated under vacuum. The residue was purified by column chromatography to give (2R,5S)-6-(benzyloxy)-N′-(cyclopropylcarbonyl)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide 197 (0.27 g, 84%) as a white solid.
Reaction SMILES: CC(C)([O-])C.[K+].[OH:7][C:8]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:9]=1[CH2:10][CH2:11][CH2:12][CH:13]2[N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.Br[CH2:25][CH2:26][CH2:27][N:28]1[C:32](=[O:33])[C:31]2=[CH:34][CH:35]=[CH:36][CH:37]=[C:30]2[C:29]1=[O:38]>CN(C)C=O>[C:29]1(=[O:38])[N:28]([CH2:27][CH2:26][CH2:25][O:7][C:8]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:9]=2[CH2:10][CH2:11][CH2:12][CH:13]3[N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:32](=[O:33])[C:31]2=[CH:34][CH:35]=[CH:36][CH:37]=[C:30]12
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: Oc1cccc2c1CCCC2N1CCOCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCCOc1cccc2c1CCCC2N1CCOCC1
Reaction time: 48 h
Yield: 85.3 %

Procedure:
Potassium t-butoxide (7.8 g) is added to a stirred solution of 5-hydroxy-1-morpholinyl-1,2,3,4-tetrahydronaphthalene (14.7 g) dissolved in dimethylformamide (150 ml) and the reaction solution stirred for a few minutes. N-(3-bromopropyl) phthalimide (33.8 g) is added to the reaction mixture and stirring is continued at RT for 2 days. The reaction mixture is partitioned between H2O and ether, the layers separated and the aqueous layer adjusted to a pH>10 with sodium hydroxide solution and extracted with additional diethyl ether. The combined ether layers are washed with H2O and aqueous 5% hydrochloric acid. The acidic aqueous extracts are made strongly alkaline with sodium hydroxide solution, resulting in an oily precipitate which is extracted with ether and methylene chloride. The combined organic layers are washed with 5% aqueous sodium hydroxide and saturated sodium chloride, dried over sodium sulfate, filtered, and evaporated, resulting in 22.6 g of an amber oil as the crude product used in the next step.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][O:7][C:8]1[C:13]2[S:14][CH:15]=[CH:16][C:12]=2[CH:11]=[CH:10][CH:9]=1.[C:17]([O-])(=[O:19])C.[Na+]>CN(C=O)C.O>[CH3:6][O:7][C:8]1[C:13]2[S:14][CH:15]=[CH:16][C:12]=2[C:11]([CH:17]=[O:19])=[CH:10][CH:9]=1
Reactant: CC(=O)[O-]
Reactant: COc1cccc2ccsc12
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C=O)c2ccsc12
Temperature: 117 °C
Reaction time: 0.5 h
Yield: 67.2 %

Procedure:
Phosphorous oxychloride (7.1 mL, 76.7 mmol) is added dropwise to a cooled dry DMF (13.2 mL, 170.4 mmol) at such rate that the temperature does not exceed 5° C. After 30 minutes at this temperature, a solution of 7-methoxybenzo[b]thiophene (7.00 g, 42.6 mmol) in dry DMF (2 mL) is added dropwise. The stirring continues at 5° C. for 30 minutes and at room temperature for 45 minutes. Afterward, the mixture is heated to 117° C. and then at 90° C. for 2 hours, cooled to 0° C., and neutralized with a solution of sodium acetate (62 g) in water (300 mL). The resulting mixture is extracted with diethyl ether (5×150 mL) and the organic layers are washed with cooled water (5×100 mL), saturated aqueous sodium chloride (100 mL), dried (MgSO4) and concentrated. The crude material is purified on slica gel (hexanes/EtOAc 9:1) to give 7-methoxybenzo[b]thiophene-4-carbaldehyde as a yellow solid (5.5 g, 68% yield). To a stirred solution of the intermediate (14.9 g, 77.5 mmol) in acetone (300 mL) is slowly added a solution of potassium permanganate (14.9 g, 94.3 mmol) in water (525 mL) at 0° C. and the mixture is stirred for 75 minutes. Then, isopropanol (100 mL) is added and the mixture is divided in two portions. Each portion is treated with HCl (100 mL, 12%), diluted with water (300 mL) and extracted with EtOAc (3×300 mL). Organic layers are washed with water (300 mL), saturated aqueous sodium chloride (300 mL), dried (MgSO4), and concentrated. Residue is collected and diluted with EtOAc (600 mL) and the suspension is warmed to 70° C. and filtered to give the title compound as a white solid (10.3 g, 63% yield). At room temperature, the filtrate forms a suspension. After filtration, an additional 3.2 g is obtained. ES+(m/z) 207 [M−H].
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][CH2:6][C:7]1([C:18]2[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=2)[O:15][CH2:14][C:13]2[CH:12]=[C:11]([C:16]#[N:17])[CH:10]=[CH:9][C:8]1=2)C.Br.ClC(OC(Cl)C)=O>CCOC(C)=O.[OH-].[NH4+]>[CH3:1][NH:2][CH2:4][CH2:5][CH2:6][C:7]1([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[C:8]2[CH:9]=[CH:10][C:11]([C:16]#[N:17])=[CH:12][C:13]=2[CH2:14][O:15]1
Reactant: CN(C)CCCC1(c2ccc(F)cc2)OCc2cc(C#N)ccc21
Agent: Br
Agent: CC(Cl)OC(=O)Cl
Agent: [NH4+]
Solvent: CCOC(C)=O
Product: CNCCCC1(c2ccc(F)cc2)OCc2cc(C#N)ccc21
Temperature: 130 °C
Reaction time: 14 h

Procedure:
The title compound was prepared according to the method of C. Jin, et al (Synthetic Communications, 2007, 37, 901-908). Thus, citalopram hydrobromide (5.5 g, 13.6 mmol) in 500 mL EtOAc was washed with dilute ammonium hydroxide (100 mL). The EtOAc layer was washed 3×100 mL saturated aqueous NaCl and dried with MgSO4. The solvent was removed in vacuo and the residue was treated with 1-chlorethyl chloroformate (29.6 mL, 27.2 mmol), heated to 130° C. for 6 hr, cooled to rt and concentrated in vacuo. The residue was dissolved with 150 mL CH3OH and heated for 5 hr at 65° C. The solvents were then removed in vacuo. The crude product was dissolved in THF (50 mL) and 50 mL of 1N NaOH were added. The mixture was stirred at rt for an additional 14 hr, then extracted with EtOAc (3×50 mL). The extracts were washed with saturated NaCl (3×100 mL), dried with Na2SO4 and the solvents removed. Chromatography on silica gel, eluting with a gradient (100% CH2Cl2 to 50% CH3OH: 50% CH2Cl2) gave the product as a clear oil, 3.102 g (74%).
Reaction SMILES: [CH3:1][O:2][C:3]1([O:10][CH3:11])[CH2:8][CH2:7][O:6][CH2:5][C:4]1=O.P([O-])(O)(O)=O.[K+].C([O-])=O.[Na+].[NH2:22][C@H](C(O)=O)C.[OH-].[Na+].C1N=C(N)C2N=CN([C@@H]3O[C@H](COP(OP(OC[C@H]4O[C@@H](N5C=C(C(N)=O)CC=C5)[C@H](O)[C@@H]4O)(O)=O)(O)=O)[C@@H](O)[C@H]3O)C=2N=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(#N)C>[CH3:1][O:2][C:3]1([O:10][CH3:11])[CH2:8][CH2:7][O:6][CH2:5][C@@H:4]1[NH2:22]
Reactant: COC1(OC)CCOCC1=O
Reactant: C[C@H](N)C(=O)O
Agent: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1
Agent: O=C([O-])[O-]
Agent: O=C[O-]
Solvent: Cc1ccccc1
Solvent: CC#N
Product: COC1(OC)CCOC[C@@H]1N
Temperature: 45 °C
Reaction time: 0.5 h

Procedure:
A solution of 4,4-dimethoxydihydro-2H-pyran-3(4H)-one (172 g, 1.07 mol, see Example 1) in 310 mL of toluene was stirred in toluene for 30 min, then extracted 3× with water (270 mL). To the aqueous solution was added potassium dihydrogenphosphate (14.1 g, 0.104 mol), sodium formate (55.1 g, 0.810 mol), and L-Alanine (72.2 g, 0.810 mol). The pH was adjusted to 7.8 with 5N NaOH, and NAD (0.810 g), PLP (0.810 g), LDH (0.162 g), FDH (1.62 g), and Codexis TA P1G5 (4.05 g) were added. The mixture was heated to 45° C. for 12 h, then cooled to rt. Potassium carbonate (324 g, 2.34 mol) was added, and after 30 min, the mixture was diluted with acetonitrile (810 mL). After 30 min, the reaction was filtered through a pad of solka-floc. The filtrate was partitioned and the aqueous layer was extracted with additional acetonitrile (810 mL). The combined organic fractions were concentrated in vacuo to provide crude (35)-4,4-dimethoxytetrahydro-2H-pyran-3-amine
Reaction SMILES: [CH2:1]([N:8]1[CH2:11][CH:10](O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-]#N.[Na+].[CH3:16][N:17](C)C=O>O>[CH2:1]([N:8]1[CH2:11][CH:10]([C:16]#[N:17])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC1CN(Cc2ccccc2)C1
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Product: N#CC1CN(Cc2ccccc2)C1

Procedure:
1.7 g of 2A, and 1.2 g of sodium cyanide were stirred together in 1 ml of water and 20 ml of dimethylformamide at 60° C. for 16 hours. The solvent was evaporated under reduced pressure and the residue was purified by chromatography on silica gel using isopropanol in dichloromethane as eluent to give 1-benzyl-3-cyanoazetidine (2B), yield 0.5 g.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=2)C(O)=O)[C:5]([Cl:18])=[CH:4][N:3]=1.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[O:40]([CH3:42])[NH2:41].[CH3:43][O:44]N.C(N(C(C)C)CC)(C)C.C([O-])(O)=O.[Na+]>CN(C)C=O.C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:17]=[CH:16][CH:15]=[CH:11][C:10]=2[C:43]([NH:41][O:40][CH3:42])=[O:44])[C:5]([Cl:18])=[CH:4][N:3]=1
Reactant: CON
Reactant: O=C(O)c1cccc(Nc2cc(Cl)ncc2Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CONC(=O)c1ccccc1Nc1cc(Cl)ncc1Cl
Reaction time: 0.17 h
Yield: 58 %

Procedure:
A solution of 3-[(2,5-dichloro-4-pyridinyl)amino]benzoic acid (500 mg, 1.766 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (EDC) (339 mg, 1.766 mmol) and 1-hydroxybenzotriazole (HOBT) (270 mg, 1.766 mmol) in N,N-dimethylformamide (3532 μl) was stirred at room temperature for 30 min. To this solution O-methylhydroxylamine (aminoxy)methane (148 mg, 1.766 mmol) was then added and stirred for another 10 min. The reaction mixture was cooled using an ice water bath. Then diisopropylethylamine (617 μl, 3.53 mmol) was added. After the addition was finished, the reaction mixture was stirred at room temperature overnight. The reaction mixture was followed by HPLC and LCMS. The final crude material was worked up by addition of saturated aqueous NaHCO3 and CH2Cl2. Organic phase was washed with brine then dried over MgSO4. The solution was filtered and solvent was removed by evaporation. The oil like crude material was loaded on silica column and eluted with MeOH in CH2Cl2 with NH4OH 0.1% to give the target compound 2-[(2,5-dichloro-4-pyridinyl)amino]-N-(methyloxy)benzamide (320 mg, 1.025 mmol, 58.0% yield) as a yellow solid; MS; M(C13H11Cl2N3O2)=312.15, (M+H)+=312, 313.9; 1H NMR (400 MHz, CHLOROFORM-d) ppm 9.66 (br. s., 1 H) 9.60 (br. s., 1 H) 8.20 (s, 1 H) 7.49-7.61 (m, 3 H) 7.24 (s, 1 H) 7.09-7.16 (m, 1 H) 3.90 (s, 3 H).
Reaction SMILES: [OH-].[Na+].Br[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][Br:10].[CH2:11]([OH:15])[CH2:12][C:13]#[CH:14].COC(C)(C)C>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl-].[Na+].O>[CH2:11]([O:15][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][Br:10])[CH2:12][C:13]#[CH:14]
Reactant: BrCCCCCCBr
Reactant: C#CCCO
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Cl-]
Solvent: O
Solvent: COC(C)(C)C
Product: C#CCCOCCCCCCBr
Temperature: 50 °C
Reaction time: 8 h
Yield: 31.1 %

Procedure:
A mixture of 50% w/v aqueous sodium hydroxide (2500 ml), 1,6-dibromohexane (2610 g) and tetra-butylammonium bromide (25 g) was warmed to 50° C., with stirring. But-3-yn-1-ol (500 g) was then added to the reaction mixture at such a rate as to ensure the content's temperature did not exceed 65° C. The reaction was left at 50° C. overnight before being cooled to room temperature. Tert-butyl methyl ether (2500 ml) and brine (2000 ml) was added to the cooled mixture and the layers allowed to separate. The ethereal layer was washed with water (2×2000 ml), brine (1×2000 ml), and then dried over anhydrous MgSO4. The solution was filtered and concentrated under reduced pressure to give crude product as a liquid. This was further purified by fractional distillation using a 60 cm vacuum jacketed Vigreux column at ca. 0.5 mbar. The product was obtained in the fraction which boiled at 92-98° C., to give the title compound (518 g), LC RT=6.16, δ (CDCl3) 3.55 (2H, t, J 6.9 Hz), 3.46 (2H, t, J 6.9 Hz), 3.41 (2H, t, J 6.9 Hz), 2.46 (2H, dt, J 2.5, 6.9 Hz), 1.98 (1H, t, J 2.5 Hz), 1.86 (2H, m), 1.59 (2H, m), 1.46 (2H, m), 1.38 (2H, m).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([NH2:18])=[C:12]2[C:19]#[N:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]([O-])([O-])=O.[Cs+].[Cs+].CI.O>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH3:21])[C:13]([NH2:18])=[C:12]2[C:19]#[N:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: N#Cc1c(N)[nH]c2ccc(OCc3ccccc3)cc12
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: Cn1c(N)c(C#N)c2cc(OCc3ccccc3)ccc21
Reaction time: 1 h
Yield: 88.8 %

Procedure:
A solution of 5-benzyloxy-2-amino-1H-indole-3-carbonitrile (2.96 g; 11.25 mmol) in DMF (20 ml) under argon was treated at room temperature with Cs2CO3 (4.4 g; 13.5 mmol). The mixture was stirred and treated dropwise with methyl iodide (0.84 ml; 13.48 mmol). Stirring was continued for 1 hour when the mixture was poured into water. The precipitate was filtered, washed with water and dried to give 5-benzyloxy-2-amino-1-methyl-1H-indole-3-carbonitrile as a beige solid (2.77 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[O:10][C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[N:13]=1.[Br:18]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:18][CH2:8][C:6]1[CH:5]=[CH:4][C:3]([C:9]2[O:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)=[C:2]([F:1])[CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(-c2nc3ccccc3o2)c(F)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1cc(CBr)ccc1-c1nc2ccccc2o1

Procedure:
To a solution of 5.0 gm. of 2-(2-fluoro-4-methylphenyl)benzoxazole in 200 cc. of carbon tetrachloride is added 4.5 gm. of N-bromosuccinimide and 50 mg. of dibenzoyl peroxide. The mixture is refluxed for 2 hours, filtered to remove succinimide and concentrated in vacuo. The residue is recrystallized from toluene to give 2-(4-bromomethyl-2-fluorophenyl)benzoxazole, m.p. 170°-173°C.