Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[Si:2]([NH:5][C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:4])[CH3:3].[CH3:10][C-:11]1[C:19]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=2[C:13]([CH3:20])=[CH:12]1.[Li+]>C1COCC1>[C:6]([NH:5][Si:2]([CH3:4])([CH3:3])[C:12]1[CH:11]([CH3:10])[C:19]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=2[C:13]=1[CH3:20])([CH3:9])([CH3:8])[CH3:7]
Reactant: Cc1c[c-](C)c2c1CCCC2
Reactant: CC(C)(C)N[Si](C)(C)Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1=C([Si](C)(C)NC(C)(C)C)C(C)C2=C1CCCC2
Temperature: 25 °C
Yield: 93.4 %

Procedure:
In an argon atmosphere drybox 0.77 g of ClSiMe2NHCMe3 (4.67 mmol) was added to 50 mL of THF. To this solution 0.75 g (4.67 mmol) of lithium 1,3-dimethyl-4,5,6,7-tetrahydroindenide was added. The solution was then brought to reflux for about 3 hours and then cooled to room temperature. Chromatographic analysis showed the reaction to be complete. The solvent was then removed under reduced pressure. The residue was extracted with pentane, filtered, and the solvent again removed under reduced pressure to give 1.21 g of product (94 percent yield).
Reaction SMILES: [CH:1]1([N:4]2[C:8]3[C:9]([O:29][C@@H:30]([C@H:32]4[CH2:36][NH:35][C:34](=[O:37])[CH2:33]4)[CH3:31])=[N:10][C:11]([C:13]4[CH:18]=[CH:17][C:16](C5CCN(C6COC6)CC5)=[CH:15][CH:14]=4)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:3][CH2:2]1.CC1(C)C(C)(C)OB(C2C=CC([N:52]3[CH2:57][CH:56]4[CH2:58][CH:54]([N:55]4[C:59]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:60])[CH2:53]3)=CC=2)O1>COCCOC.C([O-])([O-])=O.[Na+].[Na+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:1]1([N:4]2[C:8]3[C:9]([O:29][C@@H:30]([C@@H:32]4[CH2:33][C:34](=[O:37])[NH:35][CH2:36]4)[CH3:31])=[N:10][C:11]([C:13]4[CH:14]=[CH:15][C:16]([N:52]5[CH2:53][CH:54]6[CH2:58][CH:56]([N:55]6[C:59]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:60])[CH2:57]5)=[CH:17][CH:18]=4)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1C2CC1CN(c1ccc(B3OC(C)(C)C(C)(C)O3)cc1)C2
Reactant: C[C@@H](Oc1nc(-c2ccc(C3CCN(C4COC4)CC3)cc2)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: C[C@@H](Oc1nc(-c2ccc(N3CC4CC(C3)N4C(=O)OC(C)(C)C)cc2)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Temperature: 25 °C
Yield: 59 %

Procedure:
Prepared by Suzuki coupling reaction procedure, as previously described for the synthesis of (R)-4-((R)-1-((3-cyclopropyl-6-(4-(1-(oxetan-3-yl)piperidin-4-yl)phenyl)-3H-imidazo[4,5-c]pyridin-4-yl)oxy)ethyl)pyrrolidin-2-one:, using instead tert-butyl 3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (289.4 mg, 0.72 mmol), and Pd(PPh3)4 (34.8 mg, 0.030 mmol) in DME (3 mL) and 2N Na2CO3 (2 mL). The reaction mixture was sonicated for 30 sec and degassed with nitrogen gas for 30 sec, and heated at 100 C for 1 h. Then it was cooled to room temperature, directly loaded on the pre-packed silica cartridge, and purified by flash chromatography (100% dichloromethane to 25% MeOH in dichloromethane) to give 200.0 mg (59%) of tert-butyl 3-(4-(3-cyclopropyl-4-((R)-1-((R)-5-oxopyrrolidin-3-yl)ethoxy)-3H-imidazo[4,5-c]pyridin-6-yl)phenyl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate.
Reaction SMILES: C[O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:6]([N+:18]([O-:20])=[O:19])[CH:5]=1.CO.[OH-].[K+].Cl>O1CCCC1>[CH2:11]([O:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:21])=[O:2])=[CH:5][C:6]=1[N+:18]([O-:20])=[O:19])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COC(=O)c1ccc(OCc2ccccc2)c([N+](=O)[O-])c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(OCc2ccccc2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 95 %

Procedure:
A solution the crude 4-benzyloxy-3-nitro-benzoic acid methyl ester from the previous step in tetrahydrofurane (150 mL) and MeOH (600 mL) was treated with KOH 3N (152 mL) and stirred at room temperature for 18 hours. The mixture was acidified with HCl 3N. The precipitate thus formed was filtered, washing with MeOH/water 1:1 and dried under vacuum. 4-Benzyloxy-3-nitro-benzoic acid (42 g, 95% over two steps) was obtained as a white solid, which was used crude in the following reaction.
Reaction SMILES: [CH2:1]1[CH2:6][CH2:5][C:4]([CH2:11][NH2:12])([CH2:7][C:8]([OH:10])=[O:9])[CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[Si](C)(C)C.Cl[C:26]([O:28][CH:29]([Cl:31])[CH3:30])=[O:27]>ClCCl>[Cl:31][CH:29]([O:28][C:26]([NH:12][CH2:11][C:4]1([CH2:7][C:8]([OH:10])=[O:9])[CH2:3][CH2:2][CH2:1][CH2:6][CH2:5]1)=[O:27])[CH3:30]
Reactant: NCC1(CC(=O)O)CCCCC1
Reactant: CC(Cl)OC(=O)Cl
Agent: C[Si](C)(C)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(Cl)OC(=O)NCC1(CC(=O)O)CCCCC1
Reaction time: 0.5 h
Yield: 97.2 %

Procedure:
In a 5-liter, 3-neck, round bottom flask containing dichloromethane (1.6 L) is added gabapentin (120.4 g, 0.704 mol) followed by triethylamine (294 mL, 2.11 mol). Chlorotrimethylsilane (178 mL, 1.40 mol) is slowly added while maintaining the reaction temperature below 15° C. and the resulting suspension is stirred for 30 min. 1-Chloroethyl chloroformate (100 g, 0.704 mol) is then added slowly while maintaining the temperature below 15° C. After the addition is complete, additional triethylamine (88 mL, 0.63 mol) is added and the resulting suspension is stirred at room temperature for 30 min. The resulting silyl ester is converted via acidic work-up to the corresponding acid by washing the reaction mixture with water (2×1 L), followed by 1N HCl (2×2 L) then brine (2×500 mL). After drying over anhydrous sodium sulfate and removal of the solvent in vacuo, the crude product (190 g) is obtained as an orange oil and used in Step B without further purification. 1H NMR (CDCl3, 400 MHz): δ1.41-1.57 (m, 10H), 1.78 (d, 3H), 2.33 (s, 2H), 3.27 (d, 2H), 5.42 (br. s, 1H), 6.55 (q, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH2:9])[N:5]=[CH:4][N:3]=1.[C:10](OCC)(=[O:14])[C:11]([CH3:13])=O>C(O)(=O)C>[NH2:1][C:2]1[C:7]2[N:8]=[C:11]([CH3:13])[C:10](=[O:14])[NH:9][C:6]=2[N:5]=[CH:4][N:3]=1
Reactant: CCOC(=O)C(C)=O
Reactant: Nc1ncnc(N)c1N
Solvent: CC(=O)O
Product: Cc1nc2c(N)ncnc2[nH]c1=O

Procedure:
More specifically, with reference to FIG. 2, 4,5,6-triaminopyrimidine (1), (see, J. Baddiley et al., J. Chem. Soc. 386 (1943)) and ethyl pyruvate are heated in glacial acetic acid for 2 hours. After cooling the precipitate is collected and washed with water and purified by recrystallization using a suitable solvent system, such as DMF/H2O, to yield 4-amino-6-methyl-7(8H)-pteridone (3) (see, D. Söll et al., Chem. Ber. 96:2977 (1963)). Compounds wherein R1 is an methyl group can be generated similarly by starting with 4,5,triamino-2-methylpyrimidine (2).
Reaction SMILES: C1(C)C=CC=CC=1.Br.[Br:9][CH2:10][CH2:11][CH2:12][NH2:13].C(N(CC)CC)C.[N+:21]([C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1)([O-:23])=[O:22]>C(OCC)(=O)C>[Br:9][CH2:10][CH2:11][CH2:12][NH:13][C:28](=[O:29])[C:27]1[CH:26]=[CH:25][C:24]([N+:21]([O-:23])=[O:22])=[CH:32][CH:31]=1
Reactant: NCCCBr
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: Br
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(NCCCBr)c1ccc([N+](=O)[O-])cc1
Yield: 70.3 %

Procedure:
30 mL of toluene was added to 3-bromopropylamine hydrobromide (1.20 g, 5.50 mmol), and triethylamine (1.53 mL, 11.0 mmol) was added dropwise with stirring under ice cooling. After the dropwise addition was completed, 4-nitrobenzoyl chloride (928 mg, 5.50 mmol) was added little by little, and the mixture was stirred at room temperature for 15 minutes. The reaction mixture was diluted with ethyl acetate, and the organic layer was washed with an aqueous saturated sodium hydrogencarbonate solution, a 0.1 N aqueous hydrochloric acid solution, and saturated sodium chloride solution. The organic layer was dried with anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure to give the title compound (1.11 g; yield, 77%) as light yellow crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([F:10])=[CH:4][C:3]=1B(O)O.I[C:15]1[C:23]2[C:18](=[N:19][CH:20]=[N:21][C:22]=2[NH2:24])[N:17]([CH:25]([CH3:27])[CH3:26])[N:16]=1.C([O-])([O-])=O.[Na+].[Na+]>CCO.COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([F:10])=[CH:4][C:3]=1[C:15]1[C:23]2[C:18](=[N:19][CH:20]=[N:21][C:22]=2[NH2:24])[N:17]([CH:25]([CH3:27])[CH3:26])[N:16]=1
Reactant: COc1cc(F)c(B(O)O)cc1F
Reactant: CC(C)n1nc(I)c2c(N)ncnc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Product: COc1cc(F)c(-c2nn(C(C)C)c3ncnc(N)c23)cc1F
Temperature: 80 °C
Yield: 87 %

Procedure:
A solution of 2,5-difluoro-4-methoxyphenylboronic acid (84 mg, 0.45 mmol) in EtOH (3.3 ml) was added to a solution of 3-iodo-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (54 mg, 0.18 mmol) in DME (12 ml). Pd(PPh3)4 (30 mg, 0.03 mmol) and saturated Na2CO3 (1.9 ml) were added and the reaction was heated to 80° C. under an argon atmosphere overnight. After cooling, the reaction was extracted with saturated NaCl and CH2Cl2. Organic phases were combined, concentrated in vacuo and purified by silica gel column chromatography [MeOH—CH2Cl2, 2:98] to yield BA63 (50 mg, 17% yield). ESI-MS (M+H)+ m/z calcd 320.1, found 320.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[C:18]([Cl:20])[CH:19]=1)[CH2:5][C:6]1[C:7]([CH2:15][CH3:16])=[N:8][N:9]([CH2:13][OH:14])[C:10]=1[CH2:11][CH3:12].[N:21]([C:24]([O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:25])=[C:22]=[O:23]>CN(C)C=O>[C:22]([NH:21][C:24]([O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:25])([O:14][CH2:13][N:9]1[C:10]([CH2:11][CH3:12])=[C:6]([CH2:5][C:4]2[CH:17]=[C:18]([Cl:20])[CH:19]=[C:2]([Cl:1])[CH:3]=2)[C:7]([CH2:15][CH3:16])=[N:8]1)=[O:23]
Reactant: O=C=NC(=O)Oc1ccccc1
Reactant: CCc1nn(CO)c(CC)c1Cc1cc(Cl)cc(Cl)c1
Solvent: CN(C)C=O
Product: CCc1nn(COC(=O)NC(=O)Oc2ccccc2)c(CC)c1Cc1cc(Cl)cc(Cl)c1
Reaction time: 1.5 h

Procedure:
A solution of the alcohol of Example 41 (6.3 mg, 201 mol) in dimethylformamide (250 μL) was treated with phenyl isocyanatoformate (3.6 mg, 22 μmol) and the mixture was shaken for 1.5 hours. The reaction mixture was filtered and the filtrate was purified by HPLC (Hypersil Thermoquest Luna C8 150×10 mm column; a gradient mobile phase was used, 10:90 (by volume)→95:5 (by volume) acetonitrile:(water, 95% by volume/trifluoroacetic acid, 0.1% by volume/acetonitrile 5%, by volume)).
Reaction SMILES: Cl.[NH:2]1[CH2:6][C@@H:5]([OH:7])[C@H:4]([OH:8])[CH2:3]1.O.C([O-])([O-])=O.[Na+].[Na+].CS(O[CH2:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][N:27]=[C:26]([C:30]([N:32]2[CH2:35][CH:34]([C:36]3[CH:41]=[CH:40][C:39]([O:42][CH2:43][C:44]4[CH:49]=[CH:48][C:47]([CH2:50][CH3:51])=[CH:46][CH:45]=4)=[C:38]([O:52][CH3:53])[CH:37]=3)[CH2:33]2)=[O:31])[CH:25]=1)(=O)=O>C(O)CC>[OH:8][C@H:4]1[C@H:5]([OH:7])[CH2:6][N:2]([CH2:21][CH2:22][O:23][C:24]2[CH:29]=[CH:28][N:27]=[C:26]([C:30]([N:32]3[CH2:33][CH:34]([C:36]4[CH:41]=[CH:40][C:39]([O:42][CH2:43][C:44]5[CH:45]=[CH:46][C:47]([CH2:50][CH3:51])=[CH:48][CH:49]=5)=[C:38]([O:52][CH3:53])[CH:37]=4)[CH2:35]3)=[O:31])[CH:25]=2)[CH2:3]1
Reactant: CCc1ccc(COc2ccc(C3CN(C(=O)c4cc(OCCOS(C)(=O)=O)ccn4)C3)cc2OC)cc1
Reactant: O[C@@H]1CNC[C@H]1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCCO
Product: CCc1ccc(COc2ccc(C3CN(C(=O)c4cc(OCCN5C[C@@H](O)[C@H](O)C5)ccn4)C3)cc2OC)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 69.3 %

Procedure:
To a mixed solution of (3R,4R)-pyrrolidine-3,4-diol monohydrochloride (2.1 g) in 1-propanol (60 mL)/water (2.0 mL) was added Na2CO3 (4.0 g). The mixture was stirred at 60° C. for 1 hr. To the mixture was added 2-(2-{3-[4-(4-ethylbenzyloxy)-3-methoxyphenyl]azetidine-1-carbonyl}pyridin-4-yloxy)ethyl methanesulfonate (6.7 g) prepared in (1). The reaction mixture was stirred at 100° C. for 10 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and then dried over Na2SO4. The solvent was removed under reduced pressure. The residue was purified by silica gel chromatography (Developing solvent: chloroform/methanol=40/1 to 5/1) to give the title compound (4.7 g, 70%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([S:9]([N:12]2[C:16]([C:17]3[C:18]([F:23])=[N:19][CH:20]=[CH:21][CH:22]=3)=[C:15]([F:24])[C:14]([CH2:25][N:26](C)[C:27](=O)OC(C)(C)C)=[CH:13]2)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1)#[N:2].C(OCC)(=O)C.[ClH:41]>C(OCC)(=O)C.CC(O)C>[ClH:41].[F:24][C:15]1[C:14]([CH2:25][NH:26][CH3:27])=[CH:13][N:12]([S:9]([C:5]2[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=2)[C:1]#[N:2])(=[O:11])=[O:10])[C:16]=1[C:17]1[C:18]([F:23])=[N:19][CH:20]=[CH:21][CH:22]=1
Reactant: CN(Cc1cn(S(=O)(=O)c2cccc(C#N)c2)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CNCc1cn(S(=O)(=O)c2cccc(C#N)c2)c(-c2cccnc2F)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 65 %

Procedure:
To a solution of tert-butyl {[1-[(3-cyanophenyl)sulfonyl]-4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (435 mg) in ethyl acetate (3 mL) and 2-propanol (2 mL) was added 4 mol/L hydrogen chloride-ethyl acetate solution (6 mL), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from ethanol to give the title compound as a white solid (yield 245 mg, 65%).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[O:8][CH2:7][C:6]2[CH:9]=[C:10]([CH2:13][OH:14])[CH:11]=[CH:12][C:5]=2[CH2:4][O:3]1.N1C=CN=C1.[C:21]([Si:25](Cl)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([CH3:24])([CH3:23])[CH3:22]>CN(C)C=O.O>[C:21]([Si:25]([O:14][CH2:13][C:10]1[CH:11]=[CH:12][C:5]2[CH2:4][O:3][C:2]([CH3:15])([CH3:1])[O:8][CH2:7][C:6]=2[CH:9]=1)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: CC1(C)OCc2ccc(CO)cc2CO1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)OCc2ccc(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc2CO1
Reaction time: 2 h

Procedure:
To a solution of 3.227 g (15.495 mM) of (7,7-dimethyl-5,9-dihydro-6,8-dioxabenzocyclohepten-2-yl)-methanol and 1.27 g (18.6 mM) of imidazole in 20 ml of N,N-dimethylformamide was added 4.69 g (17.0 mM) of tert-butylchlorodiphenylsilane at room temperature and the mixture was stirred for 2 hours. This reaction mixture was poured in water and extracted with 3 portions of diethyl ether. The pooled organic layer was dried over MgSO4 and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=30/1) to provide the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH:5]([C:10]1[CH:11]=[C:12]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2].BrC[C:35]1[CH:36]=[CH:37][C:38]2[S:42][N:41]=[N:40][C:39]=2[CH:43]=1.[CH:44](N(C(C)C)CC)(C)C>CC#N.CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:32])[CH:5]([C:10]1[CH:11]=[C:12]([C:22]2[CH:23]=[CH:24][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:26][CH:27]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][N:18]([CH2:44][C:36]3[CH:35]=[CH:43][C:39]4[N:40]=[N:41][S:42][C:38]=4[CH:37]=3)[CH2:17]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2]
Reactant: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCCNC2)c1
Reactant: BrCc1ccc2snnc2c1
Reactant: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCCN(Cc3ccc4nnsc4c3)C2)c1
Yield: 88.3 %

Procedure:
To a solution of compound 33b, 4-Methyl-2-(5-piperidin-3-yl-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid ethyl ester (59.3 mg, 0.133 mmol) in CH3CN (5 ml) was added 5Bromomethyl-benzo 1,2,3 thiadiazole (45.5 mg, 0.20 mmol) and diisopropylethylamine (46 μl, 0.27 mmol). The reaction was microwaved at 130° C. for 10 minutes, then diluted with EtOAc and washed with brine, sat. NaHCO3, and brine, dried and filtered. Purification by silica gel chromatography (Isco) gave the desired product, (70 mg, 89%). Calcd for C33H36F3N3O2S (M+H) 595.72, Found 597.3.
Reaction SMILES: [C:1](Cl)(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[N+:12]([C:15]1[CH:16]=[C:17]([OH:24])[CH:18]=[C:19]([N+:21]([O-:23])=[O:22])[CH:20]=1)([O-:14])=[O:13].N1C=CC=CC=1>CC(C)=O>[C:1]([O:24][C:17]1[CH:16]=[C:15]([N+:12]([O-:14])=[O:13])[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=1)(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1cc(O)cc([N+](=O)[O-])c1
Reactant: O=C(Cl)C=Cc1ccccc1
Solvent: CC(C)=O
Solvent: c1ccncc1
Product: O=C(C=Cc1ccccc1)Oc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 71.6 %

Procedure:
66.64 g (0.4 mole) of cinnamoyl chloride and 300 g of methyl ketone (hereinafter referred to as MEK) were placed in a reaction vessel to be stirred by heating at 60° C. under a nitrogen current. 73.64 g (0.4 mole) of 3,5-dinitrophenol, 50 g of pyridine, and 500 g of MEK were added dropwise to the above reaction vessel using a dropping funnel. After that, reflux stirring was conducted for approximately 2 hours under a nitrogen current. After the completion of the reaction, the precipitate was separated by filtration. The filtrate was concentrated until crystals separated out and poured into methanol. 90 g of light yellow colored needle-like crystals (2, 4-dinitrophenyl cinnamate) were yielded.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[OH-].[K+].[CH2:18]([C:21]1[CH:26]=[CH:25][C:24]([CH:27]=[CH2:28])=[CH:23][N:22]=1)[CH2:19][CH3:20].[CH3:29]N1CCCC1=O>O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:28][CH2:27][C:24]3[CH:23]=[N:22][C:21]([CH2:18][CH2:19][CH3:20])=[CH:26][CH:25]=3)[C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:28][CH2:27][C:24]3[CH:23]=[N:22][C:21]([CH:18]([CH3:19])[CH3:29])=[CH:26][CH:25]=3)[C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: CN1CCCC1=O
Reactant: C=Cc1ccc(CCC)nc1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CC(C)c1ccc(CCn2c3c(c4cc(Cl)ccc42)CN(C)CC3)cn1
Product: CCCc1ccc(CCn2c3c(c4cc(Cl)ccc42)CN(C)CC3)cn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 9.6 %

Procedure:
To a solution of 8-Chloro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.1 g, 0.00045 mol) in N-methyl 2-pyrolidone (1.0 mL) was added powdered potassium hydroxide (0.20 g, 0.0036 mol) and allowed to stir for 10 min at RT. 2-propyl-5-vinyl-pyridine (0.2 g, 0.00136 mol) was added and stirred for further 24 h. at 100° C. After completion (TLC), reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (3×50 mL). The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure using rotary evaporator. The crude was semi-purified through column chromatography (7% MeOH:DCM in silica 100-200 mesh, Diameter of column—2.5 cm, Height of silica—approx. 5 inch), Then further purified by preparative TLC, to give the desired compound as yellow oil (0.016 g, 9.6% yield), 8-Chloro-5-[2-(6-isopropyl-pyridin-3-yl)-ethyl]-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.016 g, 0.000435 mol) was dissolved in THF (1.0 mL). A solution of oxalic acid dihydrate (0.005 g, 0.0007 mol) in THF (0.5 mL) was added and stirred for 30 min at RT. Precipitate obtained was filtered and dried to give oxalate salt as off white solid (0.010 g, 52% yield).
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[CH2:4][N:5]1[C:9]([CH2:10]O)=[CH:8][C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[N:6]1.[Cl-].[Li+].C(N(CC)CC)C.CS([Cl:35])(=O)=O>C(OCC)(=O)C.C1COCC1>[Cl:35][CH2:10][C:9]1[N:5]([CH2:4][C:3]2[CH:18]=[CH:19][CH:20]=[CH:21][C:2]=2[F:1])[N:6]=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCc1cc(-c2ccccn2)nn1Cc1ccccc1F
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Fc1ccccc1Cn1nc(-c2ccccn2)cc1CCl
Temperature: 0 °C
Yield: 44.6 %

Procedure:
To a cold solution of intermediate 2 (385 mg) in THF (6.0 ml) at 0° C. and under argon, was added a solution of lithium aluminum hydride (880 μl, 2.0 M in THF). The mixture was removed from the ice bath and stirred at room temperature for 2 h. Upon completion of the reaction, the mixture was cooled to 0° C. and sequentially treated with water (70 μl), 15% sodium hydroxide solution in water (130 μL), and water (70 μl). The resulting precipitate was removed by filtration. The filtrate was concentrated under vacuum to give (1-(2-fluorobenzyl)-3-(pyridin-2-yl)-1H-pyrazol-5-yl)methanol as white solid. In a separate flask, (1-(2-fluorobenzyl)-3-(pyridin-2-yl)-1H-pyrazol-5-yl)methanol (113 mg), lithium chloride (33.8 mg), triethylamine (0.1 ml), and THF were combined (2.0 ml) and cooled to 0° C. To this mixture, was added methanesulfonyl chloride (120 μl). The mixture was gradually warmed to ambient temperature over the course of 16 h. The mixture was diluted with ethyl acetate (100 ml), washed with saturated solution of sodium bicarbonate (20 ml), and brine (20 ml). The organic layer was dried, filtered, and evaporated to give 2-(5-(chloromethyl)-1-(2-fluorobenzyl)-1H-pyrazol-3-yl)pyridine as crude yellow solid. This crude solid (115 mg) was dissolved in THF (1.9 ml) in a separate flask equipped with a stir bar and a balloon filled with argon. The mixture was cooled to 0° C. To this mixture, was added dropwise, a solution of Superhydride (1.1 ml, 1.0 M in THF). The mixture was removed from the ice bath and stirred at room temperature for 24 h. Upon completion of the reaction, the mixture was cooled to 0° C. and sequentially treated with water (120 μl), 15% sodium hydroxide solution in water (240 μL), and water (120 μl). The resulting mixture was diluted in chloroform (100 ml) and washed with brine (50 ml). The organic layer was dried, filtered, and evaporated to give crude solid. The crude solid was purified using SiO2 chromatography (ethyl acetate/hexanes) to give I-55 as off-white solid (44.6% yield over three steps). 1H NMR (400 MHz, CDCl3) δ 8.63-8.59 (m, 1H), 7.93-7.89 (m, 1H), 7.68 (td, 1H), 7.27-7.20 (m, 1H), 7.19-7.14 (m, 1H), 7.09-7.01 (m, 2H), 6.93-6.88 (m, 1H), 6.71 (s, 1H), 5.42 (s, 2H), 2.27 (s, 3H) ppm.
Reaction SMILES: S(Cl)([Cl:3])=O.[OH:5][C:6]1[C:11](=[O:12])[CH:10]=[C:9]([CH:13]([OH:18])[C:14]([F:17])([F:16])[F:15])[N:8]([CH3:19])[C:7]=1[CH2:20]O.CO.[Cl:24]CCl>C(#N)C>[ClH:3].[Cl:24][CH2:20][C:7]1[N:8]([CH3:19])[C:9]([CH:13]([OH:18])[C:14]([F:17])([F:16])[F:15])=[CH:10][C:11](=[O:12])[C:6]=1[OH:5]
Reactant: ClCCl
Reactant: O=S(Cl)Cl
Reactant: Cn1c(C(O)C(F)(F)F)cc(=O)c(O)c1CO
Solvent: CO
Solvent: CC#N
Product: Cl
Product: Cn1c(C(O)C(F)(F)F)cc(=O)c(O)c1CCl

Procedure:
Thionyl chloride (0.48 mL, 6.6 mmol) was added dropwise to a suspension of 3-hydroxy-2-(hydroxymethyl)-1-methyl-6-(2,2,2-trifluoro-1-hydroxyethyl)pyridin-4(1H)-one (1.50 g, 5.9 mmol) in acetonitrile (45 mL). The progress of the reaction was monitored by TLC (eluant: methanol:dichloromethane, 15:100, v:v), and the starting material was consumed within 5 min. The reaction mixture was concentrated repeatedly in acetonitrile to give a solid, which was then washed with acetonitrile (15 mL×1). Thus, 2-(chloromethyl)-3-hydroxy-1-methyl-6-(2,2,2-trifluoro-1-hydroxyethyl)pyridin-4(1H)-one hydrochloride was obtained as a white solid (1.18 g).