Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][CH:15]=[CH:14][C:5]=1[CH2:6][N:7]1[CH2:12][CH2:11][CH2:10][O:9][C:8]1=[O:13])([O-])=O.[Cl-].[NH4+].O>C(O)C.[Fe]>[NH2:1][C:4]1[CH:17]=[CH:16][CH:15]=[CH:14][C:5]=1[CH2:6][N:7]1[CH2:12][CH2:11][CH2:10][O:9][C:8]1=[O:13]
Reactant: O=C1OCCCN1Cc1ccccc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1ccccc1CN1CCCOC1=O
Temperature: 25 °C

Procedure:
3-(2-Nitrobenzyl)-[1,3]-oxazinan-2-one (0.24 g, 1.02 mmol), iron powder (0.28 g, 5.02 mmol), ammonium chloride (0.03 g, 0.56 mmol) were suspended in ethanol (10 ml) and water (5 ml) and heated to reflux for one hour. After cooling to room temperature, the reaction mixture was filtered with suction and extracted with ethyl acetate. The organic layer was washed with a saturated brine and then dried over anhydrous sodium sulfate, and 3-(2-aminobenzyl)-[1,3]-oxazinan-2-one was obtained by evaporating the solvent under reduced pressure (0.20 g).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:20][N:21]([CH3:33])[CH2:22][CH2:23][O:24][C:25]1[CH:32]=[CH:31][C:28]([CH:29]=O)=[CH:27][CH:26]=1>>[CH3:20][N:21]([CH3:33])[CH2:22][CH2:23][O:24][C:25]1[CH:26]=[CH:27][C:28]([CH2:29][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]4[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=4)[N:12]=3)[CH2:6][CH2:5]2)=[CH:31][CH:32]=1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Reactant: CN(C)CCOc1ccc(C=O)cc1
Product: CN(C)CCOc1ccc(CN2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 4-(2-dimethylaminoethoxy)benzaldehyde was carried out according to General Synthetic Method 7. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give N,N-dimethyl-2-[4-[[4-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperazin-1-yl]methyl]phenoxy]ethanamine.
Reaction SMILES: [Na].CO.[Cl:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH:15]=[N:14][C:13]([OH:16])=[N:12]1.Br[CH:18]([CH3:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20]>CS(C)=O>[Cl:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH:15]=[N:14][C:13]([O:16][CH:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH3:24])=[N:12]1
Reactant: CCOC(=O)C(C)Br
Reactant: Oc1ncn(-c2ccccc2Cl)n1
Agent: [Na]
Solvent: CS(C)=O
Solvent: CO
Product: CCOC(=O)C(C)Oc1ncn(-c2ccccc2Cl)n1
Yield: 92.6 %

Procedure:
The process was carried out essentially according to that of Example 2 above, starting with 1.2 g of sodium, 30 ml of methanol, 10 g of 1-(2-chlorophenyl)-3-hydroxy-1,2,4-1H-triazole and 9.3 g of ethyl 2-bromopropionate. The solvent was 100 ml of dimethylsulfoxide. The product obtained was 14 g of the desired product, an oil.
Reaction SMILES: [OH2:1].Br.[CH2:3]([O:10][C@@H:11]1[C@@H:16]([CH2:17][O:18][C:19](=[O:21])[CH3:20])[O:15][CH:14]=[CH:13][C@H:12]1[O:22][C:23](=[O:25])[CH3:24])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH2:26].C(=O)(O)[O-].[Na+]>O1CCCC1>[CH2:3]([O:10][C@H:11]([C@@H:16]([CH2:17][O:18][C:19](=[O:21])[CH3:20])[OH:15])[C@H:12]([O:22][C:23](=[O:25])[CH3:24])[C@@H:13]([OH:26])[CH:14]=[O:1])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O
Reactant: CC(=O)OC[C@H]1OC=C[C@@H](OC(C)=O)[C@@H]1OCc1ccccc1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)OC[C@@H](O)[C@@H](OCc1ccccc1)[C@H](OC(C)=O)[C@@H](O)C=O
Temperature: 25 °C

Procedure:
48% Hydrobromic acid water solution (0.5 mL) was added to a mixture of 4-O-benzyl-3,6-di-O-acetyl-D-glucal (5 mmol) in tetrahydrofuran (50 mL), and obtained solution was stirred in room temperature. After reaction was completed (TLC) the reaction mixture was poured into the 10% water solution of sodium bicarbonate (125 mL), and water solution was extracted with ethyl acetate (3×30 mL). Combined organic extracts were washed with water and dried over sodium sulfate. Drying agent and solvents were removed and product was purified by column chromatography (SilicaGel 60 Merck), using hexanes:ethyl acetate as eluents.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:10])[CH:6]=[C:7]([NH2:9])[NH2:8])[CH3:3].C(N(CC)CC)C.[C:18](#[N:21])[CH:19]=[CH2:20]>O1CCCC1>[CH2:2]([O:4][C:5](=[O:10])[C:6]([CH2:20][CH2:19][C:18]#[N:21])=[C:7]([NH2:9])[NH2:8])[CH3:3]
Reactant: CCOC(=O)C=C(N)N
Reactant: C=CC#N
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)C(CCC#N)=C(N)N
Yield: 25 %

Procedure:
The resulting 3,3-diamino-acrylic acid ethyl ester hydrochloride (2.2 g, 13.2 mmol) was suspended in tetrahydrofuran (40 mL), triethylamine (2 mL, 14.3 mmol) and acrylonitrile (1.2 mL, 19.3 mmol) were added thereto, and the solution was refluxed for 6 hours. After the reaction was completed, the resulting triethylamine hydrochloride was filtered, and the filtrate was concentrated to obtain the title compound (0.6 g, 3.3 mmol, 25%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[C@H:5]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[O:28][N:27]=[CH:26][CH:25]=2)=[CH:20][CH:19]=1)[NH:6][C:7](=[O:16])[C:8]1[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH3:15])[CH:9]=1)[CH3:2].[CH3:30]I.[H-].[Na+].O>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:29])[C@H:5]([CH2:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[O:28][N:27]=[CH:26][CH:25]=2)=[CH:22][CH:23]=1)[N:6]([C:7](=[O:16])[C:8]1[CH:9]=[C:10]([CH3:15])[CH:11]=[C:12]([CH3:14])[CH:13]=1)[CH3:30])[CH3:2]
Reactant: CCOC(=O)[C@H](Cc1ccc(-c2ccno2)cc1)NC(=O)c1cc(C)cc(C)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)[C@H](Cc1ccc(-c2ccno2)cc1)N(C)C(=O)c1cc(C)cc(C)c1
Temperature: 25 °C

Procedure:
A solution of N-(3,5-dimethylbenzoyl)-3-[4-(5-isoxazolyl)-phenyl]-alanine ethyl ester (3,8 g) and methyliodide (1.8 ml) in dry N,N-dimethylformamide (40 ml) is cooled in an ice bath and sodium hydride (60% in oil, 390 mg) is added in portions. The mixture is allowed to warm to room temperature during 5 hours, then poured into water, extracted with ethyl acetate, the organic phase washed with water, and with brine, dried and evaporated. Flash chromatography of the residue on silica gel (hexane/ethyl acetate 3:1) gives pure N-(3,5-dimethylbenzoyl)-N-methyl-3-[4-(5-isoxazolyl)-phenyl]-alanine ethyl ester. NMR (CDCl3, 400 MHz) δ [ppm] 8.30 (d, broad, 1H), 7.75 (m, 2H), 7.41 (d, broad, 1H), 7.12 (d, broad, 1H), 6.97 (s, 0.5H), 6.93 (s, 0.5 H), 6.70 (s, 1H), 6.53 (d, broad, 1H), 6.36 (d, broad, 1H), 5.40 (m, 0.5H), 4.58 (m, 0.5H), 4.27 (m, 2H), 3.54 (m, 0.5H), 3.25 (m, 1H), 3.05 (m, 2H), 2.78 (s, 1.5H), 2.23 (s, 3H), 2.13 (s, 3H), 1.27 (m, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:11]2[C:6](=[CH:7][C:8]([N+:14]([O-])=O)=[C:9]([O:12][CH3:13])[CH:10]=2)[NH:5][C:4](=[O:17])[CH2:3]1.CO.[H][H]>C(OCC)(=O)C.[Pd]>[NH2:14][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([CH3:1])([CH3:18])[CH2:3][C:4](=[O:17])[NH:5]2)=[CH:10][C:9]=1[O:12][CH3:13]
Reactant: COc1cc2c(cc1[N+](=O)[O-])NC(=O)CC2(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1cc2c(cc1N)NC(=O)CC2(C)C
Yield: 92 %

Procedure:
4,4-dimethyl-6-(methyloxy)-7-nitro-3,4-dihydro-2(1H)-quinolinone (250 mg, 1.00 mmol) was dissolved in ethyl acetate (10 mL) and transferred to a Fischer Porter apparatus. 10% Palladium on carbon (250 mg, Aldrich) was added followed by methanol (20 mL) and the mixture stirred under 60 psi hydrogen pressure for 16 h. The pressure was released, the reaction vessel evacuated, and back-filled with nitrogen twice. The mixture was filtered through celite and the filtrate was concentrated to provide 7-amino-4,4-dimethyl-6-(methyloxy)-3,4-dihydro-2(1H)-quinolinone (213 mg, 0.92 mmol, 92%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.16 (s, 6 H), 2.22 (s, 2 H), 3.72 (s, 3 H), 4.66 (s, 2 H), 6.20 (s, 1 H), 6.67 (s, 1 H), 9.76 (s, 1 H).
Reaction SMILES: [C:1](Cl)(=[O:7])/[CH:2]=[CH:3]/[CH:4]=[CH:5]/[CH3:6].[CH2:9]([NH:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH:10]=[CH2:11].[OH-].[Na+]>C(Cl)Cl>[CH2:9]([N:12]([CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:1](=[O:7])/[CH:2]=[CH:3]/[CH:4]=[CH:5]/[CH3:6])[CH:10]=[CH2:11]
Reactant: C/C=C/C=C/C(=O)Cl
Reactant: C=CCNCCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: C=CCN(CCc1ccccc1)C(=O)/C=C/C=C/C
Reaction time: 1 h
Yield: 100.6 %

Procedure:
Sorboyl chloride (3.53 g) was added to a mixture of 4.0 g of N-allylphenethylamine, 25 mL of methylene chloride and 25 mL of 15% aqueous sodium hydroxide, keeping the temperature below 15°. The mixture was stirred in an ice bath for 1 hour, then at room temperature overnight. The aqueous layer was extracted several times with toluene and the combined organic phases were washed successively with 5% hydrochloric acid, water, and 10% sodium carbonate solution. Removal of the solvents gave 6.37 g of N-allyl-N-phenethylsorbamide. This product was heated under reflux in 50 mL of p-xylene for 10 hours. Removal of the solvent gave 6-methyl-3a,4,5,7a-tetrahydroisoindolin-1-one as a mixture of isomers still containing about 10% of the uncyclized starting material.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Cl[C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH3:17])[CH:14]=2)[C:9]([CH2:18][C:19]2[C:24]([Cl:25])=[CH:23][N:22]=[CH:21][C:20]=2[Cl:26])=[N:8][N:7]=1.O>CN(C=O)C>[Cl:25][C:24]1[CH:23]=[N:22][CH:21]=[C:20]([Cl:26])[C:19]=1[CH2:18][C:9]1[C:10]2[C:15](=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[C:6]2=[N:7][N:8]=[N:3][N:2]2[N:1]=1
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccc2c(Cc3c(Cl)cncc3Cl)nnc(Cl)c2c1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(Cc3c(Cl)cncc3Cl)nn3nnnc3c2c1
Temperature: 80 °C
Reaction time: 7 h
Yield: 78.5 %

Procedure:
NaN3 was added to a solution under N2 of 4-chloro-1-(3,5-dichloro-pyridin4-ylmethyl)-6-methoxy-phthalazine (1 g, 2.82 mmoles), obtained as described in example 13, in anhydrous DMF (20 ml) and the mixture was heated at 80° C. overnight, then at 120° C. for 7 hours, then poured into water (10 volumes) and extracted 3 times with CH2Cl2, dried and concentrated under vacuum to give a solid which was purified by flash chromatography (eluent:60:80 petrolatum/ethyl acetate 6:4). The eluate was crystallised from acetonitrile (75 ml) to give 0.36 g of the title compound (yield: 78.5%). m. p.: 275-276° C.
Reaction SMILES: [C:1](=[N:9][OH:10])([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].C([N+](CCCC)(CCCC)CCCC)CCC.[OH-].[Na+].[S:31]1[CH:35]=[CH:34][CH:33]=[C:32]1[C:36](Cl)=O>CC1CCCO1.O>[C:2]1([C:1]2[N:8]=[C:36]([C:32]3[S:31][CH:35]=[CH:34][CH:33]=3)[O:10][N:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=NO)c1ccccc1
Reactant: O=C(Cl)c1cccs1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC1CCCO1
Product: c1ccc(-c2noc(-c3cccs3)n2)cc1
Temperature: 70 °C
Yield: 95 %

Procedure:
A 39.45% solution of benzamide oxime in 2-methyltetrahydrofuran (33.34 g) was charged to a 100 mL flask, followed by water (9.0 g), 40% aqueous solution of tetrabutylammonium hydroxide (1.02 g), and 51% sodium hydroxide (3.52 g, 0.045 moles). To this mixture was added 2-thiophenecarbonyl chloride (13.83 g, 0.0936 moles) and 51% sodium hydroxide (7.33 g, 0.0935 moles) simultaneously over a 30 minute period while heating to about 70° C. The reaction was complete in less than 80 minutes. The aqueous salt phase was removed, water was added (30 g), and the 2-methyltetrahydrofuran partly removed by atmospheric distillation (13.5 mL). An additional amount (32 g) of hot water was added, and the remainder of the 2-methyltetrahydrofuran was distilled out, during which time the product, 3-phenyl-5-(2-thienyl)-1,2,4-oxadiazole, precipitated. The aqueous slurry of 3-phenyl-5-(2-thienyl)-1,2,4-oxadiazole was filtered, washed with water and dried overnight in a vacuum oven to yield 3-phenyl-5-(2-thienyl)-1,2,4-oxadiazole, 20.47 g, 99.1% pure, 95.0% yield.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:21][C:22]2[CH:26]=[CH:25][N:24]([CH:27]([CH3:29])[CH3:28])[N:23]=2)[C:5]2[N:6]([C:8]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][N:17]=[CH:16][C:15]=3[F:20])=[O:12])=[CH:9][N:10]=2)[N:7]=1.[NH2:30][C@H:31]1[CH2:36][CH2:35][C@H:34]([OH:37])[CH2:33][CH2:32]1>CO>[F:20][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][C:14]=1[NH:13][C:11]([C:8]1[N:6]2[N:7]=[C:2]([NH:30][C@H:31]3[CH2:36][CH2:35][C@H:34]([OH:37])[CH2:33][CH2:32]3)[CH:3]=[C:4]([NH:21][C:22]3[CH:26]=[CH:25][N:24]([CH:27]([CH3:29])[CH3:28])[N:23]=3)[C:5]2=[N:10][CH:9]=1)=[O:12]
Reactant: CC(C)n1ccc(Nc2cc(Cl)nn3c(C(=O)Nc4ccncc4F)cnc23)n1
Reactant: N[C@H]1CC[C@H](O)CC1
Solvent: CO
Product: CC(C)n1ccc(Nc2cc(N[C@H]3CC[C@H](O)CC3)nn3c(C(=O)Nc4ccncc4F)cnc23)n1

Procedure:
The title compound was prepared from 48A and (trans)-4-aminocyclohexanol in a similar way as Example 44. HPLC Rt=2.850 min (Chromolith SpeedROD 4.6×50 mm, 10-90% aqueous methanol containing 0.1% TFA, 4 min gradient, monitored at 220 nm), [M+1]=494.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.Cl[Si:12]([CH:19]([CH3:21])[CH3:20])([CH:16]([CH3:18])[CH3:17])[CH:13]([CH3:15])[CH3:14].[Li]CCCC.O>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([Si:12]([CH:19]([CH3:21])[CH3:20])([CH:16]([CH3:18])[CH3:17])[CH:13]([CH3:15])[CH3:14])[CH:6]=[CH:5]2
Reactant: Fc1ccc2[nH]ccc2c1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(F)ccc21
Temperature: -78 °C
Reaction time: 1 h
Yield: 97.6 %

Procedure:
To a mixture of 5-fluoro-1H-indole (2.5 g, 18.52 mmol) and chlorotriisopropyl-silane (3.92 g, 20.4 mmol) in anhydrous THF (75 mL) at −78° C. was added dropwise a solution of n-BuLi in THF (1.6 mol/L, 12.7 mL, 20.37 mmol) at a rate to maintain the internal reaction temperature below −70° C. After the addition was completed, the mixture was stirred at −78° C. for 1 h and then poured into water (250 mL), extracted with DCM (100 mL×3), and concentrated in vacuo to afford 5-fluoro-1-(triisopropylsilyl)-1H-indole as a yellow oil (5.27 g, 97.6%). MS (ESI): m/z=292.3 [M+1]+.
Reaction SMILES: [CH:1]1([N:4]2[C:12]([CH3:13])=[C:11]3[C:6]([CH:7]=[CH:8][C:9]([N:14]4[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]4=[O:21])=[CH:10]3)=[N:5]2)[CH2:3][CH2:2]1.Cl[CH2:23][C:24]1[S:25][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:27][CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH:1]1([N:4]2[C:12]([CH3:13])=[C:11]3[C:6]([CH:7]=[CH:8][C:9]([N:14]4[CH:19]=[CH:18][C:17]([O:20][CH2:23][C:24]5[S:25][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:27][CH:28]=5)=[CH:16][C:15]4=[O:21])=[CH:10]3)=[N:5]2)[CH2:2][CH2:3]1
Reactant: Cc1c2cc(-n3ccc(O)cc3=O)ccc2nn1C1CC1
Reactant: FC(F)(F)c1ccc(CCl)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1c2cc(-n3ccc(OCc4ccc(C(F)(F)F)s4)cc3=O)ccc2nn1C1CC1
Reaction time: 8 h
Yield: 43.6 %

Procedure:
To a mixture of 1-(2-cyclopropyl-3-methyl-2H-indazol-5-yl)-4-hydroxypyridin-2(1H)-one (200 mg) and 2-(chloromethyl)-5-(trifluoromethyl)thiophene (171 mg) in DMF (4 ml) was added potassium carbonate (118 mg) at room temperature, and the mixture was stirred at the same temperature overnight. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was fractionated by HPLC (C18, mobile phase: water/acetonitrile (containing 0.1% NH4HCO3)), and saturated aqueous sodium hydrogen carbonate solution was added to the obtained fraction. The mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was crystallized from methanol-water to give the title compound (138 mg).
Reaction SMILES: [NH2:1][C@@H:2]([C:5]([CH3:8])([CH3:7])[CH3:6])[CH2:3][OH:4].[CH:9](=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[BH4-].[Na+]>C1C=CC=CC=1>[CH2:9]([NH:1][C@@H:2]([C:5]([CH3:8])([CH3:7])[CH3:6])[CH2:3][OH:4])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(C)(C)[C@H](N)CO
Reactant: O=Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: c1ccccc1
Product: CC(C)(C)[C@@H](CO)NCc1ccccc1
Reaction time: 0.5 h
Yield: 81.4 %

Procedure:
(S)-2-Amino-3,3-dimethylbutan-1-ol (4.01 g, 34.2 mmol) was dissolved in benzene (120 mL). Benzaldehyde (3.65 mL, 35.9 mmol) and p-TsOH monohydrate (1.302 mg, 6.84 μmmol) were added. The reaction mixture was heated at reflux for 5 h using Dean-Stark to remove water, the mixture was then concentrated. The residue was dissolved in anhydrous MeOH (100 mL), cooled down in an ice-water bath, and added sodium borohydride (1.942 g, 51.3 mmol) slowly. The reaction mixture was stirred for 30 min, quenched with 1 N NaOH solution, diluted with water, and extracted with ethyl acetate. The combined organics were washed with water, dried over anhydrous Na2SO4, filtered, then concentrated to give the title compound (5.77 g) as a colorless oil without further purification. LCMS m/z=208.2 [M+H]+; 1H NMR (400 MHz, CDCl3) δ 0.88 (s, 9H), 2.33 (dd, J=6.4 and 4.7 Hz, 1H), 3.34 (dd, J=10.6 and 6.4 Hz, 1H), 3.59 (dd, J=10.6 and 4.7 Hz, 1H), 3.76 and 3.85 (dd, J=12.8 Hz, 2H), 7.20-7.27 (m, 5H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]12[CH2:18][O:17][C@@H:16]([CH2:19][OH:20])[CH2:15][C@H:14]1[C@@H:13]([CH3:21])[S:12][C:11]([NH:22][C:23](=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[N:10]2.[H-].[Na+].I[CH3:34]>O1CCCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]12[CH2:18][O:17][C@@H:16]([CH2:19][O:20][CH3:34])[CH2:15][C@H:14]1[C@@H:13]([CH3:21])[S:12][C:11]([NH:22][C:23](=[O:30])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[N:10]2
Reactant: C[C@H]1SC(NC(=O)c2ccccc2)=N[C@@]2(c3ccc(F)cc3F)CO[C@@H](CO)C[C@@H]12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC[C@H]1C[C@H]2[C@@H](C)SC(NC(=O)c3ccccc3)=N[C@@]2(c2ccc(F)cc2F)CO1
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
A solution of N-[(4R,4aR,6R,8aS)-8a-(2,4-difluorophenyl)-6-(hydroxymethyl)-4-methyl-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide (P2) (140 mg, 0.324 mmol) in tetrahydrofuran (2.5 mL) was added to a mixture of sodium hydride (60% in mineral oil, 31 mg, 0.78 mmol) in tetrahydrofuran (5 mL), and the reaction mixture was stirred at room temperature for 25 minutes. To this was added iodomethane (24.3 μL, 0.389 mmol), and the reaction mixture was heated at 41° C. for 6 hours, cooled back to room temperature, and quenched with saturated aqueous ammonium chloride solution (15 mL). After extraction with ethyl acetate (3×20 mL), the combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Silica gel chromatography (Gradient: 0% to 100% ethyl acetate in heptane) provided the product as a white solid. Yield: 110 mg, 0.246 mmol, 76%. 1H NMR (400 MHz, CD3OD) δ 8.12 (br d, J=7 Hz, 2H), 7.51-7.57 (m, 1H), 7.40-7.50 (m, 3H), 7.02-7.11 (m, 2H), 4.14 (br d, J=11.7 Hz, 1H), 3.90 (d, J=11.9 Hz, 1H), 3.83-3.9 (m, 1H), 3.44-3.54 (m, 2H), 3.37-3.38 (s, 3H), 3.18-3.28 (br m, 1H), 2.96-3.05 (br m, 1H), 1.73-1.81 (m, 1H), 1.51-1.63 (m, 1H), 1.25 (d, J=6.8 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:16])[CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.CO[CH:19](OC)[N:20]([CH3:22])[CH3:21]>>[CH3:19][N:20]([CH3:22])[CH:21]=[C:9]([C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1)[C:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)=[O:16]
Reactant: COC(OC)N(C)C
Reactant: O=C(Cc1ccncc1)c1ccc(F)cc1
Product: CN(C)C=C(C(=O)c1ccc(F)cc1)c1ccncc1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
A mixture of 1-(4-fluorophenyl)-2-(pyridin-4-yl)-ethan-1-one (5.12 g) and N,N-dimethylformamide dimethyl acetal (16 ml) was stirred at 100° C. for 3 hours under nitrogen. The cooled mixture was concentrated in vacuo. The residue was crystallized from isopropyl ether to yield 3-dimethylamino-1-(4-fluorophenyl)-2-(pyridin-4-yl)-2-propen-1-one (6.15 g).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[OH-].[NH4+:16]>>[NH2:16][S:11]([C:8]1[CH:9]=[N:10][C:2]([Cl:1])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5])(=[O:13])=[O:12]
Reactant: O=C(O)c1cc(S(=O)(=O)Cl)cnc1Cl
Reactant: [NH4+]
Agent: [OH-]
Product: NS(=O)(=O)c1cnc(Cl)c(C(=O)O)c1
Temperature: 0 °C

Procedure:
2-Chloro-5-(chlorosulfonyl)nicotinic acid (400 mg, 1.56 mmol) was stirred in a slurry of ice and excess ammonium hydroxide was added at 0° C. and stirred until all of the ice had melted. The resulting solution was evaporated to afford a white solid 5-(aminosulfonyl)-2-chloronicotinic acid. MS ES+ 237 (M+H). 1H NMR (400 MHz, DMSO-D6) δ ppm 8.1 (dd, J=2.6, 0.9 Hz, 1H), 8.6 (m, 1H).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][C:14]([NH:16][C:17]1[C:22]([CH:23]([CH3:25])[CH3:24])=[CH:21][CH:20]=[CH:19][C:18]=1[CH:26]([CH3:28])[CH3:27])=[NH:15])([CH3:3])[CH3:2].[Cl:29][CH:30](Cl)[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([CH3:37])[CH:32]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C(C)=CC=CC=1>[CH:23]([C:22]1[CH:21]=[CH:20][CH:19]=[C:18]([CH:26]([CH3:28])[CH3:27])[C:17]=1[NH:16][C:14]([NH:13][C:5]1[C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][CH:8]=[CH:7][C:6]=1[CH:10]([CH3:12])[CH3:11])=[N:15][CH2:37][C:33]1[CH:34]=[CH:35][CH:36]=[C:31]([CH2:30][Cl:29])[CH:32]=1)([CH3:25])[CH3:24]
Reactant: Cc1cccc(C(Cl)Cl)c1
Reactant: CC(C)c1cccc(C(C)C)c1NC(=N)Nc1c(C(C)C)cccc1C(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1C
Product: CC(C)c1cccc(C(C)C)c1NC(=NCc1cccc(CCl)c1)Nc1c(C(C)C)cccc1C(C)C
Yield: 32.8 %

Procedure:
11.4 g (0.03 mole) of N,N'-bis-(2,6-diisopropylphenyl) guanidine, 5.7 g (0.033 mole) of α,α-dichloro-m-xylene and 2.1 g (0.015 mole) of anhydrous potassium carbonate were added to 50 ml of xylene. The thus-formed mixture was then refluxed under heating for 10 hours. After the mixture had been allowed to cool, the insoluble substance was removed by filtration. The thus-obtained filtrate was washed with water and then concentrated for the purpose of recovering the solvent and unreacted raw materials to obtain a slightly yellow crystal. The crystal was then recrystallized from acetone to obtain 5.1 g of white powder.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.[OH:14][CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C(N(CC)CC)C>C(Cl)Cl>[F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([N:18]2[CH2:19][CH2:20][CH:15]([OH:14])[CH2:16][CH2:17]2)=[O:8])=[CH:5][CH:4]=1
Reactant: OC1CCNCC1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1ccc(C(F)(F)F)cc1)N1CCC(O)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.6 %

Procedure:
4-(Trifluoromethyl)benzoyl chloride (1.5 ml, 9.89 mmol) was added to a solution of 4-hydroxypiperidine (1 g, 9.89 mmol) and triethylamine (1.7 ml, 11.9 mmol) in methylene chloride (20 ml) while cooling in an ice-bath, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed with water, saturated sodium bicarbonate aqueous solution and brine, and dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/acetone=2/1) to afford 1-(4-trifluoromethylbenzoyl)-4-hydroxypiperidine (2.07 g, yield 77%) as a colorless crystalline powder.