Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][CH:6]1[N:24]=[C:25]=[S:26])(=[O:3])[CH3:2].[NH2:27][C:28]1[N:33]([CH3:34])[C:32](=[O:35])[N:31]([CH3:36])[C:30](=[O:37])[CH:29]=1>C1(C)C(C)=CC=CC=1>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[NH:24][C:25]([NH:27][C:28]1[N:33]([CH3:34])[C:32](=[O:35])[N:31]([CH3:36])[C:30](=[O:37])[CH:29]=1)=[S:26])(=[O:3])[CH3:2]
Reactant: Cn1c(N)cc(=O)n(C)c1=O
Reactant: CC(=O)OC[C@H]1OC(N=C=S)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: Cc1ccccc1C
Product: CC(=O)OC[C@H]1O[C@@H](NC(=S)Nc2cc(=O)n(C)c(=O)n2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C

Procedure:
To 10 ml of anhydrous xylene were added 390 mg (1 mmol) of 2,3,4,6-tetra-O-acetyl-D-glucopyranosyl isothiocyanate and 140 mg (1 mmol) of 6-amino-1,3-dimethyluracil (MW 155) and the mixture was heated on an oil bath under reflux for 9-10 hours and allowed to cool to room temperature. Crystals formed were filtered off and recrystallized from ethanol to give colourless needles melting between 171° and 173° C. (uncorrected). Yield: 240 mg (43%).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([S:11][C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:7][C:5]=1N)([O-:3])=[O:2].N(OC(C)(C)C)=O.O.[ClH:24]>C(#N)C.[Cu](Cl)Cl>[F:13][C:12]([F:15])([F:14])[S:11][C:9]1[CH:8]=[CH:7][C:5]([Cl:24])=[C:4]([N+:1]([O-:3])=[O:2])[CH:10]=1
Reactant: Cl
Reactant: Nc1ccc(SC(F)(F)F)cc1[N+](=O)[O-]
Agent: Cl[Cu]Cl
Agent: CC(C)(C)ON=O
Solvent: CC#N
Solvent: O
Product: O=[N+]([O-])c1cc(SC(F)(F)F)ccc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-Nitro-4-trifluoromethylthioaniline (0.5 g) in dry acetonitrile (3 cm3) was added over 0.5 hr. with stirring to copper (II) chloride (0.34 g) and tert-butyl nitrite (0.32 g) in dry acetonitrile (5 cm3) at 60° C. After 1 hr. the reaction was cooled to ambient temperature, poured into water, acidified with hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with water (3×50 cm3) dried (magnesium sulphate) and evaporated under reduced pressure to give the required product as an oil; M+ =257; 1H NMR (CDCl3): δ7.65(d 1H); 7.80(dd 1H); 8.20(d 1H).
Reaction SMILES: [Br:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH2:12][C:13]3[C:18]([Cl:19])=[CH:17][C:16]([C:20](=[O:27])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[CH:15][C:14]=3[Cl:28])[C:5]2=[N:4][C:3]=1[CH3:29].[BH4-].[Na+]>C(O)C>[Br:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH2:12][C:13]3[C:14]([Cl:28])=[CH:15][C:16]([CH:20]([OH:27])[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)=[CH:17][C:18]=3[Cl:19])[C:5]2=[N:4][C:3]=1[CH3:29]
Reactant: Cc1nc2c(OCc3c(Cl)cc(C(=O)c4ccccc4)cc3Cl)cccn2c1Br
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Cc1nc2c(OCc3c(Cl)cc(C(O)c4ccccc4)cc3Cl)cccn2c1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.9 %

Procedure:
To a mixture of 3-bromo-8-(2,6-dichloro-4-benzoylbenzyloxy)-2-methylimidazo[1,2-a]pyridine (80 mg), sodium borohydride (18.5 mg) and ethanol (2 ml) was stirred at ambient temperature for 1 hour. The reaction mixture was partitioned between dichloromethane and water and the aqueous layer was extracted with dichloromethane twice. The combined organic layers were washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was crystallized from diethyl ether to give 3-bromo-8-[2,6-dichloro-4-(α-hydroxybenzyl)benzyloxy]-2-methylimidazo[1,2-a]pyridine (73 mg) as crystals.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH3:12])[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].CCN(CC)CC.[S:20](Cl)([C:23]1[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=1)(=[O:22])=[O:21]>C(Cl)Cl>[CH3:27][C:26]1[CH:28]=[CH:29][C:23]([S:20]([O:1][CH2:2][CH2:3][N:4]([C:5]([O:6][C:7]([CH3:8])([CH3:9])[CH3:10])=[O:11])[CH3:12])(=[O:22])=[O:21])=[CH:24][CH:25]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CN(CCO)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCCN(C)C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 59.5 %

Procedure:
To a mixture of 112a (9.0 g, 51 mmol), and Et3N (18.6 mL, 51 mmol) in DCM (100 mL) was added TsCl (9.77 g, 51 mmol). The mixture was stirred at rt for 4 h and concentrated. The residue was diluted with EA, washed with water. The organic layer was dried and concentrated to give 2-(tert-butoxycarbonyl(methyl)amino)ethyl 4-methylbenzenesulfonate 112b (10.0 g, 61%) as light yellow oil. ESI-LCMS: m/z=230.0
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][CH:15]([C:18]([OH:21])([CH3:20])[CH3:19])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.Br[C:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32]([NH2:39])=[N:31][CH:30]=1>>[NH2:39][C:32]1[C:33]2[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:29]([C:2]2[N:3]=[C:4]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:17][CH2:16][CH:15]([C:18]([OH:21])([CH3:20])[CH3:19])[CH2:14][CH2:13]4)=[CH:8][C:6]=3[N:7]=2)=[CH:30][N:31]=1
Reactant: Nc1ncc(Br)c2ccccc12
Reactant: CC(C)(O)C1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Product: CC(C)(O)C1CCN(Cc2cc3nc(-c4cnc(N)c5ccccc45)nc(N4CCOCC4)c3s2)CC1

Procedure:
Following the procedures for 108, 2-(1-((2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)propan-2-ol and 4-bromoisoquinolin-1-amine were converted to 130. LCMS: M+H+=519. 1H NMR (400 MHz, DMSO) δ 8.99 (d, J=8.5, 1H), 8.58 (s, 1H), 8.26 (d, J=8.5, 1H), 8.17 (s, 2H), 7.68 (t, J=7.6, 1H), 7.50 (t, J=7.5, 1H), 7.37 (s, 1H), 7.12 (s, 1H), 4.00-3.89 (m, 4H), 3.86-3.75 (m, 6H), 2.99 (d, J=11.0, 2H), 1.97 (t, J=11.2, 2H), 1.65 (t, J=15.4, 2H), 1.37-1.11 (m, 3H), 1.04 (s, 6H)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[N:9])=[CH:4][N:3]=1.[CH2:10]([O:12][C:13](=[O:18])[C:14](=O)[CH2:15]Br)[CH3:11].C(=O)([O-])O.[Na+]>C(O)C.Cl.CO>[CH2:10]([O:12][C:13]([C:14]1[N:1]=[C:2]2[CH:7]=[CH:6][C:5]([C:8]#[N:9])=[CH:4][N:3]2[CH:15]=1)=[O:18])[CH3:11]
Reactant: N#Cc1ccc(N)nc1
Reactant: CCOC(=O)C(=O)CBr
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: CCOC(=O)c1cn2cc(C#N)ccc2n1
Yield: 88.5 %

Procedure:
In ethanol (30 ml), 2-amino-5-cyanopyridine (2.45 g) was dissolved. The solution was added with 3-bromo-2-oxo-propionic acid ethyl ester (3.90 g) and the whole was refluxed under heating for 7 hours. The concentrated residue was dissolved in a minimum amount of a 10% hydrogen chloride/methanol solution and the solution was adjusted to pH 8 with a saturated aqueous sodium hydrogen carbonate solution. The precipitate was collected by filtration, thereby obtaining the subject compound (3.81 g) as a pale-yellow solid.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[C:4]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)[N:3]=1.[CH2:22]([NH2:25])[CH2:23][NH2:24]>C(OCC)(=O)C>[NH2:24][CH2:23][CH2:22][NH:25][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[C:4]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)[N:3]=1
Reactant: NCCN
Reactant: CC(C)n1cnc2c(Nc3cccc(Cl)c3)nc(Cl)nc21
Solvent: CCOC(C)=O
Product: CC(C)n1cnc2c(Nc3cccc(Cl)c3)nc(NCCN)nc21
Temperature: 150 °C

Procedure:
200 mg (0.58 mmol) of 2-chloro-6-(3-chloro-phenyl-amino)-9-isopropyl-9H-purine are dissolved in 6 ml (90 mmol) of ethylenediamine and the mixture is heated under reflux for 3 hours (oil bath temperature of 150° C.). After cooling to room temperature, the reaction mixture is taken up in 250 ml of ethyl acetate and extracted with 150 ml of water. The aqueous phase is extracted twice with ethyl acetate and the combined organic extracts are washed with saturated sodium bicarbonate solution, water and saturated sodium chloride solution and dried over magnesium sulfate. After filtration, the filtrate is concentrated under reduced pressure at 35° C. and dried under an HV. 2-(2-Amino-ethylamino)-6-(3-chloro-phenyl-amino)-9-isopropyl-9H-purine is obtained; Rf=0.27 (methylene chloride:methanol:concentrated ammonium hydroxide solution=900:100:1); EI-MS: (M+H)+=346; m.p. 55–56° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:15]([O-])=O)=[C:6]([CH:14]=1)[O:7][CH:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1>C(OC(=O)C)C.[Pd]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:15])=[C:6]([O:7][CH:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:14]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1OC1CCOCC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1ccc(F)cc1OC1CCOCC1

Procedure:
4-(5-Fluoro-2-nitrophenoxy)tetrahydro-2-H-pyran (8.4 g) was dissolved in ethylacetate (30 ml) and Pd/C (500 mg) was added. The reaction was hydrogenated at room temperature and 50 PSI. The mixture was concentrated in vacuo to give the intended product.
Reaction SMILES: [OH:1][C:2]1([CH2:15][CH:16]=O)[CH2:14][CH2:13][C:5]2([O:10][CH2:9][C:8]([CH3:12])([CH3:11])[CH2:7][O:6]2)[CH2:4][CH2:3]1.[C:18]1([C@@H:24]([NH2:26])[CH3:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH3:11][C:8]1([CH3:12])[CH2:9][O:10][C:5]2([CH2:13][CH2:14][C:2]([CH2:15][CH2:16][NH:26][C@H:24]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH3:25])([OH:1])[CH2:3][CH2:4]2)[O:6][CH2:7]1
Reactant: C[C@H](N)c1ccccc1
Reactant: CC1(C)COC2(CCC(O)(CC=O)CC2)OC1
Product: C[C@H](NCCC1(O)CCC2(CC1)OCC(C)(C)CO2)c1ccccc1
Yield: 62 %

Procedure:
The title compound is prepared from (9-hydroxy-3,3-dimethyl-1,5-dioxa-spiro[5.5]undec-9-yl)-acetaldehyde and (S)-1-phenyl-ethylamine following a procedure analogous to that described in Step 3 of Intermediate 2. Yield: 62% of theory; LC (method 6): tR=1.10 min; Mass spectrum (ESI+): m/z=348 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=1)[OH:4].O=[C:13]([CH3:28])[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:18][CH:17]=1.C1C=CC=CC=1.C([BH3-])#N.[Na+]>CO>[CH3:27][O:26][C:24]([CH2:23][CH2:22][C:19]1[CH:18]=[CH:17][C:16]([O:15][CH2:14][CH:13]([NH:1][CH2:2][CH:3]([C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=2)[OH:4])[CH3:28])=[CH:21][CH:20]=1)=[O:25]
Reactant: NCC(O)c1cccc(Cl)c1
Reactant: COC(=O)CCc1ccc(OCC(C)=O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: c1ccccc1
Product: COC(=O)CCc1ccc(OCC(C)NCC(O)c2cccc(Cl)c2)cc1
Yield: 48.2 %

Procedure:
Following a procedure similar to that described in Example 6, but using 4.5 g of 2-amino-1-(3-chlorophenyl)ethanol (prepared as described in Preparation 8), 3.5 g of methyl 3-[4-(2-oxopropoxy)phenyl]propionate (prepared as described in Preparation 5), 100 ml of benzene, 100 ml of absolute methanol and 2.6 g of sodium cyanoborohydride, 2.8 g of the title compound were obtained as crystals, melting at 65°-73° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:12][C:13]([OH:15])=O)=[C:6]2[C:11]=1[CH:10]=[N:9][CH:8]=[CH:7]2.[Br:16][C:17]1[C:18]([C:23]2[NH:27][N:26]=[CH:25][N:24]=2)=[C:19]([NH2:22])[S:20][CH:21]=1>>[Br:16][C:17]1[C:18]([C:23]2[NH:27][N:26]=[CH:25][N:24]=2)=[C:19]([NH:22][C:13](=[O:15])[CH2:12][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[C:11]3[C:6]=2[CH:7]=[CH:8][N:9]=[CH:10]3)[S:20][CH:21]=1
Reactant: Nc1scc(Br)c1-c1ncn[nH]1
Reactant: O=C(O)Cc1ccc(F)c2cnccc12
Product: O=C(Cc1ccc(F)c2cnccc12)Nc1scc(Br)c1-c1ncn[nH]1

Procedure:
The title compound was prepared from 2-(8-fluoroisoquinolin-5-yl)acetic acid and 4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-amine using protocol B. Retention time (min)=1.987, method [7], MS(ESI) 432.0 (M+H); 1H NMR (300 MHz, CD3OD) δ 9.74 (s, 1H), 8.66 (d, J=6.6 Hz, 1H), 8.30 (d, J=6.1 Hz, 1H), 8.20 (b s, 1H), 8.1 (dd, J=8.24, 5.5 Hz, 1H), 7.67 (dd, J=9.9, 7.7 Hz, 1H), 7.1 (s, 1H), 4.46 (s, 2H).
Reaction SMILES: [C:1]([O:6][CH2:7][CH:8]1O[CH2:9]1)(=[O:5])[C:2]([CH3:4])=C.[CH3:11]OC1C=CC(O)=CC=1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:1]([O:6][CH2:7][CH2:8][CH2:9][CH3:11])(=[O:5])[CH:2]=[CH2:4]
Reactant: COc1ccc(O)cc1
Reactant: C=C(C)C(=O)OCC1CO1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Product: C=CC(=O)OCCCC
Temperature: 25 °C

Procedure:
After the completion of the reaction, the solution was cooled to room temperature. To the solution, 3 g of glycidyl methacrylate, 0.1 g of p-methoxyphenol and 0.3 g of tetrabutylammonium bromide were added. The mixture was stirred until these added compounds dissolved completely. The solution thus obtained was heated to 80° C., and an addition reaction was allowed to take place for 16 hours between the carboxyl group in the copolymer and the epoxy group in the glycidyl methacrylate. Thereafter, the solution was cooled to room temperature to obtain an alkali soluble resin (A-1) in the form of resin solution.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11]Br)[N:6]=1)=[O:4].[I:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].O>CC(C)=O>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][O:20][C:17]2[CH:18]=[CH:19][C:14]([I:13])=[CH:15][CH:16]=2)[N:6]=1)=[O:4]
Reactant: Oc1ccc(I)cc1
Reactant: COC(=O)c1cccc(CBr)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)c1cccc(COc2ccc(I)cc2)n1
Yield: 61.3 %

Procedure:
6-Bromomethyl-pyridine-2-carboxylic acid methyl ester (2.27 g, 9.9 mmol; from Step 2 above) was dissolved in acetone (50 mL) and 4-iodophenol (2.37 g, 10.8 mmol; available from Aldrich Chemical Company, Inc., Milwaukee, Wis.) was added, followed by finely ground potassium carbonate (1.54 g, 11.2 mmol). The mixture was heated overnight at 60 degrees, and it was then cooled and filtered. The solid was washed with acetone and the filtrate was concentrated to dryness. Ethyl acetate (100 mL) was added and the solution was washed twice with 2 M NaOH, with water, and with brine. The solution was dried (magnesium sulfate), filtered and evaporated to give the crude product. This was dissolved in acetone (approximately 25 mL) with warming, and water (approximately 20 mL) was added. An oil came out of solution and it crystallized. The mixture was heated to redissolve the solid and the solution was seeded with a crystal of the product to give crystals of the product. The recrystallization was repeated to give 6-(4-iodo-phenoxymethyl)-pyridine-2-carboxylic acid methyl ester (2.24 g, 62%) as a white crystalline solid. Mass spectrum m/z 370.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([F:19])[CH:18]=1)[C:5]([C:7]1[C:8](=[O:15])[N:9]([CH2:13][CH3:14])[CH:10]=[CH:11][CH:12]=1)=O.[NH2:20][C:21]1[CH:25]=[C:24]([NH:26]C(=O)OC(C)(C)C)[NH:23][N:22]=1.C([O-])(=O)C.[NH4+]>>[NH2:26][C:24]1[C:25]2[C:12]3[CH:11]=[CH:10][N:9]([CH2:13][CH3:14])[C:8](=[O:15])[C:7]=3[C:5]([C:4]3[CH:3]=[C:2]([F:1])[CH:18]=[C:17]([F:19])[CH:16]=3)=[N:20][C:21]=2[NH:22][N:23]=1
Reactant: CCn1cccc(C(=O)c2cc(F)cc(F)c2)c1=O
Reactant: CC(C)(C)OC(=O)Nc1cc(N)n[nH]1
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: CCn1ccc2c(c(-c3cc(F)cc(F)c3)nc3[nH]nc(N)c32)c1=O
Yield: 27.1 %

Procedure:
91 mg (0.346 mmol) of 3-(3,5-difluorobenzoyl)-1-ethylpyridin-2(1H)-one with 69 mg (0.346 mmol) of tert-butyl 3-amino-1H-pyrazol-5-ylcarbamate and 533 mg (6.91 mmol) of ammonium acetate are added to a boiling flask. The mixture is carried at 200° C. dry (i.e., without solvent) for 15 minutes. The solution is placed at room temperature, and then the solid is dissolved in a water/ethyl acetate mixture. The phases are separated and the aqueous phase is extracted several times with ethyl acetate. The organic phases are mixed, dried on magnesium sulfate and concentrated. The product is purified by silica gel chromatography (eluent: 10:1 dichloromethane/methanol) to yield 32 mg (27%) of 1-amino-5-(3,5-difluorophenyl)-7-ethyl-3H-pyrazolo[3,4-c][2,7]naphthyridin-6(7H)-one.
Reaction SMILES: [OH-].[K+].[CH2:3]([O:10][C@@H:11]([CH3:17])[CH2:12][C:13]([O:15]C)=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CO>O>[CH2:3]([O:10][C@@H:11]([CH3:17])[CH2:12][C:13]([OH:15])=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COC(=O)C[C@H](C)OCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C[C@@H](CC(=O)O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 8.73 g of potassium hydroxide in 140 mL of cold water was dissolved methyl (S)-3-benzyloxybutyrate (18) (24.21 g). The solution was stirred in an ice bath for one hour and at room temperature for one hour. Methanol was added to give a clear solution and the reaction was stirred overnight.
Reaction SMILES: C(OC(=O)[NH:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([C:11]3=[N:18][OH:19])[CH2:9]1)[CH2:15]2)(C)(C)C.[ClH:21]>O1CCOCC1>[NH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([C:11]3=[N:18][OH:19])[CH2:9]1)[CH2:15]2.[ClH:21]
Reactant: CC(C)(C)OC(=O)NC12CC3CC(C1)C(=NO)C(C3)C2
Agent: Cl
Solvent: C1COCCO1
Product: NC12CC3CC(C1)C(=NO)C(C3)C2
Temperature: 25 °C

Procedure:
A solution of oxime 14A (0.17 mmol) in 1,4-dioxane (2.0 mL) was diluted with a solution of 4 N HCl in dioxane (1.0 mL) and the reaction mixture was maintained at rt for 16 h. The reaction mixture was concentrated and dried to provide amine 14 in 88% yield as a hydrochloric acid salt. Data: LC/MS (ESR) m/z=195 [M+H]+.
Reaction SMILES: [NH2:1][C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4].S(=O)(=O)(O)O.[C:14]1(=O)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.C([BH3-])#N.[Na+]>CO>[CH:14]1([NH:1][C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: O=C1CCCCC1
Reactant: CC(C)[C@H](N)C(=O)O
Agent: O=S(=O)(O)O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CC(C)[C@H](NC1CCCCC1)C(=O)O
Reaction time: 24 h

Procedure:
To the m-phenoxybenzyl ester of valine (2 g, 0.0067 mole) in methanol (30 ml) is added concentrated sulfuric acid to bring to about pH 6. Cyclohexanone (0.6 g, 0.006 mole) is then added followed by 3A molecular sieves and sodium cyanoborohydride (0.25 g, 0.004 mole). Additional sulfuric acid is added to keep pH at about 6. After about 24 hours, the reaction is worked up by removing methanol by rotoevaporation and the residue is poured into water and 10% sodium carbonate followed by extraction with ether. The combined ether extracts are filtered and concentrated and the product is isolated by preparatory TLC (10% ether/hexane) to yield the m-phenoxybenzyl ester of N-cyclohexylvaline.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[C:15]4=[N:16][S:17](=[O:21])(=[O:20])[CH2:18][CH2:19][N:14]4[CH:13]=[CH:12][CH:11]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].I[CH2:25][CH3:26].O>CN(C=O)C.CCOC(C)=O>[CH2:25]([N:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[C:15]4=[N:16][S:17](=[O:21])(=[O:20])[CH2:18][CH2:19][N:14]4[CH:13]=[CH:12][CH:11]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1)[CH3:26]
Reactant: CCI
Reactant: O=S1(=O)CCN2C=CC=C(c3ccc4[nH]ccc4c3)C2=N1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCn1ccc2cc(C3=CC=CN4CCS(=O)(=O)N=C34)ccc21
Reaction time: 0.17 h

Procedure:
To a mixture of 9-(1H-indol-5-yl)-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (131 mg) in DMF (dry) (15 mL) was added NaH (60%, 18.38 mg) at room temperature. The mixture was stirred at the same temperature for 10 min. Iodoethane (0.039 mL) was added and the mixture was stirred at room temperature overnight. Water and EtOAc were added and the extracted organic layer was washed with brine. Silica-gel was added to the organic layer and the volatiles were removed in vacuo. The mixture supported on silica-gel was purified by column chromatography (NH-silica gel, eluted with MeOH in EtOAc) to give the title compound (34.6 mg) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH2:11][OH:12]>[O-2].[Mn+4].[O-2].C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH:11]=[O:12]
Reactant: Cc1cc([N+](=O)[O-])ccc1CO
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: Cc1cc([N+](=O)[O-])ccc1C=O
Temperature: 40 °C
Yield: 78.7 %

Procedure:
A flask was charged with (2-methyl-4-nitro-phenyl)-methanol (16.7 g, 0.100 mol) (334 mL), to manganese(IV) oxide (5 μm, 102.3 g, 1.00 mol), and CH2Cl2 (334 mL). The stirred mixture was heated at 40° C. for at least 2 h or until in-process HPLC analysis showed that conversion was greater than 95%. The cooled mixture was filtered through a celite cake (8 g) loaded onto a fritted funnel and the filter cake was rinsed with CH2Cl2 (340 mL). The filtrate and wash were concentrated under reduced pressure to dryness to afford the title compound as an amorphous solid (13.0 g, 78% yield).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:9][C:10]([F:27])([F:26])[C-:11]([C:22]([F:25])([F:24])[F:23])[C:12]([F:21])([F:20])[C:13]([F:19])([F:18])[C:14]([F:17])([F:16])[F:15].CN([S+](N(C)C)N(C)C)C.O>C(#N)C>[F:20][C:12]([F:21])([C:13]([F:18])([F:19])[C:14]([F:15])([F:16])[F:17])[C:11]([C:22]([F:25])([F:24])[F:23])([C:10]([F:27])([F:26])[F:9])[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: FC(F)(F)[C-](C(F)(F)F)C(F)(F)C(F)(F)C(F)(F)F
Agent: CN(C)[S+](N(C)C)N(C)C
Solvent: O
Solvent: CC#N
Product: FC(F)(F)C(F)(F)C(F)(F)C(Cc1ccccc1)(C(F)(F)F)C(F)(F)F
Reaction time: 8 h
Yield: 66 %

Procedure:
Benzyl bromide, 4.77 g (0.028 mol), was added dropwise to a solution of 15.0 g (0.031 mol) of tris(dimethylamino)sulfonium 1,1,1,3,3,4,4,5,5,5-decafluoro-2-(trifluoromethyl)-2-pentanide in 50 mL of acetonitrile at 25° C. and the reaction mixture was stirred overnight and then poured into water. The aqueous mixture was extracted with ether, and the ether extracts were dried (MgSO4) and then distilled to give 7.5 g (66%) of 3,3,4,4,5,5,5-heptafluoro-2,2-bis(trifluoromethyl)pentylbenzene as a colorless liquid: b.p. 62°-63° (5 mm); 19F NMR (CDCl3) δ -62.7 ppm (t,t, 6F), -80.7 ppm (t, 3F), -106.3 ppm (m, 2F) and -123.3 ppm (2F); 1H NMR (CDCl3) δ 3.52 ppm (s, 2H) and 7.27 ppm (s, 5H). Anal. Calcd. for C13H7F13 : C, 38.07; H, 1.72; F, 60.21. Found: C, 37.82; H, 1.73; F, 60.42.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[N:26]=[CH:25][CH:24]=[CH:23][N:22]=3)=[CH:17][CH:16]=2)[CH:7]=1.[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1>C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]([S:35]([C:32]2[CH:33]=[CH:34][C:29]([Cl:28])=[CH:30][CH:31]=2)(=[O:37])=[O:36])[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[N:26]=[CH:25][CH:24]=[CH:23][N:22]=3)=[CH:17][CH:16]=2)[CH:7]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: COC(=O)CCc1cccc(CNCc2ccc(-c3ncccn3)cc2)c1
Solvent: CCN(CC)CC
Product: COC(=O)CCc1cccc(CN(Cc2ccc(-c3ncccn3)cc2)S(=O)(=O)c2ccc(Cl)cc2)c1

Procedure:
The title compound of Step A was prepared following the method described in Step B of Example 1 from 3-{3-[(4-pyrimidin-2-yl-benzylamino)-methyl]-phenyl}-propionic acid methyl ester, prepared in Step A of Example 11z, and 4-chlorobenzensulfonyl chloride using triethylamine in place of N,N-iisopropylethylamine. 1H NMR (400 MHz, CDCl3) δ 8.78 (m, 2H), 8.28 (d, 2H), 7.76 (d, 2H), 7.46 (d, 2H), 7.15 (m, 4H), 7.03 (d, 1H), 6.88 (d, 1H), 6.80 (s, 1H), 4.36 (s, 2H), 4.29 (s, 2H), 3.63 (s, 3H), 2.79 (t, 2H), 2.48 (t, 2H); MS 536 (M+1).