Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]2[CH:10]=[C:11]([F:14])[CH:12]=[CH:13][C:7]=2[C:6]=1[NH2:15])([O:3]C)=[O:2].[OH-].[Na+].C(O)(C)C>O>[NH2:15][C:6]1[C:7]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:8]=2[S:9][C:5]=1[C:1]([OH:3])=[O:2]
Reactant: COC(=O)c1sc2cc(F)ccc2c1N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: Nc1c(C(=O)O)sc2cc(F)ccc12
Temperature: 8.5 °C
Reaction time: 3 h
Yield: 94.7 %

Procedure:
At 50° C., add to a stirring solution of 2-carbomethoxy-3-amino-6-fluoro-benzo[b]thiophene (prepared according to U.S. Pat. No. 5,143,923), (90.1 g, 0.4 mol) in H2O (450 mL), a 50% aqueous solution of NaOH (64 g, 0.8 mol) over 2-3 min. Heat the reaction to 70-73° C. and continue to stir for 3 h. Add 10% aqueous isopropanol (45 mL) and bring to reflux. Remove the isopropanol under N2 and add H2O (300 mL). Cool the reaction mixture to between 7-10° C. and add concentrated HCl (80 mL). Add H2O (650 mL), cool to 5-7° C., filter the resulting solid, and wash the filter cake with H2O (2×150 mL). Dry the solid under vacuum at 35° C. to obtain 80.6 g (94.7%) of solid mp 160-163° C., TLC on silica gel (dichloromethane/methanol, 3:1), Rf=0.69.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9](Cl)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].NCC(O)=O>ClC1C=C(O)C(=CC=1)C(O)=O>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1ccc(Cl)cc1Cl
Agent: NCC(=O)O
Agent: O=C(O)c1ccc(Cl)cc1O
Product: O=C(O)c1ccccc1Cl

Procedure:
If 2,4-dichlorobenzoic acid is reacted with glycine analogously to DE-C 142 507 by initially introducing all the reactants into the reaction vessel and then carrying out the reaction while stirring and heating, by-products, in particular 4-chlorosalicylic acid, form - as a corresponding comparison experiment demonstrates - to a not inconsiderable extent. The statement made in DE-C 142 507, that the yield is almost the yield in theory when 2-chlorobenzoic acid is used, cannot be confirmed if 2,4-dichlorobenzoic acid is used as the starting substance.
Reaction SMILES: [CH2:1]([N:3]([CH2:61][CH3:62])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2[CH:14]=[C:15]([C:19](=[O:40])[N:20]([CH3:39])CCOCCOCCOCCC(OC(C)(C)C)=O)[CH:16]=[CH:17][CH:18]=2)=[O:12])=[C:6]([C:41]2[CH:46]=[C:45]([C:47](=[O:60])[NH:48][CH2:49][C:50]3[CH:55]=[CH:54][CH:53]=[C:52]([C:56]([F:59])([F:58])[F:57])[CH:51]=3)[CH:44]=[CH:43][N:42]=2)[CH:5]=1)[CH3:2].[CH3:63][O:64][CH2:65][CH2:66][NH:67][C:68]([C@H:70]1[CH2:75][CH2:74][CH2:73]NC1)=[O:69]>>[CH2:1]([N:3]([CH2:61][CH3:62])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:12])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([N:20]3[CH2:73][CH2:74][CH2:75][C@H:70]([C:68](=[O:69])[NH:67][CH2:66][CH2:65][O:64][CH3:63])[CH2:39]3)=[O:40])[CH:14]=2)=[C:6]([C:41]2[CH:46]=[C:45]([CH:44]=[CH:43][N:42]=2)[C:47]([NH:48][CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[C:52]([C:56]([F:59])([F:58])[F:57])[CH:51]=2)=[O:60])[CH:5]=1)[CH3:2]
Reactant: COCCNC(=O)[C@H]1CCCNC1
Reactant: CCN(CC)c1ccc(NC(=O)c2cccc(C(=O)N(C)CCOCCOCCOCCC(=O)OC(C)(C)C)c2)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Product: CCN(CC)c1ccc(NC(=O)c2cccc(C(=O)N3CCC[C@H](C(=O)NCCOC)C3)c2)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1

Procedure:
This compound was prepared according to the procedure described for the synthesis of tert-butyl 1-(3-((4-(diethylamino)-2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)phenyl)carbamoyl)phenyl)-2-methyl-1-oxo-5,8,11-trioxa-2-azatetradecan-14-oate Example 188, using (S)—N-(2-methoxyethyl)piperidine-3-carboxamide 4.14a in place of tert-butyl 5,8,11-trioxa-2-azatetradecan-14-oate. MS (ES, m/z): 759.4 [M+H]+.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[N:7]([CH:10]1[CH2:19][N:18]2[C:14](=[N:15][C:16]3[C:17]2=[C:20]([N:24]([CH2:27][CH3:28])[CH2:25][CH3:26])[CH:21]=[CH:22][CH:23]=3)[N:13]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:30]=2[Cl:36])[CH2:12][CH2:11]1)=[N+]=[N-].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[Cl:36][C:30]1[CH:31]=[C:32]([Cl:35])[CH:33]=[CH:34][C:29]=1[N:13]1[C:14]2=[N:15][C:16]3[C:17](=[C:20]([N:24]([CH2:27][CH3:28])[CH2:25][CH3:26])[CH:21]=[CH:22][CH:23]=3)[N:18]2[CH2:19][CH:10]([NH2:7])[CH2:11][CH2:12]1
Reactant: CCN(CC)c1cccc2nc3n(c12)CC(N=[N+]=[N-])CCN3c1ccc(Cl)cc1Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: CCN(CC)c1cccc2nc3n(c12)CC(N)CCN3c1ccc(Cl)cc1Cl
Yield: 75.2 %

Procedure:
To a suspension of lithium aluminum hydride (31.8 mg, 0.858 mmol) in tetrahydrofuran (1 mL) was added a solution of 4-azido-1-(2,4-dichlorophenyl)-N,N-diethyl-2,3,4,5-tetrahydro-1H-[1,3]diazepino[1,2-a]benzimidazol-7-amine (95.0 mg, 0.214 mmol) in tetrahydrofuran (1 mL) at 0° C. After the resultant mixture was stirred at 0° C. for 2 hr, sodium sulfate decahydrate (320 mg) was added. The resultant mixture was filtered and concentrated in vacuo. The residue was recrystallized from ethyl acetate/diisopropyl ether to give the title compound as a colorless solid (67.2 mg, 0.161 mmol, 75%).
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:11]=[CH:10][C:9](B(O)O)=[CH:8][CH:7]=1)([CH3:5])[CH3:4])#[N:2].[NH2:15][C:16]1[C:17]([C:23]2[CH:24]=[C:25]3[C:30](=[CH:31][CH:32]=2)[C:29](=[O:33])[NH:28][CH2:27][CH2:26]3)=[N:18][C:19](Br)=[CH:20][N:21]=1>C(O)CCC>[NH2:15][C:16]1[N:21]=[CH:20][C:19]([C:9]2[CH:10]=[CH:11][C:6]([C:3]([CH3:5])([CH3:4])[C:1]#[N:2])=[CH:7][CH:8]=2)=[N:18][C:17]=1[C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[C:29](=[O:33])[NH:28][CH2:27][CH2:26]2
Reactant: CC(C)(C#N)c1ccc(B(O)O)cc1
Reactant: Nc1ncc(Br)nc1-c1ccc2c(c1)CCNC2=O
Solvent: CCCCO
Product: CC(C)(C#N)c1ccc(-c2cnc(N)c(-c3ccc4c(c3)CCNC4=O)n2)cc1
Yield: 81.7 %

Procedure:
General method B was applied to 4-(2-cyanopropan-2-yl)phenylboronic acid (79 mg, 0.42 mmol) and 6-(3-amino-6-bromopyrazin-2-yl)-3,4-dihydroisoquinolin-1(2H)-one (150 mg, 0.38 mmol) in n-butanol (2 mL) to give 2-{4-[5-amino-6-(1-oxo-1,2,3,4-tetrahydro-isoquinolin-6-yl)-pyrazin-2-yl]-phenyl}-2-methyl-propionitrile (119 mg, 82% yield) after purification by column chromatography on silica (2-5% MeOH/DCM eluent).
Reaction SMILES: [NH2:1][C:2]([NH:4][C:5]1[CH:6]=[C:7]([CH:33]=[CH:34][CH:35]=1)[C:8]([NH:10][C:11]1[CH:32]=[CH:31][C:14]2[N:15]([CH:18]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:19][C:20]([O:22]CC)=[O:21])[CH:16]=[N:17][C:13]=2[CH:12]=1)=[O:9])=[NH:3]>Cl>[NH2:3][C:2]([NH:4][C:5]1[CH:6]=[C:7]([CH:33]=[CH:34][CH:35]=1)[C:8]([NH:10][C:11]1[CH:32]=[CH:31][C:14]2[N:15]([CH:18]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:19][C:20]([OH:22])=[O:21])[CH:16]=[N:17][C:13]=2[CH:12]=1)=[O:9])=[NH:1]
Reactant: CCOC(=O)CC(c1ccccc1)n1cnc2cc(NC(=O)c3cccc(NC(=N)N)c3)ccc21
Agent: Cl
Product: N=C(N)Nc1cccc(C(=O)Nc2ccc3c(c2)ncn3C(CC(=O)O)c2ccccc2)c1

Procedure:
A solution of ethyl 3-{5-[(3-{[amino(imino)methyl]amino}benzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoate (32 mg, 68 μmol) in hydrochloric acid (20 mL of a 5N solution) was stirred at room temperature for 96 hours. The solution was evaporated in vacuo and the residue was purified by RP-HPLC to afford the title compound, [LCMS (Method A, Mobile Phase II) RT=2.99 min, MH+ 443].
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]#[C:11][CH3:12])[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[O:19]([C:26]1[CH:27]=[C:28]([OH:32])[CH:29]=[CH:30][CH:31]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[Cl-].[NH4+]>CN(C)C=O>[CH2:9]([O:8][C:6]1[CH:7]=[C:2]([O:32][C:28]2[CH:29]=[CH:30][CH:31]=[C:26]([O:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:27]=2)[N:3]=[CH:4][N:5]=1)[C:10]#[C:11][CH3:12]
Reactant: Oc1cccc(Oc2ccccc2)c1
Reactant: CC#CCOc1cc(Cl)ncn1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC#CCOc1cc(Oc2cccc(Oc3ccccc3)c2)ncn1
Temperature: 60 °C
Reaction time: 7 h
Yield: 90.7 %

Procedure:
To 2 ml of N,N-dimethylformamide were added 0.2 g of 4-chloro-6-(2-butynyloxy)pyrimidine, 0.23 g of potassium carbonate, and 0.24 g of 3-phenoxyphenol, followed by stirring at 60° C. for 7 hours. The reaction mixture was then left for cooling to room temperature and poured into a saturated aqueous ammonium chloride solution, which was extracted three times with chloroform. The chloroform layers were combined, washed with diluted hydrochloric acid and then with water. The organic layer was dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to silica gel column chromatography to give 0.33 g of 4-(2-butynyloxy)-6-(3-phenoxyphenoxy)pyrimidine (the present compound (70)).
Reaction SMILES: O=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]#[N:12])=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.Cl.[CH2:14]([C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([NH:30]N)[C:25]=2[F:32])=[CH:20][CH:19]=1)[CH2:15][CH2:16][CH3:17]>>[CH2:14]([C:18]1[CH:19]=[CH:20][C:21]([C:24]2[CH:29]=[CH:28][C:27]3[C:3]4[CH2:4][C:5]5[C:10](=[CH:9][CH:8]=[C:7]([C:11]#[N:12])[CH:6]=5)[C:2]=4[NH:30][C:26]=3[C:25]=2[F:32])=[CH:22][CH:23]=1)[CH2:15][CH2:16][CH3:17]
Reactant: N#Cc1ccc2c(c1)CCC2=O
Reactant: CCCCc1ccc(-c2cccc(NN)c2F)cc1
Agent: Cl
Product: CCCCc1ccc(-c2ccc3c4c([nH]c3c2F)-c2ccc(C#N)cc2C4)cc1

Procedure:
A sample of 1-oxo-indan-5-carbonitrile (133.5 mg, 0.85 mmol) (Example 74, step 1) and (4′-Butyl-2-fluoro-biphenyl-3-yl)-hydrazine hydrochloride (250.4, 0.85 mmol) are reacted together as in example 1, step 3 followed by purification by UV triggered reverse phase HPLC to afford the title compound as a white solid. LC/MS calculated for [M+H]+ C26H21FN2: 381.2, found: 381.2.
Reaction SMILES: [Cl:1][C:2]1[C:11](Cl)=[N:10][C:9]2[C:4](=[CH:5][C:6]([N+:14]([O-:16])=[O:15])=[C:7]([F:13])[CH:8]=2)[N:3]=1.[CH3:17][C:18]([CH3:21])([O-:20])[CH3:19].[K+].C1(C)C=CC=CC=1.P([O-])(O)(O)=O.[Na+]>C(O)(C)(C)C>[C:18]([O:20][C:11]1[C:2]([Cl:1])=[N:3][C:4]2[C:9](=[CH:8][C:7]([F:13])=[C:6]([N+:14]([O-:16])=[O:15])[CH:5]=2)[N:10]=1)([CH3:21])([CH3:19])[CH3:17]
Reactant: O=[N+]([O-])c1cc2nc(Cl)c(Cl)nc2cc1F
Reactant: CC(C)(C)[O-]
Agent: O=P([O-])(O)O
Agent: [K+]
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: Cc1ccccc1
Product: CC(C)(C)Oc1nc2cc(F)c([N+](=O)[O-])cc2nc1Cl
Yield: 69.9 %

Procedure:
To a solution of 2,3-dichloro-6-fluoro-7-nitroquinoxaline 5.24 g in tetrahydrofran (50 mL), was added dropwise a solution of potassium tert-butoxide 2.51 g in tert-butanol 60 mL at −10 to −8° C. for about 1 hr. After the addition, the mixture was stirred at 0° C. for 1 hr, to which toluene 100 mL and a solution of 0.1M sodium dihydrogen phosphate 20 mL were added, then which was poured into a separatory funnel. The organic layer was washed with water and saturated saline, dried over MgSO4, and evaporated under reduced pressure. The residue was purified with silica gel column (120 g, toluene:hexane=1:1), to give the title compound (pale yellow crystal) 4.19 g.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:29]=1[C:9]1([CH2:14][CH2:13][N:12]([C:15](=[O:28])[NH:16][CH:17]3[CH:24]4[CH2:25][C:20]5(F)[CH2:21][CH:22]([CH2:26][CH:18]3[CH2:19]5)[CH2:23]4)[CH2:11][CH2:10]1)[CH2:8][CH:7]2[CH2:30][C:31]([O:33]CC)=O.CC[N:38]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[NH2:38][C:31](=[O:33])[CH2:30][CH:7]1[C:6]2[C:29](=[CH:2][CH:3]=[CH:4][CH:5]=2)[C:9]2([CH2:10][CH2:11][N:12]([C:15]([NH:16][CH:17]3[CH:18]4[CH2:26][CH:22]5[CH2:21][CH:20]([CH2:25][CH:24]3[CH2:23]5)[CH2:19]4)=[O:28])[CH2:13][CH2:14]2)[CH2:8]1
Reactant: CCOC(=O)CC1CC2(CCN(C(=O)NC3C4CC5CC3CC(F)(C5)C4)CC2)c2c(Br)cccc21
Reactant: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: NC(=O)CC1CC2(CCN(C(=O)NC3C4CC5CC(C4)CC3C5)CC2)c2ccccc21
Reaction time: 8 h
Yield: 55.5 %

Procedure:
To a solution of the compound 1 (200 mg, 0.47 mmol) in CH2Cl2 (5 mL), EDCI (187 mg, 0.95 mmol), HOBt (128 mg, 0.95 mmol), DIEA (303 mg, 2.35 mmol) were added under NH3 at 0° C., and then stirred overnight. The solvent was removed under reduced pressure to give crude product, which was purified by preparative TLC to afford (±)-3-(2-amino-2-oxoethyl)-N-(2-adamantyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxamide (110 mg, 56%). 1H NMR (CDCl3): δ=1.52-1.61 (m, 4H), 1.62-1.66 (m, 2H), 1.68-1.70 (m, 2H), 1.75-1.76 (m, 2H), 1.78-1.80 (m, 1H), 1.82-1.85 (m, 6H), 1.90-1.98 (m, 2H), 2.11-2.21 (m, 1H), 2.30-2.40 (m, 1H), 2.60-2.70 (m, 1H), 2.80-2.88 (m, 1H), 2.95-3.15 (m, 2H), 3.65-3.75 (m, 2H), 3.76-3.88 (m, 1H), 4.00 (s, 2H), 5.40-5.55 (d, 2H), 7.15-7.25 (m, 4H).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11](Cl)(=[O:13])=[O:12].[CH2:15]([O:17][C:18]([CH:20]1[NH:25][CH2:24][CH2:23][N:22]([C:26]([CH:28]2[CH2:33][CH2:32][N:31]([C:34]3[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=3)[CH2:30][CH2:29]2)=[O:27])[CH2:21]1)=[O:19])[CH3:16]>>[CH2:15]([O:17][C:18]([CH:20]1[CH2:21][N:22]([C:26]([CH:28]2[CH2:33][CH2:32][N:31]([C:34]3[CH:35]=[CH:36][N:37]=[CH:38][CH:39]=3)[CH2:30][CH2:29]2)=[O:27])[CH2:23][CH2:24][N:25]1[S:11]([C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)(=[O:13])=[O:12])=[O:19])[CH3:16]
Reactant: CCOC(=O)C1CN(C(=O)C2CCN(c3ccncc3)CC2)CCN1
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Product: CCOC(=O)C1CN(C(=O)C2CCN(c3ccncc3)CC2)CCN1S(=O)(=O)c1ccc2ccccc2c1
Yield: 31 %

Procedure:
Using an analogous procedure to that described in Example 2, 2-naphthylsulphonyl chloride was reacted with 3-ethoxycarbonyl-1-[1-(4-pyridyl)piperidin-4-ylcarbonyl]piperazine to give 2-ethoxycarbonyl-1-(2-naphthylsulphonyl)-4-[1-(4-pyridyl)piperidin-4-ylcarbonyl]piperazine in 31% yield;
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:15]2[N:14]([S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)(=[O:20])=[O:19])[CH:13]=[CH:12][C:11]=2[C:10]=1[CH:27]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:29]([N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1)([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O>O>[CH2:1]([O:8][C:9]1[C:10]([CH2:27][N:39]2[CH2:38][CH2:37][N:36]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:41][CH2:40]2)=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:19])=[O:20])[CH:13]=[CH:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1c(OCc2ccccc2)ccc2c1ccn2S(=O)(=O)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(Cc2c(OCc3ccccc3)ccc3c2ccn3S(=O)(=O)c2ccccc2)CC1
Temperature: 25 °C
Yield: 88 %

Procedure:
To 5-(Benzyloxy)-1-(phenylsulfonyl)-1H-indole-4-carbaldehyde, Intermediate 62 205 mg (0.52 mmol) in dichloroethane[DCE] (10 mL) were added BOC-piperazine, 137 mg (0.74 mmol), NaBH(OAc)3, 333 mg (1.6 mmol) and HOAc, 45 mg (0.8 mmol) and the mixture was stirred at room temperature in sealed test tube over night. Water was added, the phases were separated and the dried (MgSO4) organic phase was evaporated at reduced pressure and the black residue was chromatographed on a column of silica with CHCl3 100% as eluent to yield 260 mg (88%) of a blackish oil. MS (ESI+) for C31H35N3O5S m/z 562 (M+H)+.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1([CH3:27])[O:9][CH:8]([C:10]([NH:12][CH2:13][CH2:14][C:15]([O:17]CC2C=CC=CC=2)=[O:16])=[O:11])[C:7]([CH3:26])([CH3:25])[CH2:6][O:5]1>CO>[CH3:3][C:4]1([CH3:27])[O:9][CH:8]([C:10]([NH:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[O:11])[C:7]([CH3:26])([CH3:25])[CH2:6][O:5]1
Reactant: CC1(C)OCC(C)(C)C(C(=O)NCCC(=O)OCc2ccccc2)O1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1(C)OCC(C)(C)C(C(=O)NCCC(=O)O)O1
Reaction time: 1 h
Yield: 78.5 %

Procedure:
An aqueous 1N sodium hydroxide solution (100 ml) was added to a solution 35 g of benzyl 3-[N-(2,2,5,5-Tetramethyl-1,3-dioxane-4-carbonyl)amino]propionate in 350 ml of methanol, and the mixture was stirred under ice cooling for 1 hour. After completion of the reaction, methanol was distilled off under reduced pressure. The aqueous layer was extracted with ethyl acetate. After adding 1N hydrochloric acid to the aqueous layer to render it acidic, the aqueous layer was extracted with ethyl acetate. The organic layer washed with water and then with saturated saline, and dried over anhydrous sodium sulfate. Removal of the solvent by evapoation afforded 20.4 g of the objective compound (yield: 78%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:10]([CH2:13][CH2:14][O:15][C:16](=[O:37])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][NH:22][C:23](=[O:36])[CH2:24][O:25][C:26]2[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=2)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH3:38][C:39]1[C:40]([CH2:51][S:52]([C:54]2[NH:58][C:57]3[CH:59]=[CH:60][CH:61]=[CH:62][C:56]=3[N:55]=2)=[O:53])=[N:41][CH:42]=[CH:43][C:44]=1[O:45][CH2:46][C:47]([F:50])([F:49])[F:48].[H-].[Na+].O>C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[C:6]([S:10]([CH2:13][CH2:14][O:15][C:16](=[O:37])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][NH:22][C:23](=[O:36])[CH2:24][O:25][C:26]2[CH:31]=[CH:30][C:29]([S:32]([N:55]3[C:56]4[CH:62]=[CH:61][CH:60]=[CH:59][C:57]=4[N:58]=[C:54]3[S:52]([CH2:51][C:40]3[C:39]([CH3:38])=[C:44]([O:45][CH2:46][C:47]([F:48])([F:49])[F:50])[CH:43]=[CH:42][N:41]=3)=[O:53])(=[O:34])=[O:33])=[CH:28][CH:27]=2)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: Cc1c(OCC(F)(F)F)ccnc1CS(=O)c1nc2ccccc2[nH]1
Reactant: O=C(COc1ccc(S(=O)(=O)Cl)cc1)NCCCCCC(=O)OCCS(=O)(=O)c1cccc([N+](=O)[O-])c1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Cc1c(OCC(F)(F)F)ccnc1CS(=O)c1nc2ccccc2n1S(=O)(=O)c1ccc(OCC(=O)NCCCCCC(=O)OCCS(=O)(=O)c2cccc([N+](=O)[O-])c2)cc1
Reaction time: 2 h
Yield: 92.9 %

Procedure:
6-[2-(4-chlorosulfonyl-phenoxy)-acetylamino]-n-hexanoic acid 2-(3-nitro-benzenesulfonyl)ethyl ester (Intermediate 19, 1.0 g, 1.73 mmol, 1.27 eq) in CH2Cl2 (5 mL) was added to a heterogeneous mixture of 2-[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-ylmethanesulfinyl]-1H-benzimidazole (500 mg, 1.36 mmol) in CH2Cl2 (10 mL) and NaH (40 mg, 1.65 mmol) at room temperature, and the mixture was stirred for 2 h. Thereafter water was added, the mixture was extracted with CH2Cl2, and the organic layers were dried and concentrated under reduced pressure. The residual oil was purified by column chromatography (CH2Cl2 to 3% MeOH in CH2Cl2) to yield 6-[2-(4-{2-[3-methyl-4-(2,2,2-trifluoro-ethoxy)-pyridin-2-ylmethanesulfinyl]-benzimidazole-1-sulfonyl}-phenoxy)acetylamino]hexanoic acid 2-(3-nitrobenzenesulfonyl)ethyl ester (Intermediate 20, 1.15 g, 94%) as an off-white foam.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[NH:16][C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)[CH2:4][CH2:3]1.[CH2:17]([O:19][CH2:20][CH2:21]Cl)[CH3:18]>>[CH2:17]([O:19][CH2:20][CH2:21][N:16]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:10]2[N:9]=[C:8]1[CH:5]1[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]1)[CH3:18]
Reactant: CN1CCC(c2nc3cccnc3[nH]2)CC1
Reactant: CCOCCCl
Product: CCOCCn1c(C2CCN(C)CC2)nc2cccnc21

Procedure:
Operation is carried out similarly to the above description with the difference that 2-(1-methylpiperidin-4-yl)-3H-imidazo [4,5-b] pyridine is reacted with 2-ethoxyethyl chloride to obtain 3-(2-ethoxyethyl)-2-(1-methylpiperidin-4-yl)-3H-imidazo [4,5-b] pyridine which is isolated as hemitrifumarate melting at 157°-158° C. (ethyl alcohol).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][NH:6][N:5]=1)[CH3:2].Cl[CH2:17][C:18]1[CH:36]=[CH:35][C:21]([O:22][CH:23]2[CH2:28][CH2:27][N:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)[CH2:25][CH2:24]2)=[CH:20][CH:19]=1.CN(C)C=O.[H-].[Na+]>O>[CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][N:6]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([O:22][CH:23]3[CH2:28][CH2:27][N:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=4)[CH2:25][CH2:24]3)=[CH:35][CH:36]=2)[N:5]=1)[CH3:2]
Reactant: CCOC(=O)CCc1c[nH]nc1OCC
Reactant: ClCc1ccc(OC2CCN(c3ccccn3)CC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1cn(Cc2ccc(OC3CCN(c4ccccn4)CC3)cc2)nc1OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.4 %

Procedure:
To a mixture of ethyl 3-(3-ethoxy-1H-pyrazol-4-yl]propionate (318 mg), 2-[4-(4-chloromethylphenoxy)piperidine-1-yl]pyridine (404 mg), and N,N-dimethylformamide (10 ml), sodium hydride (60%, oily, 60.0 mg) was added at 0° C., and then the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with water, then, with saturated aqueous sodium chloride solution, and dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3-[3-ethoxy-1-[4-[1-(2-pyridyl)piperidine-4-yloxy]benzyl]-1H-pyrazol-4-yl]propionate (609 mg, yield: 85%) was obtained as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([O:13]C)=[O:12])=[CH:7][C:6]=1[Cl:15])=[O:4].CO.O.[OH-].[Li+].Cl>O.O1CCCC1>[Cl:15][C:6]1[CH:7]=[C:8]([CH:9]=[CH:10][C:5]=1[C:3]([O:2][CH3:1])=[O:4])[C:11]([OH:13])=[O:12]
Reactant: COC(=O)c1ccc(C(=O)OC)c(Cl)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(=O)O)cc1Cl
Temperature: 45 °C
Reaction time: 0.17 h
Yield: 55.5 %

Procedure:
To a 2 L round-bottom flask, equipped with a mechanical stirrer, was charged 2-chloro-1,4-benzenedicarboxylic acid dimethyl ester (25.15 g, 0.11 mol), methanol (300 mL) and tetrahydrofuran (300 mL). Over 10 min, a solution of lithium hydroxide monohydrate (4.62 g, 0.11 mol) in water (200 mL) was added. After the reaction had proceeded at ambient temperature overnight, the solution was concentrated in vacuo to about 150 mL and then diluted with water (200 mL). The precipitated solid was filtered off and washed with water (2×20 mL) to give the recovered starting material, 2-chloro-1,4-benzenedicarboxylic acid dimethyl ester (1.8 g), as shiny platelets. The combined filtrates were stirred while 1N hydrochloric acid (112 mL, 0.112 mol) was added. The resulting solid was filtered off, washed with water (2×50 mL) and air dried. The solid was dissolved in methanol (300 mL) and warmed to about 45° C., then to the stirred solution, water was added to just before the cloud point. After the solution was left at room temperature overnight, the resulting colorless solid that had formed was filtered off, washed in turn with a cold mixture of methanol-water (1:2; 30 mL) and cold water (30 mL). The solid was recrystallized once more from methanol-water as described above and dried, to give 3-chloro-4-(methoxycarbonyl)benzoic acid (13.1 g, 55.5% yield) as colorless needles.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:7]([N:31]2[N:40]=[CH:39][C:38]3[C:33](=[C:34]([F:45])[CH:35]=[C:36]([C:41]([CH3:44])([CH3:43])[CH3:42])[CH:37]=3)[C:32]2=[O:46])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:28]=[C:22]3[CH:23]([CH3:27])[O:24][CH2:25][CH2:26][N:21]3[N:20]=2)[C:15](=[O:29])[N:14]([CH3:30])[CH:13]=1)(=O)C.[OH-].[Li+].C(O)(C)C.C1COCC1>O>[C:41]([C:36]1[CH:37]=[C:38]2[C:33](=[C:34]([F:45])[CH:35]=1)[C:32](=[O:46])[N:31]([C:7]1[C:6]([CH2:5][OH:4])=[C:11]([C:12]3[CH:17]=[C:16]([NH:18][C:19]4[CH:28]=[C:22]5[CH:23]([CH3:27])[O:24][CH2:25][CH2:26][N:21]5[N:20]=4)[C:15](=[O:29])[N:14]([CH3:30])[CH:13]=3)[CH:10]=[CH:9][N:8]=1)[N:40]=[CH:39]2)([CH3:42])([CH3:43])[CH3:44]
Reactant: CC(=O)OCc1c(-c2cc(Nc3cc4n(n3)CCOC4C)c(=O)n(C)c2)ccnc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)O
Product: CC1OCCn2nc(Nc3cc(-c4ccnc(-n5ncc6cc(C(C)(C)C)cc(F)c6c5=O)c4CO)cn(C)c3=O)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 15.1 %

Procedure:
A 25-mL round-bottomed flask equipped with a magnetic stirrer was charged with 150i (48 mg, 1.0 eq., 0.077 mmol), lithium hydroxide (9.2 mg, 5.0 eq., 0.38 mmol), i-propanol/THF (4/4 mL), and water (1 mL). The mixture was stirred at room temperature for 1 h and concentrated under reduced pressure. The residue was purified by reverse-phase prep-HPLC to afford 150 as a yellow solid (6.8 mg, 15%). MS-ESI: [M+H]+ 585.8. 1H NMR (500 MHz, CDCl3) δ 8.66 (d, J=4.5 Hz, 1H), 8.35 (d, J=2.0 Hz, 1H), 8.03 (d, J=1.5 Hz, 1H), 7.59-7.53 (m, 4H), 7.47 (s, 1H), 5.72 (s, 1H), 4.82-4.78 (m, 1H), 4.52-4.49 (m, 2H), 4.33-4.30 (m, 1H), 4.30-4.27 (m, 1H), 4.02-3.98 (m, 3H), 3.73 (s, 3H), 1.54 (d, J=7.0 Hz, 3H), 1.48 (s, 9H).