Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.Cl[I:10].[OH-].[Na+]>C(O)(=O)C.O>[Cl:8][C:5]1[CH:6]=[C:7]([I:10])[C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: Nc1ccc(Cl)cn1
Reactant: ClI
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: Nc1ncc(Cl)cc1I
Reaction time: 2 h
Yield: 60.1 %

Procedure:
The solution of 2-amino-5-chloropyridine (10.0 g, 77.8 mmol) potassium acetate (7.63 g, 77.8 mmol) in 100 mL of acetic acid was heated to 85° C. and ClI (12.6 g, 77.8 mmol) in 50 mL of acetic acid was added dropwise. Reaction mixture was kept 2 h at this temperature, diluted with 1 L of water, neutralized with NaOH 1N solution to pH 7 and extracted with ethyl acetate (4×75 mL). Organic fraction were combined, washed with NaHCO3, filtered through celite and evaporated. The residue was subjected to column chromatography on silica (eluent—hexane/ethyl acetate 1/1) providing 5-chloro-3-iodopyridin-2-amine as yellow solid (11.9 g, 60%).
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].O1CCCC1.C([Li])CCC.[C:18](OCC)(=[O:27])[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(O)(=O)C>[O:27]=[C:18]([CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4]
Reactant: COP(C)(=O)OC
Reactant: CCOC(=O)CCc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COP(=O)(CC(=O)CCc1ccccc1)OC
Reaction time: 2 h

Procedure:
A solution of dimethyl methylphosphonate (115.5 g.) in 2.1 l. of tetrahydrofuran is treated, while stirring at -65° C., with a solution of butyl lithium (660 ml. 1.6 M. in hexane). A solution of ethyl hydrocinnamate (93.5 g.) in 225 ml. of tetrahydrofuran is added at -65° C. Stirring is continued at -65° C. for 2 hrs. and then at about 25° C. for 16 hrs. Acetic acid (70 ml.) is added and the mixture concentrated under reduced pressure. The residue is partitioned between dichloromethane and water. The organic phase is dried and concentrated. Distillation yields the title compound, b. 188°-191° C./2 mm., having a mass spectral peak at 256.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.C([Li])CCC.CCCCCC.[CH3:20][N:21]1[CH2:26][CH2:25][CH:24]([C:27](N(C)OC)=[O:28])[CH2:23][CH2:22]1.[OH-].[Na+]>ClCCl>[Br:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:27]([CH:24]2[CH2:25][CH2:26][N:21]([CH3:20])[CH2:22][CH2:23]2)=[O:28])[N:3]=1
Reactant: CON(C)C(=O)C1CCN(C)CC1
Reactant: Brc1cccc(Br)n1
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCCCCC
Product: CN1CCC(C(=O)c2cccc(Br)n2)CC1
Temperature: -78 °C
Yield: 74 %

Procedure:
Dissolve 2,6-dibromopyridine (5.5 g, 23.2 mmol) in anhydrous dichloromethane (140 mL) under a nitrogen atmosphere. Cool the reaction mixture to −78° C. Add a solution of n-butyl lithium in hexane (1.6 M, 15.8 mL, 25.3 mmol) very slowly via a syringe. After the addition is complete, stir the reaction at −78° C. for 1 hr. Add a solution of 1-methyl-N-methyl-N-methoxy-piperidine-4-carboxamide (2 g, 11 mmol) in anhydrous dichloromethane (10 mL) dropwise to the reaction mixture. Stir the reaction at −78° C. for 2 hrs, and then allow the mixture to slowly warm to room temperature overnight. Quench the reaction with 0.1 N NaOH. Dilute the solution with dichloromethane (100 mL), transfer into a separatory funnel and shake with 2 N NaOH (50 mL). Separate the organic layer, dry it over anhydrous sodium sulfate, and then evaporate the solvent under reduced pressure. Further purify the residue by chromatography on asilica gel column (6%, 2M NH3 in methanol/CH2Cl2) to obtain 2-bromo-6-(1-methylpiperidin-4-ylcarbonyl)-pyridine e (2.3 g, 74% yield). Mass spectrum (ion spray): m/z 283 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](OS(C2C(C)=CC(C)=CC=2C)(=O)=O)[C:5]([CH2:21][C:22]2[CH:39]=[CH:38][C:25]([CH2:26][N:27]([CH2:34][CH:35]([F:37])[F:36])[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:24][C:23]=2[O:40][CH3:41])=[C:4]([CH3:42])[N:3]=1.[NH2:43][C@@H:44]([CH2:48][CH2:49][CH3:50])[CH2:45][CH2:46][OH:47]>>[NH2:1][C:2]1[N:7]=[C:6]([NH:43][C@@H:44]([CH2:48][CH2:49][CH3:50])[CH2:45][CH2:46][OH:47])[C:5]([CH2:21][C:22]2[CH:39]=[CH:38][C:25]([CH2:26][N:27]([CH2:34][CH:35]([F:36])[F:37])[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:24][C:23]=2[O:40][CH3:41])=[C:4]([CH3:42])[N:3]=1
Reactant: CCC[C@H](N)CCO
Reactant: CCOC(=O)CN(Cc1ccc(Cc2c(C)nc(N)nc2OS(=O)(=O)c2c(C)cc(C)cc2C)c(OC)c1)CC(F)F
Product: CCC[C@@H](CCO)Nc1nc(N)nc(C)c1Cc1ccc(CN(CC(=O)OCC)CC(F)F)cc1OC
Yield: 75.8 %

Procedure:
The sub-title compound was synthesized by the method of example 1 step (viii) from the product of step (ii) (520 mg) and (S)-3-aminohexan-1-ol (300 mg). The sub-title compound (340 mg) was obtained as a colourless gum; 1H NMR (CDCl3); 6.90-6.88 (2H, m), 6.78 (1H, d), 5.73 (1H, tt), 4.60 (1H, d), 4.55 (2H, br s), 4.15 (2H, q), 4.11-4.03 (1H, m), 3.88 (3H, s), 3.85 (2H, s), 3.66 (2H, s), 3.47-3.37 (3H, m), 3.25 (1H, ddd), 3.04 (2H, dt), 2.33 (3H, s), 1.83-1.73 (1H, m), 1.51-1.32 (3H, m), 1.25 (3H, t), 1.06-0.99 (2H, m), 0.73 (3H, t).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([OH:9])[CH:6]=[CH:5][C:4]=1[CH:10]1[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[O:13][C:12]([CH3:20])([CH3:19])[C:11]1=[O:21])[CH3:2].Cl[C:23]1[CH:32]=[N:31][C:30]2[C:25](=[CH:26][CH:27]=[C:28]([Cl:33])[CH:29]=2)[N:24]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O.ClCCl>[Cl:33][C:28]1[CH:29]=[C:30]2[C:25](=[CH:26][CH:27]=1)[N:24]=[C:23]([O:9][C:7]1[CH:6]=[CH:5][C:4]([CH:10]3[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[O:13][C:12]([CH3:20])([CH3:19])[C:11]3=[O:21])=[C:3]([CH2:1][CH3:2])[CH:8]=1)[CH:32]=[N:31]2
Reactant: CCc1cc(O)ccc1C1C(=O)C(C)(C)OC(C)(C)C1=O
Reactant: Clc1ccc2nc(Cl)cnc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCc1cc(Oc2cnc3cc(Cl)ccc3n2)ccc1C1C(=O)C(C)(C)OC(C)(C)C1=O
Temperature: 140 °C

Procedure:
4-(2-Ethyl-4-hydroxyphenyl)-2,2,6,6-tetramethylpyran-3,5-dione (0.100 g, 0.34 mmol) is added to a mixture of 2,6-dichloroquinoxaline (0.081 g, 0.41 mmol) and potassium carbonate (0.110 g, 0.69 mmol) in N,N-dimethylformamide (3 ml), and the mixture is heated at 140° C. under microwave irradiation for 40 minutes. The mixture is cooled to room temperature, then acidified by addition of 2M aqueous hydrochloric acid. The mixture is diluted with dichloromethane and passed through a phase separation cartridge. The organic phase is concentrated to around 2 ml, and purified by preparative reverse phase HPLC to give 4-[4-(6-choroquinoxalin-2-yloxy)-2-ethylphenyl]-2,2,6,6-tetramethylpyran-3,5-dione.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][CH2:19][OH:20]>CN(C=O)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:18][CH2:19][OH:20])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: OCCBr
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(OCCO)cc1
Temperature: 90 °C
Reaction time: 16 h
Yield: 59.2 %

Procedure:
4-nitrophenol (10 g) was dissolved in DMF (100 ml), potassium carbonate (12.9 g) and 2-bromoethanol (10.8 g) were added to the mixture, and the mixture was stirred for 16 hours at 90° C. After cooling to room temperature, the mixture was filtered, and the solvent was removed under reduced pressure. The obtained residue was added to water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 2-(4-nitrophenoxy)ethanol (7.8 g).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][O:11][NH:12][C:13](=[O:37])[C:14]1[CH:19]=[C:18]([CH:20]=[N:21][O:22][CH2:23][CH:24]=[O:25])[C:17]([F:26])=[C:16]([F:27])[C:15]=1[NH:28][C:29]1[CH:34]=[CH:33][C:32]([I:35])=[CH:31][C:30]=1[F:36])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:38][Mg]Br>O1CCCC1>[Si:1]([O:8][CH2:9][CH2:10][O:11][NH:12][C:13](=[O:37])[C:14]1[CH:19]=[C:18](/[CH:20]=[N:21]/[O:22][CH2:23][CH:24]([OH:25])[CH3:38])[C:17]([F:26])=[C:16]([F:27])[C:15]=1[NH:28][C:29]1[CH:34]=[CH:33][C:32]([I:35])=[CH:31][C:30]=1[F:36])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C[Mg]Br
Reactant: CC(C)(C)[Si](C)(C)OCCONC(=O)c1cc(C=NOCC=O)c(F)c(F)c1Nc1ccc(I)cc1F
Solvent: C1CCOC1
Product: CC(O)CO/N=C/c1cc(C(=O)NOCCO[Si](C)(C)C(C)(C)C)c(Nc2ccc(I)cc2F)c(F)c1F
Temperature: -78 °C
Reaction time: 8 h

Procedure:
N-[2-(t-butyldimethylsilanyloxy)-ethoxy]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-[(2-oxo-ethoxyimino)-methyl]-benzamide (60 mg, 0.092 mmol) prepared in Process A was dissolved in anhydrous tetrahydrofuran (2.0 mL) under an argon atmosphere. This reaction solution was cooled to −78° C., and then 0.93 M methyl magnesium bromide (0.25 mL) was added thereto. The reaction solution was allowed to gradually warm to room temperature, and stirred for eight hours. The reaction was quenched with saturated aqueous solution of ammonium chloride, and the solution was extracted with ethyl acetate.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]([CH2:12][NH2:13])[CH2:4][CH2:3]1.F[C:15]1[CH:23]=[N:22][CH:21]=[CH:20][C:16]=1[C:17]([OH:19])=[O:18]>>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]([CH2:12][NH:13][C:21]2[CH:20]=[C:16]([C:17]([OH:19])=[O:18])[CH:15]=[CH:23][N:22]=2)[CH2:4][CH2:3]1
Reactant: CN1CCC(CN)c2ccccc21
Reactant: O=C(O)c1ccncc1F
Product: CN1CCC(CNc2cc(C(=O)O)ccn2)c2ccccc21
Yield: 18 %

Procedure:
The title compound was prepared in 18% yield from 1-(1-methyl-1,2,3,4-tetrahydroquinolin-4-yl)methanamine and 3-fluoroisonicotinic acid according to the procedure for the preparation of Example 53. 1H NMR (400 MHz, DMSO-d6): δ 13.36 (br s, 1H), 8.35 (s, 1H), 7.83 (d, 1H, J=5.0 Hz), 7.72 (br s, 1H), 7.56 (d, 1H, J=5.0 Hz), 7.01-7.08 (m, 2H), 6.52-6.62 (m, 2H), 3.45-3.51 (m, 2H), 3.04-3.32 (m, 3H), 2.85 (s, 3H), 1.89-1.95 (m, 2H). [M+H] calc'd for C17H19N3O2, 298; found 298.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([O:12][C:13]1[C:14]([NH2:30])=[N:15][CH:16]=[C:17]([C:19]2[N:20]=[N:21][N:22]([CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[CH:23]=2)[CH:18]=1)[CH3:11].CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].[CH2:42](Br)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>O>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([O:12][C:13]1[C:14]([NH2:30])=[N:15][CH:16]=[C:17]([C:19]2[N:20]=[N:21][N:22]([CH:24]3[CH2:29][CH2:28][N:27]([CH2:42][C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[CH2:26][CH2:25]3)[CH:23]=2)[CH:18]=1)[CH3:11]
Reactant: BrCc1ccccc1
Reactant: CC(Oc1cc(-c2cn(C3CCNCC3)nn2)cnc1N)c1c(Cl)ccc(F)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(Oc1cc(-c2cn(C3CCN(Cc4ccccc4)CC3)nn2)cnc1N)c1c(Cl)ccc(F)c1Cl
Temperature: 90 °C

Procedure:
The product of the above mentioned Example 2 3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-1,2,3-triazol-4-yl)-2-aminopyridine (451 mg, 1 mmol) was added to N,N-dimethyl formamide (10 mL), and to which were added potassium carbonate (276 mg, 2 mmol) and benzyl bromide (342 mg, 2 mmol). The reaction mixture was warmed to 90° C. for 5 h. After the reaction mixture was cooled to room temperature, to which was added water. The reaction mixture was extracted with dichloromethane, the organic layer was washed with water for several times, dried over anhydrous sodium sulfate, and then filtered, the filtrate was rotatedly concentrated to dryness to yield a solid, which was purified via silica gel column chromatography (dichloromethane:methanol=10:1) to yield the title compound as gray solid powder.
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[C:14]2[C:5]([S:6][C:7]3[CH:8]=[C:9]([C:17]([OH:19])=O)[CH:10]=[CH:11][C:12]=3[C:13]2=[O:16])=[CH:4][CH:3]=1.S(Cl)([Cl:22])=O.CN(C)C=O>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:15]=[C:14]2[C:5]([S:6][C:7]3[CH:8]=[C:9]([C:17]([Cl:22])=[O:19])[CH:10]=[CH:11][C:12]=3[C:13]2=[O:16])=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1ccc2sc3cc(C(=O)O)ccc3c(=O)c2c1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: Cc1ccc2sc3cc(C(=O)Cl)ccc3c(=O)c2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 85 %

Procedure:
The 7-methyl-9-oxothioxanthene-3-carboxylic acid (MTA), 50.0 g (0.185 mol), was dissolved in 350 ml of toluene and 415 ml (5.69 mol) of thionyl chloride using an overhead stirrer in a 2 liter 3-neck round bottom flask. N,N-Dimethylformamide (DMF), 2 ml, was added and the reaction was brought to reflux for 2 hours. After this time, the mixture was stirred at room temperature for 16 hours. The solvent was removed under vacuum and the product was azeotroped with 3×350 ml of toluene to remove the excess thionyl chloride. The product was recrystallized from 800 ml of chloroform and the resulting solid was placed in a vacuum oven for 16 hours at 45° C. to complete removal of solvent. The isolated product weighed 45.31 g (85% yield) and nuclear magnetic resonance spectroscopy (NMR) confirmed the desired structure. This product was used for the preparation of a photoreactive monomer as described in Example 2.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:21]2[CH:31]=[CH:30][C:24]([C:25]([N:27]([CH3:29])[CH3:28])=[O:26])=[CH:23][CH:22]=2)=[N:6][C:7]=1[C:8]1[O:9][C:10]([C:13]2[CH:18]=[CH:17][C:16]([CH2:19]Br)=[CH:15][CH:14]=2)=[N:11][N:12]=1.[C:32]([O-:35])(=[O:34])[CH3:33].[K+].Cl>CN(C=O)C>[C:32]([O:35][CH2:19][C:16]1[CH:17]=[CH:18][C:13]([C:10]2[O:9][C:8]([C:7]3[C:2]([NH2:1])=[N:3][CH:4]=[C:5]([C:21]4[CH:22]=[CH:23][C:24]([C:25](=[O:26])[N:27]([CH3:29])[CH3:28])=[CH:30][CH:31]=4)[N:6]=3)=[N:12][N:11]=2)=[CH:14][CH:15]=1)(=[O:34])[CH3:33]
Reactant: CN(C)C(=O)c1ccc(-c2cnc(N)c(-c3nnc(-c4ccc(CBr)cc4)o3)n2)cc1
Reactant: CC(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)OCc1ccc(-c2nnc(-c3nc(-c4ccc(C(=O)N(C)C)cc4)cnc3N)o2)cc1
Temperature: 100 °C
Yield: 78.4 %

Procedure:
A mixture of 4-[5-amino-6-[5-[4-(bromomethyl)phenyl]-1,3,4-oxadiazol-2-yl]pyrazin-2-yl]-N,N-dimethyl-benzamide (200 mg, 0.4172 mmol) and potassium acetate (102.4 mg, 1.043 mmol) in DMF (5.714 mL) was heated at 100° C. for 4 h in a sealed microwave tube. The reaction mixture was cooled to room temperature and poured onto ice/water and acidified by HCl (1.043 mL of 1 M, 1.043 mmol). The mixture was extracted with ethyl acetate (3×10 mL) and the combined organic extracts washed with brine (3×10 mL). The extracts were dried over MgSO4 and concentrated under reduced pressure to give a yellow solid (150 mg, 74% yield); 1H NMR (400 MHz, DMSO) d 2.13 (s, 3H), 2.98-3.02 (m, 6H), 5.22 (s, 2H), 7.55 (d, 2H), 7.66 (d, 2H), 7.78 (br s, 2H), 8.16-8.19 (m, 4H) and 8.99 (s, 1H) ppm; MS (ES+) 459.18
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:8]2[Si](C)(C)CC[Si]2(C)C)=[N:6][CH:7]=1.[CH2:17]([SH:19])[CH3:18].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CCN(C(C)C)C(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[CH2:17]([S:19][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1)[CH3:18]
Reactant: C[Si]1(C)CC[Si](C)(C)N1c1ccc(Br)cn1
Reactant: CCS
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CCSc1ccc(N)nc1
Temperature: 110 °C
Reaction time: 17 h

Procedure:
In a 100 mL round-bottomed flask, 5-bromo-2-(2,2,5,5-tetramethyl-1,2,5-azadisilolidin-1-yl)pyridine (519 mg, 1.65 mmol), ethanethiol (102 mg, 122 μl, 1.65 mmol), xantphos (47.6 mg, 82.3 μmol) and Hunig's base (425 mg, 575 μl, 3.29 mmol) were combined with dioxane (10.0 ml) to give a light yellow solution. Pd2(dba)3 (37.7 mg, 41.1 μmol) was added and the mixture was evacuated and filled with Argon. The reaction mixture was heated to 110° C. and stirred for 17 h under argon. The mixture was cooled to 25° C. and conc. in vacuo. The residue was partitioned between 1M HCl and ether. Separated and basified aqueous phase with 3M NaOH. The aqueous layer was extracted with EtOAc (2×125 mL). The organic layers were combined, washed with H2O (1×50 mL), sat NaCl (1×25 mL), dried over Na2SO4 and concentrated in vacuo to an orange oil. The oil was dried overnight at 25° C. under vacuum to give an orange gum that was used crude in the subsequent oxidation. (M+H)+=155 m/e.
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][C@H:3]1[NH2:12].O.[C:14](=S)=[S:15]>C(O)C>[NH:1]1[C@@H:2]2[C:11]3[C:6]([CH2:5][CH2:4][C@H:3]2[NH:12][C:14]1=[S:15])=[CH:7][CH:8]=[CH:9][CH:10]=3
Reactant: N[C@@H]1CCc2ccccc2[C@H]1N
Reactant: S=C=S
Solvent: CCO
Solvent: O
Product: S=C1N[C@@H]2c3ccccc3CC[C@H]2N1
Temperature: 25 °C
Yield: 60 %

Procedure:
Trans-1,2-diamino-1,2,3,4-tetrahydronaphthalene (461 mg, 2.84 m mol) was dissolved in ethanol (8 ml), water (4 ml) was added to the solution, then carbon disulfide (190 μl, 3.17 m mol) was added thereto under stirring at room temperature. The mixture was heated under reflux for 4 hours and cooled in an ice-water bath. The crystals precipitating out were separated by filtration, washed with ether and dried in vacuum to give trans-3a,4,5,9b-tetrahydronaphth[1,2-d]imidazoline-2-thione (350 mg, 1.71 m mol) in 60% yield. The data spectroscopy and elemental analysis were as follows:
Reaction SMILES: [CH3:1][S:2]([N:5]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:7]2([CH2:12][CH2:11][N:10]([C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19](C(=O)C)=[CH:18][CH:17]=3)=[O:14])[CH2:9][CH2:8]2)[CH2:6]1)(=[O:4])=[O:3].[BH4-].[Na+].Cl.[CH2:34]([OH:36])[CH3:35].ClCCl>>[CH3:1][S:2]([N:5]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:7]2([CH2:12][CH2:11][N:10]([C:13]([NH:15][C:16]3[CH:17]=[CH:18][C:19]([CH2:35][CH2:34][OH:36])=[CH:20][CH:21]=3)=[O:14])[CH2:9][CH2:8]2)[CH2:6]1)(=[O:3])=[O:4]
Reactant: CC(=O)c1ccc(NC(=O)N2CCC3(CC2)CN(S(C)(=O)=O)c2ccccc23)cc1
Reactant: CCO
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)(=O)N1CC2(CCN(C(=O)Nc3ccc(CCO)cc3)CC2)c2ccccc21
Reaction time: 1 h

Procedure:
To a stirred solution of 1-methylsufonyl-N-(4-acetylphenyl)spiro[indoline-3,4′-piperidine]-1′-carboxamide (400 mg) in ethanol/dichloromethane (5/5 mL) at 0° C., was added sodium borohydride (100 mg). The mixture was stirred for 1 hour, then 3N HCl (0.2 mL) was added to destroy the excess hydride. The mixture was then concentrated and partitioned between water and dichloromethane. The organic layer was dried over MgSO4 and evaporated to give the title compound, 1600 as white powder (386 mg).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[C:7]([CH3:12])=[N:8][NH:9][C:10]=1[CH3:11])[CH3:2].[Cl:14][C:15]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:19][C:16]=1[CH2:17]Br.C([O-])([O-])=O.[K+].[K+]>C(#N)C.CO>[CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[C:7]([CH3:12])=[N:8][N:9]([CH2:17][C:16]2[CH:19]=[CH:20][C:21]([N+:23]([O-:25])=[O:24])=[CH:22][C:15]=2[Cl:14])[C:10]=1[CH3:11])[CH3:2]
Reactant: CCOC(=O)Cc1c(C)n[nH]c1C
Reactant: O=[N+]([O-])c1ccc(CBr)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CO
Product: CCOC(=O)Cc1c(C)nn(Cc2ccc([N+](=O)[O-])cc2Cl)c1C
Temperature: 25 °C
Reaction time: 48 h
Yield: 88.3 %

Procedure:
To a solution of (3,5-dimethyl-1H-pyrazol-4-yl)acetic acid ethyl ester (1.40 g, 7.7 mmol) and 2-chloro-4-nitrobenzyl bromide (4.60 g, 20.7 mmol) in 20 mL acetonitrile is added K2CO3 (1.59 g, 11.5 mmol) and the mixture is stirred for 48 hours at room temperature. The solvent is removed by evaporation and the residue is dissolved in dichloromethane/water. After extraction with dichloromethane the organic layer is dried over Na2SO4 and evaporated under reduced pressure to yield 2.79 g of [3,5-dimethyl-1-(2-chloro-4-nitro-benzyl)-1H-pyrazol-4-yl]-acetic acid ethyl ester (ESI mass spectrum: [M+H]+=352; Retention time: 1.95 min (method A). b) To a solution [3,5-dimethyl-1-(2-chloro-4-nitrobenzyl)-1H-pyrazol-4-yl]acetic acid ethyl ester (2.39 g, 6.8 mmol) in methanol (40 mL) is added Raney nickel (250 mg) and the mixture is hydrogenated. The catalyst is filtered off and the filtrate is concentrated under reduced pressure to yield 1.18 g of the title compound (ESI mass spectrum: [M+H]+=322; Retention time HPLC: 1.76 min (method A)).
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][N:3]=1.[CH3:11]C(C)([O-])C.[K+].CI>C1COCC1>[I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH3:11])[N:3]=1
Reactant: Ic1n[nH]c2ccccc12
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: Cn1nc(I)c2ccccc21
Temperature: 0 °C
Reaction time: 1.25 h
Yield: 85.7 %

Procedure:
In a 50 ml round-bottomed flask, 3-iodo-1H-indazole (1.0 g, 3.9 mmol) was dissolved in THF (12 ml) and the solution was cooled to 0° C. Potassium tert-butoxide (612 mg, 5.45 mmol) was added and the reaction mixture was stirred at 0° C. for 1.25 h. Methyl iodide (0.29 ml, 4.64 mmol) was added dropwise then the ice bath was removed and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with water and extracted with EtOAc (2×). The combined organic layers were washed with water and brine then dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography over silica gel with EtOAc/Hexanes (gradient 0-10% EtOAc) to afford 863 mg (86%) of 3-iodo-1-methyl-1H-indazole as a yellow oil. 1H NMR (CDCl3, 300 MHz): δ (ppm) 7.42-7.53 (m, 2H), 7.33-7.40 (m, 1H), 7.22 (ddd, J=8.0, 6.9, 0.9 Hz, 1H), 4.11 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12][NH:11][C:10]=1[CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:23]([CH:27](OC)[OH:28])([F:26])([F:25])[F:24].ClCCl>O>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[C:13]([CH:27]([OH:28])[C:23]([F:26])([F:25])[F:24])=[CH:12][NH:11][C:10]=1[CH3:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1[nH]ccc(=O)c1OCc1ccccc1
Reactant: COC(O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: Cc1[nH]cc(C(O)C(F)(F)F)c(=O)c1OCc1ccccc1
Yield: 24 %

Procedure:
A mixture of 3-benzyloxy-2-methyl-1H-pyridin-4-one (10.0 g, 46.4 mmol), potassium carbonate (19 g, 138 mmol), and CF3CH(OH)OCH3 (35 mL, 0.35 mol) in a 500 mL 3-necked round bottom flask equipped with a mechanical stirrer was heated to reflux for 6 days. The progress of the reaction was monitored by HPLC Method 3 (Example 24). Analysis of the HPLC data indicated that there was about 42% conversion. The reaction was stopped, and dichloromethane and deionized water were added. The organic fraction was collected, washed with brine, dried over Na2SO4, filtered and concentrated to dryness. Purification of the residue by column chromatography on silica (methanol/dichloromethane 2/100 to 5/100 v:v) afforded 3-benzyloxy-2-methyl-5-(2,2,2-trifluoro-1-hydroxy-ethyl)-1H-pyridin-4-one as a solid product (3.5 g, 24% yield, HPLC Method 3 (Example 24), RT=14.3 min). 1H NMR (DMSO-d6) δ ppm: 11.68 (br s, 1H), 7.58 (s, 1H), 7.35, (m, 5H), 5.34 (q, J=7.3 Hz, 1H), 5.06 (m, 2H), 2.08 (s, 3H); MS-ESI (m/z) 313.7 [M+1]+, 206.1, 91.1 (100%).