Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][NH:16][C:17]([C:19]3[CH:28]=[CH:27][C:22]([C:23]([O:25]C)=[O:24])=[CH:21][CH:20]=3)=[O:18])[CH2:11][CH2:10]2)[N:4]=1.CO.O.[OH-].[Li+]>O1CCCC1>[F:29][C:2]([F:1])([F:30])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([N:9]2[CH2:10][CH2:11][CH:12]([CH2:15][NH:16][C:17]([C:19]3[CH:28]=[CH:27][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=3)=[O:18])[CH2:13][CH2:14]2)[N:4]=1
Reactant: COC(=O)c1ccc(C(=O)NCC2CCN(c3nccc(C(F)(F)F)n3)CC2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(C(=O)NCC2CCN(c3nccc(C(F)(F)F)n3)CC2)cc1
Temperature: 50 °C
Reaction time: 1.25 h
Yield: 81 %

Procedure:
Methyl 4-{[({1-[4-(trifluoromethyl)pyrimidin-2-yl]piperidin-4-yl}methyl)amino]carbonyl}benzoate was dissolved in 24 ml of tetrahydrofuran, 23 ml of methanol, and 23 ml of water. To this solution was added lithium hydroxide (817 mg) and the mixture was stirred at 50° C. for 1.25 h. The solvents were removed in vacuo and the residue was taken up in 1 N HCl (70 ml) and 70 ml of ethyl acetate. The mixture was sonicated until the solid residue mostly dissolved in the ethyl acetate. The two phases were separated, and any remaining product in the aqueous layer was extracted out with ethyl acetate (70 ml). The organic layers were combined, washed with brine (20 ml), and concentrated in vacuo to yield the title compound (1.09 g, 81%). Mass spectrum (ESI) 409.1 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:16]=2[CH2:25][NH:26][CH2:27][CH3:28])[CH:7]=1)[CH3:2].Cl[C:31]([O:33][CH3:34])=[O:32]>>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:17][C:16]=2[CH2:25][N:26]([CH2:27][CH3:28])[C:31]([O:33][CH3:34])=[O:32])[CH:7]=1)[CH3:2]
Reactant: CCNCc1cc(C(F)(F)F)ccc1Oc1cc(CC(=O)OCC)ccc1OC
Reactant: COC(=O)Cl
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(C(F)(F)F)cc2CN(CC)C(=O)OC)c1

Procedure:
Prepared according to the procedure described in Example 3, Step 3, using the following starting materials: [3-(2-ethylaminomethyl-4-trifluoromethyl-phenoxy)-4-methoxy-phenyl]-acetic acid ethyl ester and methyl chloroformate.
Reaction SMILES: [C:1]1([CH:7]2[CH2:19][C:18](=O)[C:10]3[C:11]([C:14]([F:17])([F:16])[F:15])=[CH:12][O:13][C:9]=3[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:21]([NH:24][NH2:25])([NH2:23])=[NH:22].[ClH:26].Cl>C(O)C>[ClH:26].[NH:24](/[N:25]=[C:18]1\[CH2:19][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][C:9]2[O:13][CH:12]=[C:11]([C:14]([F:17])([F:16])[F:15])[C:10]\1=2)[C:21]([NH2:23])=[NH:22]
Reactant: N=C(N)NN
Reactant: O=C1CC(c2ccccc2)Cc2occ(C(F)(F)F)c21
Agent: Cl
Solvent: CCO
Product: N=C(N)N/N=C1\CC(c2ccccc2)Cc2occ(C(F)(F)F)c21
Temperature: 900 °C
Reaction time: 4 h
Yield: 69.8 %

Procedure:
To 6-phenyl-3-trifluoromethyl-4,5,6,7-tetrahydrobenzofuran-4-one (0.13 g) and aminoguanidine hydrochloride (51 mg) were added ethanol (10 ml) and 6N hydrochloric acid (0.04 ml), and the mixture was stirred at 900° C. for 4 hours and cooled. The reaction solution was concentrated under reduced pressure, and the residue was washed with ethanol, ethyl acetate and isopropylether and dried to give (E)-4-guanidinoimino-6-phenyl-3-trifluoromethyl-4,5,6,7-tetrahydrobenzofuran hydrochloride (Compound 50) (0.12 g).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[NH:5]1[CH2:10][CH2:9][O:8][CH:7]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:6]1.C(N(C(C)C)C(C)C)C.[CH3:30][C:31]1([CH3:37])[CH2:36][CH2:35][CH2:34][NH:33][CH2:32]1>C(Cl)Cl>[CH3:30][C:31]1([CH3:37])[CH2:36][CH2:35][CH2:34][N:33]([C:1]([N:5]2[CH2:10][CH2:9][O:8][CH:7]([C:11]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:12])[CH2:6]2)=[O:2])[CH2:32]1
Reactant: O=C(OCc1ccccc1)C1CNCCO1
Reactant: O=C(Cl)Cl
Reactant: CC1(C)CCCNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC1(C)CCCN(C(=O)N2CCOC(C(=O)OCc3ccccc3)C2)C1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
In a dry 25-mL RBF, phosgene (0.25 ml, 0.47 mmol) was dissolved in DCM (2 mL) and the solution was cooled to 0° C. A solution of benzyl morpholine-2-carboxylate (50%, 0.070 g, 0.16 mmol, Example 458, Step 2) and N-ethyl-N-isopropylpropan-2-amine (0.041 ml, 0.24 mmol) in DCM (2 mL) was added. The solution was stirred at 0° C. for 4 h, and the ice bath was removed, and the mixture stirred at RT for 1 hour. The reaction mixture was concentrated, and the residue dissolved in DCM (2 mL), and N-ethyl-N-isopropylpropan-2-amine (0.041 ml, 0.24 mmol) and 3,3-dimethylpiperidine (0.022 g, 0.20 mmol) were added by syringe. After 14 h, the reaction mixture was concentrated. The residue was purified through silica gel (20 mL) using 50% EtOAc-hexane to afford the title compound. MS m/z 361 (M+1).
Reaction SMILES: [F:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([CH3:9])[CH:3]=1.CC(OC)(C)C.[Br:16]Br>O>[Br:16][C:6]1[CH:5]=[C:4]([CH3:9])[CH:3]=[C:2]([F:1])[C:7]=1[NH2:8]
Reactant: Cc1ccc(N)c(F)c1
Reactant: BrBr
Solvent: O
Solvent: COC(C)(C)C
Product: Cc1cc(F)c(N)c(Br)c1
Temperature: 18 °C
Reaction time: 0.5 h

Procedure:
6-fluoro-4-methylaniline 6 (15 kg) was added to a mixture of MTBE (92 L, 66.6 kg) calcium carbonate (12 kg) and water (135 kg), inserted and cooled to <5° C. Bromine (18.22 kg) was charged, keeping T<10° C. Age for 30 minutes at T<10° C. The batch was warmed to ˜18° C. and allowed to settle.
Reaction SMILES: S(Cl)(C1C=CC(C)=CC=1)(=O)=O.[C:12]([NH:31][C:32]1[S:33][CH:34]=[C:35]([C:37](=[N:41][O:42][CH3:43])[C:38]([OH:40])=O)[N:36]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl.[S:45]([CH2:48][C@H:49]1[NH:52][C:51](=[O:53])[C@H:50]1[NH2:54])[C:46]#[N:47]>C(Cl)Cl.C(N(CC)CC)C>[S:45]([CH2:48][C@H:49]1[NH:52][C:51](=[O:53])[C@H:50]1[NH:54][C:38](=[O:40])[C:37]([C:35]1[N:36]=[C:32]([NH:31][C:12]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[S:33][CH:34]=1)=[N:41][O:42][CH3:43])[C:46]#[N:47]
Reactant: N#CSC[C@H]1NC(=O)[C@H]1N
Reactant: CON=C(C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON=C(C(=O)N[C@@H]1C(=O)N[C@@H]1CSC#N)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
1 ml of triethylamine and then 1.38 g of tosyl chloride were added to a suspension of 3.19 g of the syn isomer of 2-(2-tritylamino-4-thiazolyl)-2-methoxyimino-acetic acid in 50 ml of methylene chloride and the mixture was stirred at room temperature for 40 minutes. A solution of 1.162 g of the product of Step C in 40 ml of methylene chloride and 2 ml of trietylamine were added to the mixture over 5 minutes and the mixture was stirred for 4 hours, was washed with water, then with water containing 4 ml of N hydrochloric acid, dried and evaporated to dryness. The residue was dissolved in ethyl acetate and the solution was iced and vacuum filtered. The product was washed with methanol and dried to obtain 0.709 g of racemate of syn isomer of cis 4-thiocyanatomethyl-3-[2-(2-tritylamino-4-thiazolyl)-2-methoxyimino-acetamido]-2-oxo-azetidine. The mother liquors were evaporated to dryness and the residue was chromatographed over silica gel. Elution with a 93-7 chloroform-methanol mixture yielded another 1.069 g of the said product.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[NH:13][C:6]2=[N:7][CH:8]=[C:9]([CH2:11][NH2:12])[CH:10]=[C:5]2[CH:4]=1.Cl[C:17]1[N:22]=[CH:21][N:20]=[C:19]([C:23]#[N:24])[CH:18]=1.CCN(C(C)C)C(C)C>CN1CCCC1=O.C(OCC)(=O)C>[F:15][C:2]([F:1])([F:14])[C:3]1[NH:13][C:6]2=[N:7][CH:8]=[C:9]([CH2:11][NH:12][C:17]3[N:22]=[CH:21][N:20]=[C:19]([C:23]#[N:24])[CH:18]=3)[CH:10]=[C:5]2[CH:4]=1
Reactant: N#Cc1cc(Cl)ncn1
Reactant: NCc1cnc2[nH]c(C(F)(F)F)cc2c1
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cc(NCc2cnc3[nH]c(C(F)(F)F)cc3c2)ncn1
Temperature: 100 °C
Yield: 21.6 %

Procedure:
1-[2-(Trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]methanamine (Intermediate 5, 100 mg, 0.465 mmol), 6-chloro-4-pyrimidinecarbonitrile (Intermediate 8, 97 mg, 0.697 mmol) and DIPEA (0.162 mL, 0.929 mmol) were added together in N-methyl-2-pyrrolidone (2 mL) and the resulting mixture was heated at 100° C. for 2 hours and allowed to cool to room temperature. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was separated, dried under magnesium sulfate and evaporated under reduced pressure. The residue was purified by MDAP. Product containing fractions were combined and evaporated under reduced pressure. The resulting solid was dried under high vacuum at 45° C. for 18 hours to give the title compound as an off-white solid (32 mg);
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])/[CH:4]=[CH:5]/[C:6]([C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=1[F:15])=[O:7].C([O:19][C:20]1O[C:23](C(O)=O)=[N:22][CH:21]=1)C>>[OH:19][C:20]1[CH:21]=[N:22][CH:23]=[C:4]([C:5]=1[C:6](=[O:7])[C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=1[F:15])[C:3]([O:2][CH3:1])=[O:16]
Reactant: COC(=O)/C=C/C(=O)c1cc(Cl)ccc1F
Reactant: CCOc1cnc(C(=O)O)o1
Product: COC(=O)c1cncc(O)c1C(=O)c1cc(Cl)ccc1F

Procedure:
Diels-Alder reaction of intermediate (XX) with the known 5-ethoxyoxazole-2-carboxylic acid (XXI) (step w) to give methyl 5-hydroxy-4-(2'-fluoro-5'-chlorobenzoyl)nicotinate (XXII);
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C:5]1=[O:10].Cl.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19]N)=[CH:15][CH:14]=1.[CH3:21][N:22]1[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]1>C(N(CC)CC)C>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]2[N:19]([CH2:2][CH2:3][N:4]3[CH2:9][CH2:8][CH2:7][CH2:6][C:5]3=[O:10])[C:25]3[CH2:26][CH2:27][N:22]([CH3:21])[CH2:23][C:24]=3[C:15]=2[CH:14]=1
Reactant: CN1CCC(=O)CC1
Reactant: O=C1CCCCN1CCBr
Reactant: NNc1ccc(Cl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Product: CN1CCc2c(c3cc(Cl)ccc3n2CCN2CCCCC2=O)C1

Procedure:
The title compound is prepared by following Method 8 by using 1-(2-bromoethyl)piperidin-2-one, 4-chlorophenylhydrazine hydrochloride, triethylamine and N-methyl-4-piperidone
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:23][C@@H:24]([CH3:27])[CH2:25][OH:26])=[C:7]([CH:22]=1)[C:8]([NH:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=1)=[O:9])#[N:2].[CH3:28][S:29](Cl)(=[O:31])=[O:30]>N1C=CC=CC=1.C(OCC)(=O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:23][C@@H:24]([CH3:27])[CH2:25][O:26][S:29]([CH3:28])(=[O:31])=[O:30])=[C:7]([CH:22]=1)[C:8]([NH:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=1)=[O:9])#[N:2]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(CNC(=O)c2cc(C#N)ccc2N[C@@H](C)CO)cc1OC
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COc1ccc(CNC(=O)c2cc(C#N)ccc2N[C@@H](C)COS(C)(=O)=O)cc1OC
Temperature: 0 °C
Yield: 112.1 %

Procedure:
To a solution of (S)-5-cyano-N-(3,4-dimethoxybenzyl)-2-(2-hydroxy-1-methylethylamino)benzamide (4 g) in pyridine (20 mL) was added methanesulfonyl chloride (1.36 g), and the mixture was stirred for an hour at 0° C. The resulting mixture was diluted with ethyl acetate and washed successively with water and brine. The organic layer was dried over sodium sulfate and evaporated in vacuo. The residue was triturated with diisopropyl ether to give (S)-5-cyano-N-(3,4-dimethoxybenzyl)-2-[2-(methanesulfonyloxy)-1-methylethylamino]benzamide (5.43 g) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](=O)[CH:8]=[CH:9][NH:10]2)=[CH:5][N:4]=1.C(=O)([O-])[O-].[Na+].[Na+].O=P(Cl)(Cl)[Cl:22]>>[Cl:22][C:7]1[C:6]2[C:11](=[CH:12][C:3]([O:2][CH3:1])=[N:4][CH:5]=2)[N:10]=[CH:9][CH:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cc2[nH]ccc(=O)c2cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COc1cc2nccc(Cl)c2cn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A two neck RBF equipped with CaCl2 guard tube was charged with 7-Methoxy-1H-[1.6]naphthyridin-4-one (28 g, 159 mmol) and POCl3 (280 mL). The reaction mixture was stirred at RT for 3 h. The reaction mixture was poured into ice water and the pH was carefully adjusted to 8 with solid sodium carbonate (highly exothermic reaction). The product was extracted with EtOAc. The combined organic layer was washed with water, dried over Na2SO4 and concentrated. The crude product was purified by column chromatography on silica gel (230-400 mesh) eluting with ethyl acetate hexane mixture.
Reaction SMILES: [F:1][C:2]1([F:14])[CH2:7][CH2:6][CH:5]([CH:8]=[CH:9][C:10]([O:12][CH3:13])=[O:11])[CH2:4][CH2:3]1.[N+:15]([CH3:18])([O-:17])=[O:16].N12CCCN=C1CCCCC2>>[F:1][C:2]1([F:14])[CH2:3][CH2:4][CH:5]([CH:8]([CH2:18][N+:15]([O-:17])=[O:16])[CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH2:6][CH2:7]1
Reactant: C[N+](=O)[O-]
Reactant: COC(=O)C=CC1CCC(F)(F)CC1
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)CC(C[N+](=O)[O-])C1CCC(F)(F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68 %

Procedure:
Methyl 3-(4,4-difluorocyclohexyl)prop-2-enoate (4.054 g, 0.198 mol, 1 eq) is dissolved in nitromethane (23 L, 0.423 mol, 21.3 eq) and 1,8-diazabicyclo[5,4,0]undec-7-ene (3.025 g, 0.198 mol, 1 eq) is added at room temperature. The solution is stirred overnight at room temperature then evaporated. The residue is dissolved in ethyl acetate and the solution is washed with 1 M HCl and water. The organic phase is dried with MgSO4 and evaporated under vacuum. The residue is purified by chromatography over silicagel (eluent: CH2Cl2 100%) to afford methyl 3-(4,4-difluorocyclohexyl)-4-nitrobutanoate a1-20.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1/[CH:10]=[CH:11]/[S:12]([NH2:15])(=[O:14])=[O:13].[Br:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[C:19]([Cl:26])[CH:18]=1.O>O1CCOCC1>[Br:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([NH:15][S:12](/[CH:11]=[CH:10]/[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[Cl:3])(=[O:13])=[O:14])=[O:22])=[C:19]([Cl:26])[CH:18]=1
Reactant: NS(=O)(=O)/C=C/c1ccccc1Cl
Reactant: O=C(Cl)c1ccc(Br)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(NS(=O)(=O)/C=C/c1ccccc1Cl)c1ccc(Br)cc1Cl
Reaction time: 0.5 h

Procedure:
Sodium hydride (60% dispersion in mineral oil) (36 mg, 0.9 mmol) was added to a solution of (E)-2-(2-chloro-phenyl)-ethenesulfonic acid amide (65 mg, 0.3 mmol) in 1,4-dioxane (1.5 mL) and the reaction mixture was shaken for 30 minutes. Crude 4-bromo-2-chloro-benzoyl chloride (114 mg, 0.45 mmol) in dioxane (0.5 mL) was added and the reaction mixture was shaken at room temperature for 18 hours. Water (0.1 mL) was added to the reaction mixture and the whole was concentrated in vacuo. The resultant residue was purified by preparative HPLC under neutral conditions to give (E)-2-(2-chloro-phenyl)-ethenesulfonic acid 4-bromo-2-chloro-benzoylamide; sodium salt (38 mg, 29% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:17]=[CH:18][C:19]=1[N+:20]([O-:22])=[O:21])[CH:12]=[CH:13][C:14]([OH:16])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.[NH2:27][CH:28]([C:30]1[CH:35]=[C:34]([CH3:36])[CH:33]=[CH:32][N:31]=1)[CH3:29].C1(N=C=NC2CCCCC2)CCCCC1.C(N(CC)CC)C>CN(C)C=O>[CH3:36][C:34]1[CH:33]=[CH:32][N:31]=[C:30]([CH:28]([NH:27][C:14](=[O:16])[CH:13]=[CH:12][C:11]2[CH:17]=[CH:18][C:19]([N+:20]([O-:22])=[O:21])=[C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:10]=2)[CH3:29])[CH:35]=1
Reactant: Cc1ccnc(C(C)N)c1
Reactant: O=C(O)C=Cc1ccc([N+](=O)[O-])c(OCc2ccccc2)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: Cc1ccnc(C(C)NC(=O)C=Cc2ccc([N+](=O)[O-])c(OCc3ccccc3)c2)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a mixture of 3-benzyloxy-4-nitrocinnamic acid (12.9 g) and 2-(1-aminoethyl)-4-methylpyridine acetate (8.5 g) in N,N-dimethylformamide (150 ml) were added 1-hydroxybenzotraizole (7 g), N,N'-dicyclohexylcarbodiimide (10.65 g) and triethylamine (4.36 g), which was stirred at ambient temperature for 24 hours. After filtration, the filtrate was evaporated under reduced pressure. The residue was suspended in ethyl acetate (100 ml), which was filtered, and evaporated. The residue was subjected to column chromatography on silica gel to give 4-methyl-2-[1-(3-benzyloxy-4-nitrocinnamoylamino)ethyl]pyridine.
Reaction SMILES: [F:1][C@@H:2]1[C@@H:7]([OH:8])[CH2:6][CH2:5][C@@H:4]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:3]1.[CH3:14][C:15]([Si:18](Cl)([CH3:20])[CH3:19])([CH3:17])[CH3:16].C(Cl)Cl.N1C=CN=C1>O>[Si:18]([O:8][C@H:7]1[CH2:6][CH2:5][C@@H:4]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:3][C@@H:2]1[F:1])([C:15]([CH3:17])([CH3:16])[CH3:14])([CH3:20])[CH3:19]
Reactant: CCOC(=O)[C@@H]1CC[C@H](O)[C@@H](F)C1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)[C@@H]1CC[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](F)C1
Reaction time: 16 h
Yield: 75.8 %

Procedure:
To a 500 mL flask was added (1R,3S,4S)-ethyl 3-fluoro-4-hydroxycyclohexane-carboxylate (17 g, 89.3 mmol, 97.9% ee), TBSCl (17.5 g, 116.1 mmol) and DCM (200 mL). Imidazole (12.1 g, 178 mmol) was added to the resultant clear solution and the reaction mixture was stirred for 16 hours. Water (100 mL) was added and the mixture was stirred for a further 10 minutes. The phases were separated and the organic layer was washed with water (100 mL) and concentrated under reduced pressure (40±5° C., 50˜250 mbar). Purification by flash chromatography on silica eluting with a mixture of heptane and ethyl acetate (100:1) gave (1R,3S,4S)-ethyl 4-((tert-butyldimethylsilyl)oxy)-3-fluorocyclohexanecarboxylate as a colorless oil (20.6 g, yield 75.7%). 1H NMR (400 MHz, DMSO-d6): 4.38˜4.52 (m, 1H), 4.03˜4.08 (dd, J=12 Hz, J=8 Hz, 2H), 3.77˜3.81 (m, 1H), 2.54˜2.60 (m, 1H), 1.93˜2.06 (m, 1H), 1.58˜1.86 (m, 4H), 1.46˜1.50 (m, 1H), 1.17˜1.20 (t, J=12 Hz, J=6 Hz, 3H), 0.85 (s, 9H), 0.03˜0.04 (d, J=4 Hz, 8H), [M+H]+=305.1 via GC-MS (Instrument: Agilent Technologies, GC 6890N, MS 5975C. GC conditions: Column: HP—5 MS, Capillary: 30.0 m×250 μm×0.25 μm, Detecor parameters: Temperature: 350° C., Flow H2: 40 mL/min, Air flow: 400 mL/min, Makeup (He): 40 mL/min. Injector parameters: temperature: 200° C. Split ratio: 100:1. Carrier gas: He, Flow: 2.0 mL/min, Mode: Constant flow. Oven parameters: 0 min, 50° C.; 2.0 min, 50° C.; 5.33 min, 100° C.; 15.83 min, 270° C. Injection volume: 1 μL, Syringe wash solvent: acetonitrile. MS conditions: Volt: 70 EV, Scan range: m/z=50˜550)
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[Cl-].[CH:12](=[N+:19]([CH3:21])[CH3:20])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH3:20][N:19]([CH:12]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:4]1[C:3]2[C:2]([OH:1])=[CH:10][CH:9]=[CH:8][C:7]=2[NH:6][CH:5]=1)[CH3:21]
Reactant: Oc1cccc2[nH]ccc12
Reactant: C[N+](C)=Cc1ccccc1
Agent: [Cl-]
Product: CN(C)C(c1ccccc1)c1c[nH]c2cccc(O)c12

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 4-hydroxy-1H-indole and benzylidene-dimethyl-ammonium chloride, which had been prepared in accordance with example 1.
Reaction SMILES: [CH3:1][S:2]([O-:5])(=[O:4])=[O:3].C(N(C(C)C)C(C1C=CC(OCCCCO[C:22]2[CH:23]=[CH:24][C:25]3[O:29][N:28]=[C:27]([NH:30][C:31]([C@@H:33]([NH3+:35])[CH3:34])=[O:32])[C:26]=3[CH:36]=2)=C(OC)C=1)=O)(C)C.CS(O)(=O)=O.[CH:49]([N:52]([CH:83]([CH3:85])[CH3:84])[C:53]([C:55]1[CH:80]=[CH:79][C:58]([O:59][CH2:60][CH2:61][CH2:62][CH2:63][O:64]C2C=CC3ON=C(NC([NH2+]C)=O)C=3C=2)=[C:57]([O:81][CH3:82])[CH:56]=1)=[O:54])([CH3:51])[CH3:50].C([O:90][C:91]([NH:93][CH2:94]C(O)=O)=O)(C)(C)C>>[CH3:1][S:2]([O-:5])(=[O:4])=[O:3].[CH:83]([N:52]([CH:49]([CH3:51])[CH3:50])[C:53]([C:55]1[CH:80]=[CH:79][C:58]([O:59][CH2:60][CH2:61][CH2:62][CH2:63][O:64][C:23]2[CH:22]=[CH:36][C:26]3[C:27]([NH:30][C:31]([C@@H:33]([NH:35][C:91]([NH2+:93][CH3:94])=[O:90])[CH3:34])=[O:32])=[N:28][O:29][C:25]=3[CH:24]=2)=[C:57]([O:81][CH3:82])[CH:56]=1)=[O:54])([CH3:84])[CH3:85]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: COc1cc(C(=O)N(C(C)C)C(C)C)ccc1OCCCCOc1ccc2onc(NC(=O)[C@H](C)[NH3+])c2c1
Reactant: C[NH2+]C(=O)Nc1noc2ccc(OCCCCOc3ccc(C(=O)N(C(C)C)C(C)C)cc3OC)cc12
Agent: CS(=O)(=O)O
Agent: CS(=O)(=O)[O-]
Product: C[NH2+]C(=O)N[C@@H](C)C(=O)Nc1noc2cc(OCCCCOc3ccc(C(=O)N(C(C)C)C(C)C)cc3OC)ccc12
Yield: 72 %

Procedure:
(1S)-1-{5-[4-(4-diisopropylcarbamoyl-2-methoxy-phenoxy)-butoxy]-benzo[d]isoxazole-3-ylcarbamoyl}-ethyl-ammonium methane sulfonic acid salt, the compound of EXAMPLE 2, was used as a starting material in place of {5-[4-(4-diisopropylcarbamoyl-2-methoxy-phenoxy)-butoxy]-benzo[d]isoxazole-3-ylcarbamoyl}-methyl-ammonium methane sulfonic acid used in the above EXAMPLE 6. According to the same method as in EXAMPLE 6, N-(t-butoxycarbonyl)glycine was used, the above title compound was obtained. (yield: 72%)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH2:6][CH2:5]2.Cl[C:12]1[NH:16][C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=2[N:13]=1.O>CC(N(C)C)=O.CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:12]1[NH:16][C:15]3[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=3[N:13]=1)[CH2:6][CH2:5]2
Reactant: Brc1ccc2c(c1)CCN2
Reactant: Clc1nc2ccccc2[nH]1
Solvent: CN(C)C=O
Solvent: CC(=O)N(C)C
Solvent: O
Product: Brc1ccc2c(c1)CCN2c1nc2ccccc2[nH]1
Temperature: 150 °C
Reaction time: 12 h
Yield: 69.4 %

Procedure:
A mixture of 5-bromoindoline (1 g) and 2-chloro-1H-benzo[d]imidazole (0.770 g) in DMA/DMF (5 mL, 3/2) was stirred at 150° C. for 12 h, treated with water, and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (AcOEt/hexane) to give the title compound (1.1 g).
Reaction SMILES: [N:1]1([C@@H:7]2[CH2:10][C@H:9]([C:11]3[S:12][C:13]4[CH:19]=[C:18]([NH2:20])[CH:17]=[CH:16][C:14]=4[N:15]=3)[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:28](Cl)(=[O:30])[CH3:29]>ClCCl.O>[N:1]1([C@@H:7]2[CH2:10][C@H:9]([C:11]3[S:12][C:13]4[CH:19]=[C:18]([NH:20][C:28](=[O:30])[CH3:29])[CH:17]=[CH:16][C:14]=4[N:15]=3)[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Nc1ccc2nc([C@H]3C[C@@H](N4CCCCC4)C3)sc2c1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc2nc([C@H]3C[C@@H](N4CCCCC4)C3)sc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The product of Example 101A (20 mg, 0.070 mmole) was dissolved in anhydrous dichloromethane (1.5 mL). To the solution was added triethylamine (35.6 mg, 49 μL, 0.35 mmole) and acetyl chloride (10 μL, 0.14 mmole). The mixture was stirred at room temperature overnight then diluted with water. The aqueous layer was extracted three times with dichloromethane and the combined organic layers were concentrated to give the crude product. The crude product was purified by column chromatography (0.5% ammonium hydroxide and 5% methanol in dichloromethane) to give the title compound. 1H NMR (500 MHz, CDCl3) δ ppm 8.39 (d, J=2.14 Hz, 1H) 7.84 (d, J=8.54 Hz, 1H) 7.37 (s, 1H) 7.22 (dd, J=8.85, 2.14 Hz, 1H) 3.48-3.59 (m, 1H) 2.72-2.83 (m, 1H) 2.60-2.70 (m, 2H) 2.24-2.39 (m, 6H) 2.21 (s, 3H) 1.54-1.64 (m, 4H) 1.40-1.51 (m, 2H). MS: (M+H)+=330.
Reaction SMILES: [OH:1][C:2]1[CH2:3][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C:5](O)=[CH:6][CH:7]=1.ClC1C=C(C=CC=1)C(O)=O.C(OC(=O)C)C>C(Cl)Cl>[CH:2]12[O:1][CH:7]1[CH2:6][CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3]2
Reactant: CC(C)(C)OC(=O)N1CC(O)=CC=C1O
Agent: O=C(O)c1cccc(Cl)c1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC2OC2C1
Reaction time: 5 h
Yield: 91.3 %

Procedure:
2.1 g (11.5 mmol) of t-butyl 3,6-dihydroxypyridin-1(2H)-carboxylate (product of step 1) and 3.1 g (12.6 mmol) of m-chloro benzoic acid was dissolved in 30 mL of methylene chloride, and after stirring for 5 hour, 100 mL of ethylacetate was added thereto. After washing with water, an organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by column chromatography to give 2.1 g (10.5 mmol) of the title compound in a yield of 87%.