Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[S:2]1(=[O:15])[CH2:7][CH2:6][N:5]([C:8]2[N:13]=[CH:12][N:11]=[C:10]([NH2:14])[CH:9]=2)[CH2:4][CH2:3]1.[H-].[Na+].Cl[C:19]1[S:20][C:21]([C:24]#[N:25])=[CH:22][N:23]=1>>[O:15]=[S:2]1(=[O:1])[CH2:7][CH2:6][N:5]([C:8]2[N:13]=[CH:12][N:11]=[C:10]([NH:14][C:19]3[S:20][C:21]([C:24]#[N:25])=[CH:22][N:23]=3)[CH:9]=2)[CH2:4][CH2:3]1
Reactant: Nc1cc(N2CCS(=O)(=O)CC2)ncn1
Reactant: N#Cc1cnc(Cl)s1
Agent: [H-]
Agent: [Na+]
Product: N#Cc1cnc(Nc2cc(N3CCS(=O)(=O)CC3)ncn2)s1

Procedure:
6-(1,1-Dioxidothiomorpholin-4-yl)pyrimidin-4-amine 8-2 (0.237 g, 1.04 mmol), sodium hydride (0.083 g, 2.08 mmol) and 2-chloro-1,3-thiazole-5-carbonitrile 2-2 (0.15 g, 1.04 mmol) were treated as in Scheme 4 above. The product was purified on a preparative hplc column and isolated via lyophilization to yield 8-3. Hi-Res MS: calc: 337.0536 found: 337.0530. 1NMR(DMSO): 8.51 ppm (s, 1H); 8.27 ppm (s, 1H); 6.36 ppm (s, 1H); 4.05 ppm (s, 4H); 3.21 ppm (s, 4H).
Reaction SMILES: [CH3:1][N:2]1[C:7]([CH:8]2[CH2:12][CH2:11][NH:10][CH2:9]2)=[CH:6][C:5]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[C:4]([C:19]2[CH:28]=[CH:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=2)[C:3]1=[O:29].CN1C(=O)C(C2C=CC3C(=CC=CC=3)C=2)=C(C2C=CN=CC=2)C=C1C1CCNCC1.[C:60]([O:64][C:65](=[O:70])[NH:66][CH2:67][CH:68]=O)([CH3:63])([CH3:62])[CH3:61].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl.C(Cl)Cl>[C:60]([O:64][C:65](=[O:70])[NH:66][CH2:67][CH2:68][N:10]1[CH2:11][CH2:12][CH:8]([C:7]2[N:2]([CH3:1])[C:3](=[O:29])[C:4]([C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:20]=3)=[C:5]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)[CH:6]=2)[CH2:9]1)([CH3:63])([CH3:62])[CH3:61]
Reactant: Cn1c(C2CCNC2)cc(-c2ccncc2)c(-c2ccc3ccccc3c2)c1=O
Reactant: CC(C)(C)OC(=O)NCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cn1c(C2CCNCC2)cc(-c2ccncc2)c(-c2ccc3ccccc3c2)c1=O
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: Cn1c(C2CCN(CCNC(=O)OC(C)(C)C)C2)cc(-c2ccncc2)c(-c2ccc3ccccc3c2)c1=O
Temperature: 80 °C
Yield: 18 %

Procedure:
To a solution of 1-methyl-3-naphthalen-2-yl-6-pyrrolidin-3-yl-1H-[4,4′]bipyridinyl-2-one (prepared following the same method as described for 1′-methyl-5′-naphthalen-2-yl-1,2,3,4,5,6-hexahydro-1′H-[4,2′;4′,4″]terpyridin-6′-one, Scheme 12) (200 mg, 0.52 mmol) in dry CHCl3 (5 mL) under nitrogen was added (2-oxo-ethyl)-carbamic acid tert-butyl ester (209 mg, 1.3 mmol) and sodium triacetoxy borohydride (165 mg, 0.78 mmol) and then heated at 80° C. for 2 h. After cooling down to RT the mixture was diluted with CH2Cl2 and sat solution of NaHCO3 and the organic layer was taken. The organic phase was successively washed with H2O, brine and dried (Na2SO4). The crude was purified by flash chromatography (3%, 2M methanol ammonia in DCM) to obtain the title compound (50 mg, 18%) as a yellow solid. MS (ES+): 525 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]([O:13][CH3:14])=[O:12])=[CH:10][C:4]=2[N:3]1C(OCC1C=CC=CC=1)=O.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:32][C:33]1[CH:42]=[C:41]2[C:36]([CH:37]=[CH:38][C:39]([C:43]#[N:44])=[CH:40]2)=[CH:35][CH:34]=1>CN(C=O)C.C(OCC)(=O)C>[C:43]([C:39]1[CH:40]=[C:41]2[C:36]([CH:35]=[CH:34][C:33]([CH2:32][N:6]3[C:5]4[CH:7]=[CH:8][C:9]([C:11]([O:13][CH3:14])=[O:12])=[CH:10][C:4]=4[NH:3][C:2]3=[O:1])=[CH:42]2)=[CH:37][CH:38]=1)#[N:44]
Reactant: N#Cc1ccc2ccc(CBr)cc2c1
Reactant: COC(=O)c1ccc2[nH]c(=O)n(C(=O)OCc3ccccc3)c2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2c(c1)[nH]c(=O)n2Cc1ccc2ccc(C#N)cc2c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 69.7 %

Procedure:
To a chilled solution of methyl 2-oxo-3-(benzyloxycarbonyl)—(3H)—benzimidazole-5-carboxylate (110 mg, 0.337 mmol) in DMF (3 mL) was added cesium carbonate (0.275 g, 0.84 mmol) followed by 7-(bromomethyl)naphthalene-2-carbonitrile (108 mg, 0.44 mmol). The reaction was stirred at room temperature for 1.5 hours, diluted with ethyl acetate, washed with water and brine, dried over sodium sulfate and concentrated in vacuo. This residue was redissolved in methanol (4 mL), CH3CN (3 mL) and IN LiOH (0.7 mL). The reaction mixture was stirred for 1 hour, acidified with 1N HCl (0.7 mL), filtered and dried to yield methyl 1-[(7-cyano(2-naphthyl))methyl]-2-oxo-(3H)—benzimidazole-5-carboxylate (84 mg, 70%) as awhite solid. ES-MS (M+H)+=358.1.
Reaction SMILES: [Cl:1][CH:2]1[CH2:6][O:5][CH:4]([CH2:7][NH2:8])[O:3]1.[N+:9]([C:12]1[CH:23]=[CH:22][C:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=2)=[CH:20][C:13]=1[O:14][CH:15]([CH3:19])[C:16](Cl)=[O:17])([O-:11])=[O:10]>C(Cl)Cl>[Cl:1][CH:2]1[CH2:6][O:5][CH:4]([CH2:7][NH:8][C:16](=[O:17])[CH:15]([O:14][C:13]2[CH:20]=[C:21]([O:24][C:25]3[CH:26]=[CH:27][C:28]([C:31]([F:33])([F:34])[F:32])=[CH:29][CH:30]=3)[CH:22]=[CH:23][C:12]=2[N+:9]([O-:11])=[O:10])[CH3:19])[O:3]1
Reactant: NCC1OCC(Cl)O1
Reactant: CC(Oc1cc(Oc2ccc(C(F)(F)F)cc2)ccc1[N+](=O)[O-])C(=O)Cl
Solvent: ClCCl
Product: CC(Oc1cc(Oc2ccc(C(F)(F)F)cc2)ccc1[N+](=O)[O-])C(=O)NCC1OCC(Cl)O1
Temperature: -15 °C

Procedure:
N-(4-Chloro-1,3-dioxolan-2-ylmethyl)amine (0.015 mole) triethylamine (5 ml) and methylene chloride (50 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and addition funnel. The reaction mixture is cooled to about -15° C. and a solution of 2-[2-nitro-5-(4-trifluoromethylphenoxy)phenoxy]propionyl chloride (0.01 mole) in methylene chloride (50 ml) is added dropwise with stirring. After the addition is completed the reaction mixture is allowed to warm to room temperature with continued stirring. After this time the mixture is transferred to a separatory funnel and is washed with water and dilute aqueous sodium bicarbonate. The washed solution is then dried, filtered and stripped of solvent leaving a residue. The residue is then recrystallized from a toluene/hexane mixture to yield the desired product N-(4-chloro-1,3-dioxolan-2-ylmethyl)-2-[2-nitro-5-(4-trifluoromethylphenoxy)phenoxy]propionamide.
Reaction SMILES: [NH2:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].CO[CH:15]1[CH2:19][CH2:18][CH:17](OC)O1.Cl>O1CCOCC1>[N:1]1([N:2]2[C:3](=[O:12])[C:4]3[C:5](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]2=[O:7])[CH:15]=[CH:19][CH:18]=[CH:17]1
Reactant: NN1C(=O)c2ccccc2C1=O
Reactant: COC1CCC(OC)O1
Agent: Cl
Solvent: C1COCCO1
Product: O=C1c2ccccc2C(=O)N1n1cccc1
Temperature: 25 °C
Yield: 53205 %

Procedure:
To a stirred solution of 1,4-dioxane (50 mL) and N-aminophthalimide (5.0 g, 0.031 mmol) at rt was slowly added 2,5-dimethoxy tetrahydrofuran (15 g, 0.061 mmol). The resulting light yellow solution was heated to 100° C. for ˜16 h whereupon 5N HCl was carefully added at 100° C. giving a brown mixture. The mixture was allowed to cool room temperature, the solid thus separated was filtered and was rinsed with 1:3 of 1,4-dioxane in water. Drying afforded 3.5 g (54%) of the title compound as a white solid. LCMS (Condition D) m/z: 213+ve.
Reaction SMILES: FC1C=C(C2CC(=O)C3C(=CC=C(O)C=3)O2)C=CC=1.[OH:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][C:22]=1[C:28](=[O:30])[CH3:29].[Cl:31][C:32]1[CH:39]=[C:38]([Cl:40])[CH:37]=[CH:36][C:33]=1[CH:34]=O>>[Cl:31][C:32]1[CH:39]=[C:38]([Cl:40])[CH:37]=[CH:36][C:33]=1[CH:34]1[CH2:29][C:28](=[O:30])[C:22]2[C:21](=[CH:26][CH:25]=[C:24]([OH:27])[CH:23]=2)[O:20]1
Reactant: CC(=O)c1cc(O)ccc1O
Reactant: O=Cc1ccc(Cl)cc1Cl
Agent: O=C1CC(c2cccc(F)c2)Oc2ccc(O)cc21
Product: O=C1CC(c2ccc(Cl)cc2Cl)Oc2ccc(O)cc21

Procedure:
2-(2,4-Dichlorophenyl)-6-hydroxychroman-4-one was prepared as described for 2-(3-fluorophenyl)-6-hydroxychroman-4-one in Example 9(a) starting from 1.0 g of 2′,5′-dihydroxyacetophenone and 1.4 g of 2,4-dichlorobenzaldehyde. The product was recrystallised from acetic acid. 1H NMR (400 MHz, d6-DMSO) δ: 9.49 (s, 1H), 7.78 (d, 1H, J 8.5 Hz), 7.71(d, 1H, J 2.0 Hz), 7.57 (dd, 1H, J 8.5, 2.0 Hz), 7.14 (d, 1H, J 3.0 Hz), 7.06 (dd, 1H, J 8.8, 3.0 Hz), 6.97 (d, 1H, J 8.8 Hz), 5.77 (dd, 1H, J 13.5, 2.7 Hz), 3.18 (dd, 1H, J −16.9, 13.5 Hz), 2.78 (dd, 1H, J −16.9, 2.7 Hz).
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][O:7]1)[CH:2]=[CH2:3].[CH2:11]([O:13][SiH:14]([O:18][CH2:19][CH3:20])[O:15][CH2:16][CH3:17])[CH3:12]>>[CH2:5]([O:4][CH2:1][CH2:2][CH2:3][Si:14]([O:18][CH2:19][CH3:20])([O:15][CH2:16][CH3:17])[O:13][CH2:11][CH3:12])[CH:6]1[O:7][CH2:8][CH2:9][CH2:10]1
Reactant: C=CCOCC1CCCO1
Reactant: CCO[SiH](OCC)OCC
Product: CCO[Si](CCCOCC1CCCO1)(OCC)OCC
Temperature: 80 °C
Yield: 98.7 %

Procedure:
A 1 liter 3 neck flask equipped with a magnetic stirrer, pot thermometer, dry-ice condenser and an addition funnel was charged with 106.6 g of allyloxymethyltetrahydrofuran. The flask was heated to 80° C., and 8.7 g of triethoxysilane was added, followed by 0.5 g of Karstedt's catalyst with a Pt concentration of 2%. An exotherm was observed and an additional 120.6 g of triethoxysilane was added while maintaining the temperature between 80°-100° C. After the addition was complete, an additional 0.25 g of Karstedt's catalyst was added, and the mixture was heated to 90° C. for 1 hour. The mixture was distilled through a short Vigreux column. Tetrahydrofurfuryloxypropyltriethoxysilane (98.7% purity by GC) was obtained in 60% yield, having a boiling point of 130° C./3 mm and a density at 25° C. of 0.9899.
Reaction SMILES: C([O:3][C:4]([C:6]1[O:7][C:8]2[C:14]([N:15]3[CH2:20][CH2:19][N:18]([CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:17][CH2:16]3)=[CH:13][CH:12]=[CH:11][C:9]=2[CH:10]=1)=O)C.[NH:28]1[CH2:31][CH2:30][CH2:29]1>>[N:28]1([C:4]([C:6]2[O:7][C:8]3[C:14]([N:15]4[CH2:20][CH2:19][N:18]([CH2:21][C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=5)[CH2:17][CH2:16]4)=[CH:13][CH:12]=[CH:11][C:9]=3[CH:10]=2)=[O:3])[CH2:31][CH2:30][CH2:29]1
Reactant: C1CNC1
Reactant: CCOC(=O)c1cc2cccc(N3CCN(Cc4ccccc4)CC3)c2o1
Product: O=C(c1cc2cccc(N3CCN(Cc4ccccc4)CC3)c2o1)N1CCC1

Procedure:
The compound was prepared according to the procedure disclosed in Example 39c starting from ethyl 7-(4-benzylpiperazin-1-yl)benzofuran-2-carboxylate (1.0 g, 2.74 mmol) (Example 39b) and azetidine (0.20 mL, 3.02 mmol). Yield: 0.52 g (51%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[F:8].I[C:11]1[CH:12]=[CH:13][C:14]2[N:15]([CH:17]=[C:18]([NH:20][C:21]([CH:23]3[CH2:25][CH:24]3[CH3:26])=[O:22])[N:19]=2)[N:16]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.[Cl-].[Na+].O>[NH2:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[F:8])[O:9][C:11]1[CH:12]=[CH:13][C:14]2[N:15]([CH:17]=[C:18]([NH:20][C:21]([CH:23]3[CH2:25][CH:24]3[CH3:26])=[O:22])[N:19]=2)[N:16]=1
Reactant: Nc1cc(O)ccc1F
Reactant: CC1CC1C(=O)Nc1cn2nc(I)ccc2n1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1CC1C(=O)Nc1cn2nc(Oc3ccc(F)c(N)c3)ccc2n1
Temperature: 140 °C
Reaction time: 16 h
Yield: 84.3 %

Procedure:
To a solution of 3-amino-4-fluorophenol (0.42 g, 3.29 mmol) in N,N-dimethylformamide (9.0 mL) were added N-(6-iodoimidazo[1,2-b]pyridazin-2-yl)-2-methylcyclopropanecarboxamide (0.75 g, 2.19 mmol) and potassium carbonate (0.61 g, 4.38 mmol), and the mixture was stirred at 140° C. for 16 hr. Saturated brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate/tetrahydrofuran, washed with saturated brine, dried over anhydrous sodium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate alone), and the obtained residue was washed with hexane/ethyl acetate and filtrated to give the title compound (0.63 g, 88%) as a brown powder.
Reaction SMILES: FC(F)(F)C([N:5]([CH2:15][C:16]1([C:22]([O:24]C)=[O:23])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)[C@@H:6]1[CH2:8][C@H:7]1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=O.[OH-].[Na+]>CO>[C:9]1([C@@H:7]2[CH2:8][C@H:6]2[NH:5][CH2:15][C:16]2([C:22]([OH:24])=[O:23])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: COC(=O)C1(CN(C(=O)C(F)(F)F)[C@@H]2C[C@H]2c2ccccc2)CCNCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C1(CN[C@@H]2C[C@H]2c2ccccc2)CCNCC1
Temperature: 25 °C
Reaction time: 30 h
Yield: 65 %

Procedure:
To a solution of methyl 4-((2,2,2-trifluoro-N-(trans-2-phenylcyclopropyl)acetamido)methyl)piperidine-4-carboxylate (110 mg, 0.286 mmol) in methanol (2 mL) was added sodium hydroxide (6M, 0.5 mL, 3.00 mmol), and the mixture was stirred at room temperature for 30 h. The mixture was purified using reverse-phase HPLC. The fractions containing the product were combined, treated with 1N HCl and concentrated. The residue was dried under vacuum to give 51 mg of product (HCl salt) as white solid. MS: (M+H)+=275.2. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.23-1.33 (m, 1H), 1.60 (br. s., 1H), 1.87 (br. s., 2H), 2.10-2.21 (m, 2H), 2.54-2.64 (m, 1H), 3.04 (br. s., 3H), 3.17-3.30 (m, 2H), 3.40-3.55 (m, 2H), 7.10-7.40 (m, 5H).
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[C:16](=[O:17])[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[N:9]([C:18]3[CH:19]=[C:20]([C:24]4[CH:29]=[CH:28][C:27]([C:30]([OH:32])=[O:31])=[CH:26][CH:25]=4)[CH:21]=[CH:22][CH:23]=3)[CH:8]=2)=[O:6])[CH2:3][CH2:2]1.Br[C:34]1C=CC(C(OCC)=O)=C[CH:35]=1.C([O-])([O-])=O.[Na+].[Na+]>C(O)CC.CN(C=O)C.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([NH:4][C:5]([C:7]2[C:16](=[O:17])[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[N:9]([C:18]3[CH:19]=[C:20]([C:24]4[CH:25]=[CH:26][C:27]([C:30]([O:32][CH2:34][CH3:35])=[O:31])=[CH:28][CH:29]=4)[CH:21]=[CH:22][CH:23]=3)[CH:8]=2)=[O:6])[CH2:2][CH2:3]1
Reactant: O=C(O)c1ccc(-c2cccc(-n3cc(C(=O)NC4CC4)c(=O)c4cccnc43)c2)cc1
Reactant: CCOC(=O)c1ccc(Br)cc1
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: CCCO
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(-c2cccc(-n3cc(C(=O)NC4CC4)c(=O)c4cccnc43)c2)cc1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A mixture of NAPHTHYRIDINONE 3 (1 eq), ethyl 4-bromobenzoate (3 eq), Na2CO3 (3.5eq.; 2M in H2O), Pd(PPh3)4 (0.15eq.) in n-propanol-DMF (1:1, 0.1M) was stirred at 80° C. for 2 h. The mixture was cooled to rt, quenched with brine and diluted with EtOAc. The organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was triturated in ether/EtOAc and then isolated by filtration to afford the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]([SH:18])[CH2:16][SH:17])[CH:6]=[C:7]([O:13][CH3:14])[C:8]=1[O:9][CH2:10]OC.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:26]=[C:27]([N+:33]([O-:35])=[O:34])[C:28]=1[O:29][CH2:30][CH2:31][CH3:32])[CH:24]=O.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C1C=CC=CC=1>C1C=CC=CC=1.O>[CH3:19][O:20][C:21]1[CH:22]=[C:23]([C@H:24]2[S:18][C@H:15]([C:5]3[CH:6]=[C:7]([O:13][CH3:14])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH2:16][S:17]2)[CH:26]=[C:27]([N+:33]([O-:35])=[O:34])[C:28]=1[O:29][CH2:30][CH2:31][CH3:32]
Reactant: COCOc1c(OC)cc(C(S)CS)cc1OC
Reactant: CCCOc1c(OC)cc(C=O)cc1[N+](=O)[O-]
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: c1ccccc1
Solvent: O
Product: CCCOc1c(OC)cc([C@@H]2SC[C@@H](c3cc(OC)c(OC)c(OC)c3)S2)cc1[N+](=O)[O-]

Procedure:
1-(3,4,5-trimethoxyphenyl)-1,2-ethanedithiol (39) (FIG. 19) (0.689 g,2.65 mmole), 3-methoxy-5-nitro-4-propoxybenzaldehyde (40) (0.633 g, 2.65 mmole) and 0.266 g of pyridinium para-toluenesulfonate was added to 50 ml dry benzene and refluxed with Dean-Stark removal of the benzene- water azeotrope for 24 hours. The benzene was removed in vacuo, and the remaining oil redissolved in dichloromethane and was purified by flash column chromatography with 9:1 hex/ethyl acetate as eluent. The product mixture contains a 1/1 cis/trans ratio (0.600 g, 47%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:26]=[CH:27][CH:28]=1)[O:16][CH2:17][C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=1.[N-:29]=[N+:30]=[N-:31].[Na+].Cl.[NH+]1C=CC=CC=1>CN(C=O)C>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:26]=[CH:27][CH:28]=1)[O:16][CH2:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]2[NH:31][N:30]=[N:29][N:23]=2)=[CH:24][CH:25]=1
Reactant: N#Cc1ccc(COc2cccc(OCc3ccc4ccccc4n3)c2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Agent: c1cc[nH+]cc1
Solvent: CN(C)C=O
Product: c1cc(OCc2ccc(-c3nnn[nH]3)cc2)cc(OCc2ccc3ccccc3n2)c1
Temperature: 25 °C

Procedure:
A slurry of 2.0 g (5.48 mol) of 4-(3-(2-quinolinylmethyloxy)phenoxymethyl)benzonitrile, 1.78 g (27.4 mmol) of sodium azide, and 3.16 g (27.4 mmol) of pyridinium hydrochloride in 12 ml of dry DMF is stirred under nitrogen at 100° C. for 20 hrs. The reaction mixture is then cooled to room temperature and concentrated. The residue is taken up on 100 ml of 1N aqueous NaOH and the solution extracted with ether. The aqueous layer is acidified to pH 6 with 1N aqueous HCl, and the precipitate collected, triturated with water, filtered and lyophilized to obtain 5-(4-(3-(2quinolinylmethyloxy)phenoxy-methyl)phenyl)tetrazole. (M.P. 91° C. dec.)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]([N+:11]([O-:13])=[O:12])=[CH:9][N:10]=1)[C:5]([OH:7])=[O:6].[CH2:14](C(CC)(CC)C([O-])([O-])[O-])[CH3:15].Cl>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]([N+:11]([O-:13])=[O:12])=[CH:9][N:10]=1)[C:5]([O:7][CH2:14][CH3:15])=[O:6]
Reactant: O=C(O)c1cc(Cl)ncc1[N+](=O)[O-]
Reactant: CCC(CC)(CC)C([O-])([O-])[O-]
Agent: Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc(Cl)ncc1[N+](=O)[O-]

Procedure:
A mixture of 2-chloro-5-nitroisonicotinic acid (Intermediate 208) and 16 ml triethylorthoacetate in 100 ml toluene was heated at reflux for 2 h. The mixture as stirred with 1N HCl for 30 min before being partitioned between EtOAc and water. The EtOAc was separated, washed with water and brine, dried (MgSO4) and concentrated. Chromatographed on silica gel (100% hexanes with gradient elution to 100% CH2Cl2 to give product as an oil. MS (ES) (MH+): 231 for C8H7ClN2O4; NMR (d6-DMSO): 1.3 (t, 3H), 4.4 (m, 2H), 8.1 (s, 1H), 9.2 (s, 1H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([SH:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2].[C:17]([C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22]Br)#[N:18].[OH-].[Na+].C(O)C>O>[C:12]([C:7]1[CH:8]=[C:9]([S:11][CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[C:19]([C:17]#[N:18])[CH:20]=2)[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]=1[OH:16])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Reactant: N#Cc1cccc(CBr)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C)c1cc(SCc2cccc(C#N)c2)cc(C(C)(C)C)c1O

Procedure:
A solution containing 2.009 (8.39 mmole) of 2,6-di-t-butyl-4-mercaptophenol, 1.65 g (8.39 mmole) of m-cyanobenzyl bromide, 5 ml of 1.68N sodium hydroxide and 75 ml of ethanol was heated at reflux for 48 hours The reaction mixture was poured into water and was then extracted with diethyl ether. The ether extract was washed with water, dried with magnesium sulfate and evaporated to give the crude product This material was purified by silica gel chromatography eluting with 1% ethyl acetate in hexane, followed by four recrystallizations from hexane to give 0.75 g of 2,6-di-t-butyl-4-[(3-cyanophenyl)methylthio]phenol as white needles, m.p. 61°-63° C. Analysis: Calculated for C22H27NOS: %C, 74 7%; %H, 7.7; %N, 4.0; Found: %C. 74.5; %H, 8.0; %N, 3.8.
Reaction SMILES: N.[Na].[CH3:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([O:15][CH3:16])[CH:8]=1)=[O:6].[Cl-].[NH4+]>C(Cl)Cl>[CH3:16][O:15][C:9]1[CH:8]=[C:7]([CH:12]=[CH:11][C:10]=1[O:13][CH3:14])[C:5]([CH:4]([CH:4]([C:5](=[O:6])[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([O:15][CH3:16])[CH:8]=1)[CH3:3])[CH3:3])=[O:6]
Reactant: CCC(=O)c1ccc(OC)c(OC)c1
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: COc1ccc(C(=O)C(C)C(C)C(=O)c2ccc(OC)c(OC)c2)cc1OC
Temperature: -40 °C
Reaction time: 1 h
Yield: 189.3 %

Procedure:
To 100 ml of liquid NH3 and 100 mg FeCl3, 1 g of sodium was added and stirred for 1 hr at -40° C. To that 7.7 g of 3,4-dimethoxypropiophenone was added and stirred for 1/2 hr. Eleven g of α-bromo-3,4-dimethoxypropiophenone was then added and stirring continued for 11/2 hrs. At this point, 11 g of ammonium chloride and 200 ml of methylene chloride was added and the temperature allowed to rise to room temperature. Filtration, evaporation and crystalization of the residue from methanol gave 14.5 g of racemic-2,3-bis(3,4-dimethoxybenzoyl)butane as a white solid. NMR (CDCl3) δ1.32(6H, d, J=7Hz), 3.92 and 3.94 (6H each, s, OCH3, 6.8-7.8 (6H, ArH); m.p. 141°-142° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]4[CH:18]=[N:19][N:20]([CH2:22][C:23]5[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=5)[CH:21]=4)=[CH:15][NH:14][C:11]3=[N:12][CH:13]=2)[CH:5]=[CH:4][C:3]=1[N:30]1[CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32][CH2:31]1>Cl.CCOCC.CO>[F:29][C:25]1[CH:24]=[C:23]([CH:28]=[CH:27][CH:26]=1)[CH2:22][N:20]1[CH:21]=[C:17]([C:16]2[C:10]3[C:11](=[N:12][CH:13]=[C:8]([C:6]4[CH:5]=[CH:4][C:3]([N:30]5[CH2:31][CH2:32][NH:33][CH2:34][CH2:35]5)=[C:2]([CH:7]=4)[NH2:1])[CH:9]=3)[NH:14][CH:15]=2)[CH:18]=[N:19]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3cnc4[nH]cc(-c5cnn(Cc6cccc(F)c6)c5)c4c3)cc2N)CC1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: Nc1cc(-c2cnc3[nH]cc(-c4cnn(Cc5cccc(F)c5)c4)c3c2)ccc1N1CCNCC1
Yield: 7.1 %

Procedure:
Using similar reaction conditions as described in step-ii of example-7, tert-butyl 4-(2-amino-4-(3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazine-1-carboxylate (90 mg, 0.15 mmol) was deprotected in HCl in ether/MeOH (0.2/5 ml). This afforded 5 mg (6.3% yield) of the titled compound. 1H NMR (CD3OD, 400 MHz): δ 9.00 (s, 1H), 8.70 (s, 1H), 8.40 (s, 1H), 8.06 (s, 1H), 7.98 (s, 1H), 7.90-7.80 (m, 2H), 7.63-7.61 (d, 1H), 7.45-7.35 (q, 1H), 7.20-7.00 (m, 3H), 5.45 (s, 2H), 3.12 (s, 2H), 2.76 (s, 4H). MS: m/z=467.9 (M+1), HPLC: 95.53% in method A.
Reaction SMILES: [NH2:1][C:2]([N:4]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][C:24]=1[C:33]([F:36])([F:35])[F:34])[CH2:5][CH2:6][C:7]1[CH:21]=[CH:20][C:10]([O:11][C:12]([CH3:19])([CH3:18])[C:13]([O:15]CC)=[O:14])=[CH:9][CH:8]=1)=[S:3].Br[CH2:38][C:39](=O)[C:40]([CH3:43])([CH3:42])[CH3:41]>>[F:35][C:33]([F:34])([F:36])[C:24]1[CH:25]=[C:26]([C:29]([F:32])([F:31])[F:30])[CH:27]=[CH:28][C:23]=1[CH2:22][N:4]([C:2]1[S:3][CH:38]=[C:39]([C:40]([CH3:43])([CH3:42])[CH3:41])[N:1]=1)[CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:11][C:12]([CH3:19])([CH3:18])[C:13]([OH:15])=[O:14])=[CH:20][CH:21]=1
Reactant: CC(C)(C)C(=O)CBr
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)C(N)=S)cc1
Product: CC(C)(Oc1ccc(CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)c2nc(C(C)(C)C)cs2)cc1)C(=O)O

Procedure:
Similarly prepared from ethyl 2-[4-(2-{(aminocarbonothioyl)[2,4-bis(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoate and 1-bromopinacolone.
Reaction SMILES: [CH3:1][SH:2].O[CH2:4][C:5]1[C:6](=[O:12])[NH:7][C:8](=[O:11])[NH:9][CH:10]=1>FC(F)(F)C(O)=O>[CH3:1][S:2][CH2:4][C:5]1[C:6](=[O:12])[NH:7][C:8](=[O:11])[NH:9][CH:10]=1
Reactant: O=c1[nH]cc(CO)c(=O)[nH]1
Reactant: CS
Solvent: O=C(O)C(F)(F)F
Product: CSCc1c[nH]c(=O)[nH]c1=O
Reaction time: 2 h

Procedure:
Methylmercaptan is introduced into a solution of 14 g of 5-hydroxymethyluracil in 80 ml of trifluoroacetic acid over the course of one hour until saturation is reached, the temperature being kept at 25° C. The solution is then left to stand for 2 hours, the solvent is evaporated under reduced pressure and the residue is crystallised from glacial acetic acid. 5-Methylthiomethyluracil is obtained as colourless crystals of melting point 239°-241° C.