Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[S@:12](=[O:13])[CH2:11][CH2:10][CH2:9][CH:8]=2)[CH:2]=1.[BH4-].[Na+].O.C(OCC)(=O)C>C(O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C@H:7]2[CH2:8][CH2:9][CH2:10][CH2:11][S@:12]2=[O:13])[CH:2]=1
Reactant: O=[S@@]1CCCC=C1c1cccnc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: O=[S@@]1CCCC[C@@H]1c1cccnc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 35.4 %

Procedure:
A stirred solution of (R)-6-(3-pyridyl)-3,4-dihydro-2H-thiopyran 1-oxide (22.43 g;88.2%ee) in ethanol (227 ml) is treated, portionwise, with sodium borohydride powder (3.52 g) under nitrogen at room temperature, and the mixture is stirred for 2.5 hours. It is then treated with a further quantity of sodium borohydride (0.43 g), and the mixture is stirred for a further period of 15 minutes. The mixture is treated with water (454 ml) and extracted with dichloromethane (2×340 ml). The combined extracts are washed with water 340 ml), dried over magnesium sulphate and the solvent is removed by evaporation under reduced pressure, to give an oily paste (18.1 g). This paste is treated with ethyl acetate (72 ml) and the mixture is heated at reflux, with stirring. The solution is allowed to cool to room temperature, and stirred for 3 hours. The resulting suspension is cooled to 0° C. for 1 hour, and then filtered. The pale yellow solid is washed with a little cold ethyl acetate and sucked dry using vacuum filtration, to give (1R,2R)-2-(3-pyridyl)tetrahydro-2H-thiopyran 1 -oxide (8.03 g;99.7%ee), m.p. 124.5°-126.50° C. [Elemental analysis:- C,61.2;H,6.67; N,7.1 ;S,16.7%. Calculated:- C,61.51 ;H,6.71 ;N,7.17; S,16.42%. NMR (CDCl3):- 1.6(m,1H), 8(m,2H),2.0(m,1H),2.4(m,1H),2.7(m,2H),3.2(m,1H), 3.5(dd,1H),7.3(m,1H),7.7(dt,1H),8.6(m,2H)].
Reaction SMILES: C[S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[N:13]=[C:12]2[C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH3:26][Si:27]([CH3:55])([CH3:54])[CH2:28][CH2:29][S:30]([C:33]1[CH:38]=[CH:37][C:36]([N:39]2[CH:43]=[C:42]([C:44]([F:47])([F:46])[F:45])[N:41]=[C:40]2[C:48]2[CH:49]=[N:50][CH:51]=[CH:52][CH:53]=2)=[CH:35][CH:34]=1)(=[O:32])=[O:31].[N+:56](CCCC)(CCCC)(CCCC)CCCC.[F-].C([O-])(=O)C.[Na+].NOS(O)(=O)=O>C1COCC1.O.C(OCC)(=O)C>[CH3:26][Si:27]([CH3:55])([CH3:54])[CH2:28][CH2:29][S:30]([C:33]1[CH:34]=[CH:35][C:36]([N:39]2[CH:43]=[C:42]([C:44]([F:45])([F:46])[F:47])[N:41]=[C:40]2[C:48]2[CH:49]=[N:50][CH:51]=[CH:52][CH:53]=2)=[CH:37][CH:38]=1)(=[O:31])=[O:32].[N:22]1[CH:23]=[CH:24][CH:25]=[C:20]([C:12]2[N:11]([C:8]3[CH:9]=[CH:10][C:5]([S:2]([NH2:56])(=[O:4])=[O:3])=[CH:6][CH:7]=3)[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[N:13]=2)[CH:21]=1
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: CS(=O)(=O)c1ccc(-n2cc(C(F)(F)F)nc2-c2cccnc2)cc1
Agent: CC(=O)[O-]
Agent: C[Si](C)(C)CCS(=O)(=O)c1ccc(-n2cc(C(F)(F)F)nc2-c2cccnc2)cc1
Agent: NOS(=O)(=O)O
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: NS(=O)(=O)c1ccc(-n2cc(C(F)(F)F)nc2-c2cccnc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
3-[1-[4-[[2-(Trimethylsilyl)ethyl]sulfonyl]phenyl]-4-(trifluoromethyl)-1H-imidazol-2-yl]pyridine was prepared with the product of Example 28 with a method similar to that described in Example 45, Step 1. To a solution of 3-[1-[4-[[2-(trimethylsilyl)ethyl]sulfonyl]phenyl]-4-(trifluoromethyl)-1H-imidazol-2-yl]pyridine (0.200 g, 0.46 mmol) in 1.0 mL of dry THF was added n-Bu4NF (1.38 mL of 1.0 M THF solution, 1.38 mmol). The mixture was heated to reflux for 1 hour and cooled to room temperature. A solution of sodium acetate (0.17 g, 2.1 mmol) in 3 mL of water and hydroxylamine-O-sulfonic acid (0.26 g, 2.3 mmol) were added sequentially and the mixture was stirred for 1 hour. Water (7 mL) and ethyl acetate (7 mL) were added. The organic phase was separated and washed with saturated NaHCO3 solution, water, brine, dried over MgSO4 and filtered. The filtrate was concentrated and the residue was purified by chromatography on silica gel (ethyl acetate/acetone, 95:5) to give 0.147 g of 4-[2-(pyridin-3-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]benzenesulfonamide as a colorless solid (87%): mp(DSC) 213–215° C. Anal. Calc'd. for C15H11F3N4O2S: C, 48.91; H. 3.01; N, 15.21; S, 8.71. Found: C, 48.58; H, 2.99; N, 14.87; S. 8.85.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)([NH2:12])[CH:9]([NH2:11])[CH3:10])=[CH:4][CH:3]=1.CO[C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]#N)[CH:25]=1)=[NH:23].C(Cl)(Cl)Cl>CO>[C:22]([C:24]1[CH:25]=[C:26]([C:30]2[NH:11][CH:9]([CH3:10])[C:8]([C:13]3[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=3)([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[N:12]=2)[CH:27]=[CH:28][CH:29]=1)#[N:23]
Reactant: CC(N)C(N)(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: COC(=N)c1cccc(C#N)c1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC1NC(c2cccc(C#N)c2)=NC1(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 14 %

Procedure:
1,1-bis(4-fluorophenyl)-1,2-propanediamine (50 mg) was dissolved in methanol (1 mL), and to the solution was added 3-cyanobenzeneimidic acid methyl ester (75 mg). The mixture was stirred at room temperature for 24 hrs. After chloroform (5 ml) was added to the reaction mixture, insolubles were removed by filtration. After concentrating the filtrate in vacuo, the obtained residue was purified by silica gel column chromatography (C-300; hexane: ethyl acetate=3:1→1:1) to give the objective compound (10 mg).
Reaction SMILES: O1CCCC1.[CH2:6]([Sn:10]([CH2:17][CH2:18][CH2:19][CH3:20])([CH2:13][CH2:14][CH2:15][CH3:16])[C:11]#[CH:12])[CH2:7][CH2:8][CH3:9].[N+:21]([CH2:24][CH2:25][C:26]1[CH:39]=[CH:38][C:29]([CH2:30][O:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=2)=[CH:28][CH:27]=1)([O-:23])=O.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O>CN(C)C1C=CN=CC=1.O.C(OCC)(=O)C>[CH2:17]([Sn:10]([CH2:13][CH2:14][CH2:15][CH3:16])([CH2:6][CH2:7][CH2:8][CH3:9])[C:11]1[O:23][N:21]=[C:24]([CH2:25][C:26]2[CH:39]=[CH:38][C:29]([CH2:30][O:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=3)=[CH:28][CH:27]=2)[CH:12]=1)[CH2:18][CH2:19][CH3:20]
Reactant: C#C[Sn](CCCC)(CCCC)CCCC
Reactant: O=[N+]([O-])CCc1ccc(COc2ccccn2)cc1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CCCC[Sn](CCCC)(CCCC)c1cc(Cc2ccc(COc3ccccn3)cc2)no1
Temperature: 25 °C
Reaction time: 15 h
Yield: 100.2 %

Procedure:
To a tetrahydrofuran solution (90 mL) of tri-n-butylethynyltin (3 g), 2-(4-(2-nitro-ethyl)-benzyloxy)-pyridine (4.9 g) described in Manufacturing Example 1-1-4, and 4-dimethylaminopyridine (116 mg) was added a tetrahydrofuran solution (30 mL) of di-tert-butyl dicarbonate (7.3 g), which was stirred for 15 hours at room temperature. Ethyl acetate and water were added to this mixture. The organic layer was separated, washed with water and saturated saline, dried over anhydrous magnesium sulfate, and filtered. The filtrate was adsorbed to silica gel, and then purified by silica gel column chromatography (heptane:ethyl acetate=4:1) to obtain the title compound (5.3 g).
Reaction SMILES: Cl[C:2]1[C:3](=[O:16])[N:4]([CH3:15])[S:5](=[O:14])(=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[F:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1>>[F:17][C:18]1[CH:24]=[CH:23][C:21]([NH:22][C:2]2[C:3](=[O:16])[N:4]([CH3:15])[S:5](=[O:14])(=[O:13])[C:6]=2[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:20][CH:19]=1
Reactant: Nc1ccc(F)cc1
Reactant: CN1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Product: CN1C(=O)C(Nc2ccc(F)cc2)=C(c2ccccc2)S1(=O)=O

Procedure:
The title compound was prepared from 4-chloro-2-methyl-5-phenylisothiazol-3(2H)-one 1,1-dioxide and 4-fluoroaniline in a similar manner as described for e.g. Examples 9 and 13. 1H NMR (400 MHz, CDCl3): δ 3.27 (s, 3H), 6.66-6.71 (m, 4H), 7.12-7.26 (m, 5H); 13C NMR (100 MHz, CDCl3): δ 24.2, 111.1, 115.1, 115.3, 123.8, 123.9, 124.5, 128.2, 129.0, 129.2, 129.3, 131.1, 131.2, 131.8, 131.9, 158.6, 159.0, 161.1; 13C NMR (100 MHz, CDCl3): δ 24.2, 111.1, 123.8, 123.9, 124.5, 128.2, 129.2, 129.3, 131.2, 131.8, 131.9, 158.6, 159.0, 161.1; Mass Spectrum: M−H+ 331.
Reaction SMILES: O=[CH:2][C:3](=[CH2:5])[CH3:4].[C:6](=[O:11])([O:8][CH2:9][CH3:10])[NH2:7]>COC1C=CC(O)=CC=1.C(Cl)(Cl)Cl>[CH3:4][CH:3]([CH2:2][NH:7][C:6]([O:8][CH2:9][CH3:10])=[O:11])[CH:5]([NH:7][C:6]([O:8][CH2:9][CH3:10])=[O:11])[NH:7][C:6]([O:8][CH2:9][CH3:10])=[O:11]
Reactant: C=C(C)C=O
Reactant: CCOC(N)=O
Agent: COc1ccc(O)cc1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)NCC(C)C(NC(=O)OCC)NC(=O)OCC
Reaction time: 1 h
Yield: 60.8 %

Procedure:
35 g of methacrolein are added dropwise at 60°-65° C. to a mixture of 133.5 g of ethyl carbamate, 30 g of acid ion exchanger resin (Duolite C 265), 0.4 g of hydroquinone monomethyl ether and 400 ml of chloroform in the course of 40 minutes. The mixture is left at that temperature for 1 hour, the ion exchanger is filtered off, the chloroform is distilled off, and the residue is crystallized from ethyl acetate/petroleum ether. This gives 97 g of 2-methyl-1,1,3-tri(ethoxycarbonylamino)propane (60.8% yield, based on starting methacrolein) having a melting point of 138°-140° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:12])=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH3:13][C:14]([CH3:16])=O.C([BH3-])#N.[Na+]>CO.[Cl-].[Zn+2].[Cl-]>[Cl:12][C:5]1[CH:4]=[CH:3][C:2]([NH:1][CH:14]([CH3:16])[CH3:13])=[CH:7][C:6]=1[C:8]([F:9])([F:10])[F:11]
Reactant: Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: CC(C)=O
Agent: [BH3-]C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: CC(C)Nc1ccc(Cl)c(C(F)(F)F)c1
Temperature: 40 °C
Reaction time: 8 h
Yield: 74.3 %

Procedure:
5-Amino-2-chlorobenzotrifluoride (0.587 g, 3.0 mmol) was dissolved in methanol (30 ml). Then acetone (1.58 ml, 30 mmol) and zinc chloride (1.635 g, 12 mmol) were added and the reaction mixture was cooled with an ice bath. After adding sodium cyanoborohydride (0.566 g, 9.0 mmol) the mixture was allowed to stir at 40° C. overnight. After cooling, the reaction mixture was poured onto ammonium chloride/ice and extracted with ethyl acetate (2 times 50 ml). The organic layer was dried over magnesium sulfate and evaporated. The residue was purified using flash chromatography (SiO2; eluent: heptane/ethyl acetate=95:5) to yield a light yellow oil (0.530 g, 74%) that was directly used for the next step; MS (EI): 222.1 ((M-CH3)+); 237.1 (M+.).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=2)(O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O.[OH-].[Na+]>C1(C)C=CC=CC=1>[CH2:1]([N:8]1[CH2:9][CH:10]=[C:11]([C:15]2[CH:16]=[CH:17][C:18]([Br:21])=[CH:19][CH:20]=2)[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC1(c2ccc(Br)cc2)CCN(Cc2ccccc2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: Brc1ccc(C2=CCN(Cc3ccccc3)CC2)cc1
Temperature: 25 °C
Yield: 95 %

Procedure:
A mixture of 121.6 g (0.35 mol) of 1-benzyl-4-(4-bromo-phenyl)-piperidin-4-ol and 121.6 g of p-toluenesulphonic acid monohydrate (0.64 mol) in 1200 ml of toluene was heated to reflux on a water separator for 4.5 hours. Subsequently, the reaction mixture was cooled to room temperature and adjusted to pH 10 with 3N sodium hydroxide solution. Thereafter, the mixture was extracted firstly with 200 ml and then with 500 ml of methylene chloride. The combined organic phases were washed twice with 100 ml of water each time, dried over magnesium sulphate and then evaporated under reduced pressure. There were obtained 109.1 g (99% of theory) of 1-benzyl-4-(4-bromo-phenyl)-1,2,3,6-tetrahydro-pyridine as a yellowish solid; MS: 328, 330 (M+H)+.
Reaction SMILES: [C:1]([N:9]1[C:14](=[O:15])[C:13]([I:16])=[CH:12][N:11]([CH2:17][CH2:18][CH:19]=O)[C:10]1=[O:21])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:22][C:23]([F:37])([F:36])[C:24]1[CH:29]=[CH:28][C:27]([C@:30]23[CH2:35][C@H:34]2[CH2:33][NH:32][CH2:31]3)=[CH:26][CH:25]=1.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCl.O>[C:1]([N:9]1[C:14](=[O:15])[C:13]([I:16])=[CH:12][N:11]([CH2:17][CH2:18][CH2:19][N:32]2[CH2:33][C@H:34]3[C@:30]([C:27]4[CH:26]=[CH:25][C:24]([C:23]([F:22])([F:37])[F:36])=[CH:29][CH:28]=4)([CH2:35]3)[CH2:31]2)[C:10]1=[O:21])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=CCCn1cc(I)c(=O)n(C(=O)c2ccccc2)c1=O
Reactant: FC(F)(F)c1ccc([C@@]23CNC[C@@H]2C3)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CC(=O)O
Product: O=C(c1ccccc1)n1c(=O)c(I)cn(CCCN2C[C@@H]3C[C@]3(c3ccc(C(F)(F)F)cc3)C2)c1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 84.9 %

Procedure:
To a solution of 3-(3-benzoyl-5-iodo-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-propionaldehyde (Prep 38, 700 mg, 1.7 mmol) in dichloromethane (20 mL), (1S,5R)-1-(4-trifluoromethyl-phenyl)-3-aza-bicyclo[3.1.0]hexane (Prep 4, 399 mg, 1.7 mmol), AcOH (158 mg, 2.5 mmol) and NaBH(AcO)3 (410 mg, 1.9 mmol) were added at 0° C. The mixture was stirred at 0° C. for further 1 hours. Water was added and the solvent was evaporated under vacuum, the residue re-dissolved in ethyl acetate and the mixture washed with a 5% solution of aqueous NaHCO3. The organic phase was dried (Na2SO4) and evaporated. The crude was purified by flash chromatography with DCM-MeOH—NH4OH (97-3-1) to give the title compound as a white solid (880 mg, 83% yield).
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([CH3:8])[CH:2]=1.O[C@H:10]([CH3:15])[C:11]([O:13][CH3:14])=[O:12]>>[C:3]1([CH3:8])[CH:4]=[CH:5][C:6]([O:7][C@@H:10]([CH3:15])[C:11]([O:13][CH3:14])=[O:12])=[CH:1][CH:2]=1
Reactant: Cc1ccc(O)cc1
Reactant: COC(=O)[C@@H](C)O
Product: COC(=O)[C@H](C)Oc1ccc(C)cc1

Procedure:
The title compound was prepared following the same protocol as described in Step 1, Example 42, using the p-cresol instead of the m-cresol and the (R)-methyl 2-hydroxypropanoate instead of the (S)-methyl 2-hydroxypropanoate.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:34]=[CH:33][C:11]([NH:12]/[C:13](=[C:20]3\[C:21](=[O:32])[NH:22][C:23]4[C:28]\3=[CH:27][CH:26]=[C:25]([C:29]([OH:31])=[O:30])[CH:24]=4)/[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:35](O)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[N:1]1([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([NH:12]/[C:13](=[C:20]3\[C:21](=[O:32])[NH:22][C:23]4[C:28]\3=[CH:27][CH:26]=[C:25]([C:29]([O:31][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[O:30])[CH:24]=4)/[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:33][CH:34]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1Nc2cc(C(=O)O)ccc2/C1=C(/Nc1ccc(CN2CCCCC2)cc1)c1ccccc1
Reactant: OCc1ccccc1
Product: O=C1Nc2cc(C(=O)OCc3ccccc3)ccc2/C1=C(/Nc1ccc(CN2CCCCC2)cc1)c1ccccc1

Procedure:
Prepared from 3-Z-[1-(4-(piperidin-1-yl-methyl)-anilino)-1-phenyl-methylene]-6-carboxy-2-indolinone and benzyl alcohol Rf value: 0.6 (aluminium oxide, methylene chloride/methanol=30:1) C35H33N3O3
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][C:8]1[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=O.[NH2:18][C:19]1[CH:31]=[C:30]([C:32]2[CH:40]=[CH:39][C:35]3[O:36][CH2:37][O:38][C:34]=3[CH:33]=2)[CH:29]=[CH:28][C:20]=1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].C(=O)([O-])O.[Na+]>C(N(CC)CC)C.C(Cl)Cl.CN(C)C=O>[O:36]1[C:35]2[CH:39]=[CH:40][C:32]([C:30]3[CH:29]=[CH:28][C:20]([C:21]([O:23][C:24]([CH3:26])([CH3:27])[CH3:25])=[O:22])=[C:19]([NH:18][C:10](=[O:12])[C:9]4[CH:13]=[CH:14][CH:15]=[C:16]([CH3:17])[C:8]=4[CH3:7])[CH:31]=3)=[CH:33][C:34]=2[O:38][CH2:37]1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccc3c(c2)OCO3)cc1N
Reactant: Cc1cccc(C(=O)O)c1C
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cccc(C(=O)Nc2cc(-c3ccc4c(c3)OCO4)ccc2C(=O)OC(C)(C)C)c1C
Reaction time: 1 h

Procedure:
1.7 mL of methylene chloride, 1.0 μL N,N-dimethylformamide and 0.025 mL of oxalyl chloride were added to 41 mg of 2,3-dimethylbenzoic acid at room temperature sequentially and stirred ad the same temperature for 1 hour. The reaction mixture was added to a mixed solution of 50 mg of tert-butyl 2-amino-4-(benzo[1,3]dioxol-5-yl)benzoate, 2.8 mL of methylene chloride and 0.36 mL of triethylamine and stirred at room temperature for 1 hour. A saturated sodium hydrogen carbonate aqueous solution was added to the reaction mixture, and the organic layer was separated, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [Flash Tube 2008 manufactured by Trikonex Company, eluent; hexane:ethyl acetate=4:1]to obtain tert-butyl 4-(benzo[1,3]dioxol-5-yl)-2-(2,3-dimethylbenzamido)benzoate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][CH:9]([OH:15])[CH:10]([N+:12]([O-])=O)[CH3:11])[CH:5]=[CH:6][CH:7]=1.O>CCO.[Fe]>[NH2:12][CH:10]([CH3:11])[CH:9]([OH:15])[CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1
Reactant: CC(C(O)Cc1cccc(Br)c1)[N+](=O)[O-]
Agent: [Fe]
Solvent: O
Solvent: CCO
Product: CC(N)C(O)Cc1cccc(Br)c1
Temperature: 25 °C
Yield: 68.3 %

Procedure:
To a solution of 1-(3-bromophenyl)-3-nitrobutan-2-ol (1.0 g, 3.6 mmol) in EtOH (20 mL)/H2O (1 mL), iron powder (2.0 g, 36 mmol) was added in one portion. The suspension was refluxed overnight, cooled to RT, and filtered. The filtrate was evaporated, diluted with H2O (30 mL), and extracted with EtOAc (50 mL×3). The organic layers were combined, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (Petroleum ether:EtOAc=3:1) to afford 3-amino-1-(3-bromophenyl)butan-2-ol (600 mg, 68%). MS (ES+) C10H14BrNO requires: 243, 245 found: 244, 246[M+2+H]+(1:1).
Reaction SMILES: C([Si](C)(C)[N:6]1[C:10]2=[N:11][CH:12]=[C:13]([S:15][CH2:16][CH3:17])[CH:14]=[C:9]2[CH:8]=[CH:7]1)(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>[Cl-].[Na+].O>[CH2:16]([S:15][C:13]1[CH:14]=[C:9]2[CH:8]=[CH:7][NH:6][C:10]2=[N:11][CH:12]=1)[CH3:17]
Reactant: CCSc1cnc2c(ccn2[Si](C)(C)C(C)(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CCSc1cnc2[nH]ccc2c1
Yield: 38.8 %

Procedure:
A mixture of 1-(tert-butyl-dimethyl-silanyl)-5-ethylsulfanyl-1H-pyrrolo[2,3-b]pyridine (2.5 g, 8.68 mmol) and a solution of tetrabutylammonium fluoride in tetrahydrofuran (1 M, 9.11 mL, 9.11 mmol) was stirred for 2 h at room temperature. The mixture was poured into brine (15 mL), extracted with ethyl acetate (2×50 mL), washed with a saturated aqueous ammonium chloride solution (3×20 mL), dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by flash column chromatography (Qingdao silica gel, 300 mesh, 20% ethyl acetate/hexanes) afforded 5-ethylsulfanyl-1H-pyrrolo[2,3-b]pyridine (600 mg, 48%) as a white solid which was used in the next step without purification: LC/MS m/e calcd for C9H10N2O [M+H]+ 179.26, observed 179.2.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=[CH:8][N:7]=2)[N:3]=[CH:2]1.Cl.Cl[CH2:18][CH2:19][N:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[N:20]1([CH2:19][CH2:18][N:1]2[CH:5]=[C:4]([C:6]3[CH:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=[CH:8][N:7]=3)[N:3]=[CH:2]2)[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: COC(=O)c1ccnc(-c2c[nH]cn2)c1
Reactant: ClCCN1CCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccnc(-c2cn(CCN3CCCC3)cn2)c1
Temperature: 120 °C

Procedure:
A mixture of methyl 2-(1H-imidazol-4-yl)pyridine-4-carboxylate (20 mg, 0.10 mmol), 1-(2-chloroethyl)pyrrolidine hydrogen chloride (34 mg, 0.2 mmol) and cesium carbonate (130 mg, 0.4 mmol) in 2 mL DMF was heated at 120° C. for 2 hr. The reaction mixture was purified by ISCO flash column chromatography (MeOH/DCM=0-100%). 1H NMR (400 MHz, DMSO-d6): δ 1.77 (4H, m), 2.67 (4H, m), 2.74 (2H, t, J=6.2 Hz), 3.92 (3H, s), 4.17 (2H, t, J=6.2 Hz), 7.62 (1H, dd, J=1.3 Hz and 5.0 Hz), 7.79 (1H, s), 7.87 (1H, s), 8.30 (1H, s), 8.69 (1H, d, J=4.9 Hz). [M+H] Calc'd for C16H20N4O2, 301. Found, 301.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:19]=[C:18]2[C:9]([O:10][CH2:11][CH2:12][N:13]3[C:17]2=[N:16][C:15]([C:20]2[N:24]([CH:25]([CH3:27])[CH3:26])[N:23]=[C:22]([CH3:28])[N:21]=2)=[CH:14]3)=[CH:8][C:7]=1[CH3:29])=[CH2:5])C.CC1C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[CH3:29][C:7]1[CH:8]=[C:9]2[C:18](=[CH:19][C:6]=1[C:4](=[O:3])[CH3:5])[C:17]1[N:13]([CH:14]=[C:15]([C:20]3[N:24]([CH:25]([CH3:26])[CH3:27])[N:23]=[C:22]([CH3:28])[N:21]=3)[N:16]=1)[CH2:12][CH2:11][O:10]2
Reactant: C=C(OCC)c1cc2c(cc1C)OCCn1cc(-c3nc(C)nn3C(C)C)nc1-2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Product: CC(=O)c1cc2c(cc1C)OCCn1cc(-c3nc(C)nn3C(C)C)nc1-2
Temperature: 60 °C
Reaction time: 1.25 h
Yield: 118.4 %

Procedure:
A mixture of 13-(1-ethoxyethenyl)-12-methyl-4-[3-methyl-1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca-1(14),2,4,10,12-pentaene (2.0 g) and 4-methylbenzenesulfonic acid (438 mg, 2.54 mmol) in acetone (20.0 mL) was stirred at 60° C. for 75 min. The solvent was removed to give the desired compound (2.20 g, over 100% yield) as yellow oil, which was used directly in the next step without further purification. LCMS m/z [M+H]+ 366.2
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:13][C:14]1([CH3:29])[O:19][CH2:18][CH:17]([NH:20]C2COC(C)(C)OC2)[CH2:16][O:15]1>CN(C)C1C=CN=CC=1.N1C=CC=CC=1.ClCCl.C(OCC)(=O)C>[CH3:13][C:14]1([CH3:29])[O:19][CH2:18][CH:17]([NH:20][C:8](=[O:9])[C:7]2[CH:11]=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH2:16][O:15]1
Reactant: CC1(C)OCC(NC2COC(C)(C)OC2)CO1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC1(C)OCC(NC(=O)c2ccc([N+](=O)[O-])cc2)CO1
Temperature: 60 °C
Reaction time: 5 h
Yield: 100.8 %

Procedure:
4-Dimethylaminopyridine (20 mg, 0.164 mmol) and 4-nitrobenzoyl chloride (9) (276 mg, 1.49 mmol) were added to a solution of bis-(2,2-dimethyl-1,3-dioxane-5-yl)-amine (4) (79 mg, 0.322 mmol) in pyridine (2.5 ml) and dichloromethane (5 ml). The mixture was stirred for 5 hours at 60° C. before being diluted with ethyl acetate (80 ml) and successively washed with saturated sodium bicarbonate solution (2×25 ml) and brine (25 ml). Drying over magnesium sulfate, concentration and purification by flash chromatography (hexane/ethyl acetate, 1.5:1) gave bis-N-(2,2-dimethyl-1,3-dioxane-5-yl)-p-nitrobenzamide (10) (91 mg, 72%) as colourless crystals; mp.: 211° C. (needles, from hexane/acetone); m/z (CI, NH3) 337 (M+H+-acetone, 100%).