Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:13]2[C:5](=[CH:6][CH:7]=[C:8]3[C:12]=2[CH:11]=[N:10][NH:9]3)[CH:4]=[C:3]1[C:14]([OH:16])=O.C[N:18](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[OH-].[NH4+].O>C(#N)C.C(N(CC)CC)C>[CH3:1][N:2]1[C:13]2[C:5](=[CH:6][CH:7]=[C:8]3[C:12]=2[CH:11]=[N:10][NH:9]3)[CH:4]=[C:3]1[C:14]([NH2:18])=[O:16]
Reactant: Cn1c(C(=O)O)cc2ccc3[nH]ncc3c21
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: [NH4+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC#N
Product: Cn1c(C(N)=O)cc2ccc3[nH]ncc3c21
Temperature: 25 °C
Reaction time: 2 h
Yield: 10 %

Procedure:
To a solution of 1-methyl-1,6-dihydro-1,6,7-triaza-as-indacene-2-carboxylic acid D2 (0.46 mmol) in dry acetonitrile (6 mL) and triethylamine (0.13 mL), first TBTU (2 eq) and, after 10 min, 30% aq ammonium hydroxide solution (2 eq) were added under stirring at rt. After 2 h at rt, the mixture was poured into water and the slurry was extracted with AcOEt. The organic layer was washed with brine, dried (Na2SO4) and concentrated to yield a crude product that was purified by chromatography on silica gel (eluant: MeOH/DCM 1:9). Obtained the title compound (10%). ESI (+) MS: m/z 215 (MH+). 1H NMR: 4.36 (s, 3H), 6.95 (bs, 2H), 7.29 (s, 1H), 7.31 (d, J=8.73, 1H), 7.58 (d, J=8.73, 1H), 8.73 (s, 1H), 13.32 (s, 1H).
Reaction SMILES: [CH3:1][CH:2]([O:5][C:6]1[CH:17]=[CH:16][C:9]([O:10][CH2:11][CH:12]([OH:15])[CH2:13][OH:14])=[CH:8][CH:7]=1)[CH2:3][CH3:4].[CH3:18][C:19]([CH3:21])=O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[CH3:18][C:19]1([CH3:21])[O:15][CH:12]([CH2:11][O:10][C:9]2[CH:16]=[CH:17][C:6]([O:5][CH:2]([CH3:1])[CH2:3][CH3:4])=[CH:7][CH:8]=2)[CH2:13][O:14]1
Reactant: CCC(C)Oc1ccc(OCC(O)CO)cc1
Reactant: CC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CCC(C)Oc1ccc(OCC2COC(C)(C)O2)cc1

Procedure:
A mixture of 3-[4-(1-methylpropoxy)phenoxy]-1,2-propanediol (1.0 g, 4.2 mmol), acetone (0.24 g, 4.2 mmol) and p-toluenesulfonic acid (0.03 g) in 20 ml of petroleum ether is heated under reflux for 7 hours. Water generated from the reaction is removed. The final solution is concentrated to remove the solvent and the product is purified by column chromatography to give 2,2-dimethyl-4-[4-(1-methylpropoxy)phenoxymethyl]-1,3-dioxolane, MS m/e 280 (M+).
Reaction SMILES: C(O)(C(F)(F)F)=O.[C:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[N:18][N:19]([C:22]3[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][N:23]=3)[C:20]=2[OH:21])=[C:12]([CH3:31])[CH:11]=1)#[N:9].[CH3:32][N:33]1[CH2:37][CH2:36][CH2:35][CH:34]1[CH2:38][CH2:39][NH2:40]>>[C:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[N:18][N:19]([C:22]3[CH:30]=[CH:29][C:25]([C:26]([NH:40][CH2:39][CH2:38][CH:34]4[CH2:35][CH2:36][CH2:37][N:33]4[CH3:32])=[O:27])=[CH:24][N:23]=3)[C:20]=2[OH:21])=[C:12]([CH3:31])[CH:11]=1)#[N:9]
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Reactant: CN1CCCC1CCN
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)NCCC3CCCN3C)cn2)c1O

Procedure:
The title compound, as a TFA salt, was prepared in a manner similar to Example 74 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and 2-(1-methylpyrrolidin-2-yl)ethanamine. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.60-1.83 (m, 2H) 1.83-2.08 (m, 2H) 2.18 (dd, J=12.88, 4.29 Hz, 1H) 2.27-2.41 (m, 1H) 2.44 (s, 3H) 2.84 (d, J=3.54 Hz, 3H) 3.08 (br. s., 1H) 3.29 (br. s., 1H) 3.40 (q, J=6.57 Hz, 2H) 3.58 (d, J=4.29 Hz, 1H) 7.67 (d, J=7.58 Hz, 1H) 7.70-7.89 (m, 2H) 8.20 (br. s., 1H) 8.42 (br. s., 1H) 8.50-8.71 (m, 1H) 8.84 (br. s., 1H) 8.89-8.95 (m, 1H) 9.53 (br. s., 1H) 12.81-13.56 (m, 1H). MS m/z [M+H]+ 431.2.
Reaction SMILES: [O:1]([C@H:8]([CH3:11])[CH2:9][NH2:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:20][C@@H:21]1[C@H:25]([O:26]C(=O)C2C=CC=CC=2)[C@@H:24]([CH2:35][O:36]C(=O)C2C=CC=CC=2)[O:23][C@H:22]1[N:45]1[CH:53]=[N:52][C:51]2[C:46]1=[N:47][C:48]([Cl:55])=[N:49][C:50]=2Cl)(=O)C1C=CC=CC=1.C(N(CC)CC)C>O1CCOCC1>[Cl:55][C:48]1[N:49]=[C:50]([NH:10][CH2:9][C@H:8]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH3:11])[C:51]2[N:52]=[CH:53][N:45]([C:46]=2[N:47]=1)[C@@H:22]1[O:23][C@H:24]([CH2:35][OH:36])[C@@H:25]([OH:26])[C@H:21]1[OH:20]
Reactant: O=C(OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Reactant: C[C@H](CN)Oc1ccccc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: C[C@H](CNc1nc(Cl)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O)Oc1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 66.9 %

Procedure:
(R)-2-Phenoxy-1-propylamine (0.6 g, 2.9 mmol)(prepared by the method described in example 2) was reacted with 9-(2,3,5-tri- O-benzoyl-β-D-ribofuranosyl)-2,6-dichloro-9H-purine (1.5 g, 2.4 mmol) in dioxan (20 ml) in the presence of triethylamine (0.5 g, 5.3 mmol). The reaction mixture was stirred at room temperature for 72 h before being filtered and evaporated. The product, following purification by flash chromatography, was treated with saturated methanolic ammonia (30 ml) for 18 h and evaporated to provide a solid residue. This solid was washed thoroughly with dichloromethane to provide the title 2-chloro- N-[(R)-2-phenoxy-1-propyl]adenosine (0.7 g, 65%), mp 175°-177° C., 1H NMR (DMSO-d6)δ 1.39 (3H, d, --CH3), 3.56 (1H, ABX, H-5'a), 3.68 (1H, m, H-5'b), 3.33-3.40 (1H, m, --C--H), 3.83-3.92 (1H, --C--H), 3.96 (1H, q, H-4'), 4.14 (1H, m, H-3'), 4.53 (1H, dd, H-2'), 4.70 (1H, q, --C--H), 5.08, 5.34, 5.50 (3H, 3 br, 2', 3' and 5'-OH), 5.85 (1H, d, H-1'), 6.90 (1H, t, Ar--H), 7.11 (2H, d, Ar--H), 7.28 (2H, t, Ar--H), 8.45 (1H, s, H-8), 8.63 (1H, t, N--H).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][C:7](=[O:12])[N:8]2[CH3:11])=[CH:4][N:3]=1.N12CCN(CC1)CC2.[N:21]1([C:26](Cl)=[O:27])[CH2:25][CH2:24][CH2:23][CH2:22]1.O>CN(C)C=O>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]([C:26]([N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[O:27])[C:7](=[O:12])[N:8]2[CH3:11])=[CH:4][N:3]=1
Reactant: O=C(Cl)N1CCCC1
Reactant: Cn1c(=O)[nH]c2cnc(Cl)nc21
Agent: C1CN2CCN1CC2
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(=O)n(C(=O)N2CCCC2)c2cnc(Cl)nc21
Reaction time: 1 h

Procedure:
To a solution of 2-chloro-9-methyl-7,9-dihydro-8H-purine-8-one <the compound of Reference Example 1> (3.0 g) in N,N-dimethylformamide (50 ml) were added 1,4-diazabicyclo[2.2.2]octane (5.5 g) and 1-pyrrolidine carbonyl chloride (2.7 ml) and the mixture was stirred for 1 hour. The reaction mixture was poured into cold water and the crystals precipitated were collected by filtration to give the title compound 3.0 g.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=O)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18].C(O)(=O)C>C1(C)C=CC=CC=1>[Br:8][C:6]1[CH:5]=[CH:4][C:3]2[NH:9][C:10]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])=[N:1][C:2]=2[CH:7]=1
Reactant: COC(=O)CCCCCCC(=O)Nc1ccc(Br)cc1N
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: COC(=O)CCCCCCc1nc2cc(Br)ccc2[nH]1
Temperature: 110 °C
Yield: 84.3 %

Procedure:
To a solution of methyl 8-(2-amino-4-bromophenylamino)-8-oxooctanoate (140 mg, 0.395 mmol) in toluene was added a drop of acetic acid. The reaction was heated to 110° C. overnight and concentrated. The residue was purified by biotage column chromatography to give methyl 7-(5-bromo-1H-benzimidazol-2-yl)heptanoate (113 mg)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][CH:21]=2)[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=O)=[C:4]([CH3:30])[CH:3]=1.Cl.[NH2:32][OH:33].C(=O)([O-])O.[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:21]=[CH:22][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:24][CH:25]=2)[CH2:9]/[C:10](/[C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=[N:32]\[OH:33])=[C:4]([CH3:30])[CH:3]=1
Reactant: Cc1cc(Cl)ccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(S(C)(=O)=O)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(Cl)ccc1C(C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(S(C)(=O)=O)cc1

Procedure:
In analogy to example 151, step 3, 5-(3-(4-chloro-2-methylphenyl)-3-(4-(methylsulfonyl)phenyl)propanoyl)-1-methylpyridin-2(1H)-one was reacted with hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate to give the title compound as a colourless foam, MS (ESI+): m/z=459.2 [M+H]+.
Reaction SMILES: O[CH2:2][CH:3]([CH:6]([CH3:14])[CH2:7][CH:8]([CH3:13])[CH2:9][CH:10]([CH3:12])[CH3:11])[C:4]#[N:5].N12CCCN=C1CCCCC2.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(Cl)Cl>[CH2:2]=[C:3]([CH:6]([CH3:14])[CH2:7][CH:8]([CH3:13])[CH2:9][CH:10]([CH3:12])[CH3:11])[C:4]#[N:5]
Reactant: CC(C)CC(C)CC(C)C(C#N)CO
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: C=C(C#N)C(C)CC(C)CC(C)C
Temperature: 0 °C
Reaction time: 16 h
Yield: 89.2 %

Procedure:
A 250 ml three-neck round-bottom flask which is dry and is purged with nitrogen is charged in succession with 19.7 g of the cyano alcohol (VII) (0.1 mol), 150 ml of anhydrous methylene chloride, and then 18.26 g (0.11 mol) of DBU (1,8-diazabicyclo[5.4.0]undec-7-ene). The solution is cooled to 0° C. and then 22.05 g (0.105 mol) of trifluoroacetic anhydride are added dropwise, without 5° C. being exceeded in the mass. The resulting solution is stirred at ambient temperature for 16 hours and then hydrolyzed, dried, and concentrated. The residue is distilled under vacuum (6 torr) to give 16 g of unsaturated nitrile (VIII), which distills at 105-108° C. The yield is 89%.
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([S:9](Cl)(=[O:11])=[O:10])=[C:4]([F:13])[CH:3]=1.[CH:14]1([NH2:17])[CH2:16][CH2:15]1>ClCCl>[Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([S:9]([NH:17][CH:14]2[CH2:16][CH2:15]2)(=[O:11])=[O:10])=[C:4]([F:13])[CH:3]=1
Reactant: NC1CC1
Reactant: O=S(=O)(Cl)c1cc(F)c(Br)cc1F
Solvent: ClCCl
Product: O=S(=O)(NC1CC1)c1cc(F)c(Br)cc1F

Procedure:
According to general procedure C, 4-Bromo-2,5-difluorobenzenesulfonyl chloride (0.20 g, 0.68 mmol) and cyclopropylamine were stirred together in dichloromethane (1 mL) for 16 hours. The reaction afforded 4-bromo-N-cyclopropyl-2,5-difluorobenzenesulfonamide (0.17 g) after purification. HPLC purity 99.2% at 210-370 nm, 10.2 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min. HRMS: calcd for C9H8BrF2NO2S−H+, 309.93544; found (ESI-FTMS, [M−H]1−), 309.93545
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]=[C:21]3[C:17]([N:18]=[C:19]([C:23]4[C:24](=[O:40])[NH:25][CH:26]=[CH:27][C:28]=4[NH:29][CH2:30][C@H:31]([C:33]4[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[CH:34]=4)[OH:32])[NH:20]3)=[C:16]([CH3:41])[N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>C(Cl)Cl>[Cl:39][C:35]1[CH:34]=[C:33]([C@H:31]([OH:32])[CH2:30][NH:29][C:28]2[CH:27]=[CH:26][NH:25][C:24](=[O:40])[C:23]=2[C:19]2[NH:20][C:21]3[C:17]([N:18]=2)=[C:16]([CH3:41])[N:15]=[C:14]([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[N:22]=3)[CH:38]=[CH:37][CH:36]=1
Reactant: Cc1nc(N2CCN(C(=O)OC(C)(C)C)CC2)nc2[nH]c(-c3c(NC[C@@H](O)c4cccc(Cl)c4)cc[nH]c3=O)nc12
Solvent: ClCCl
Product: Cc1nc(N2CCNCC2)nc2[nH]c(-c3c(NC[C@@H](O)c4cccc(Cl)c4)cc[nH]c3=O)nc12
Temperature: 23 °C
Reaction time: 16 h

Procedure:
To a solution of 4-(8-{4-[2-(3–Chloro-phenyl)-2(S)-hydroxy-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-methyl-9H-purin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester (72 mg, 0.124 mmol) in CH2Cl2 (30 mL) was added benzenesulfonyl fonctionalized silica gel, 0.79 meq/g (7.2 g). The heterogeneous mixture was stirred at 23° C. for 16 hours. The solvent was removed by filtration and the silica gel was washed with a mixture of ammonia 2N in MeOH:CH2Cl2 (1:1, 20 mL). The ammoniac solution was evaporated in vacuo to give the title compound as a light yellow solid. (0.053 g, 89%). HPLC 98%; LCMS (+ESI, M+H+) m/z 481; IR (KBr, cm−1) 3262, 2922, 1646, 1597, 1489, 1232; 1H NMR (400 MHz, DMSO+D2O) δ 10.80 (br s, 1H), 7.59–7.29 (m, 5H), 6.23 (d, J=8.2 Hz, 1H), 5.00 (br t, 1H), 3.75 (br s, 4H), 3.62 (m, 1H), 2.89 (br s, 4H), 2.60 (s, 3H); HRMS calcd for C23H25ClN8O2: 480.1789; found 480.1804.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:7][C:8]1([CH3:45])[CH2:13][N:12]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[CH3:21])[C:11](=[O:22])[CH2:10][N:9]1[CH2:23][C@H:24]([NH:32]S(C1C=CC=CC=1[N+]([O-])=O)(=O)=O)[C@@H:25]1[CH2:29][C@@H:28]([CH3:30])[C:27](=[O:31])[O:26]1.C1(S)C=CC=CC=1.C(=O)(O)[O-].[Na+].[C:58](OC(OC(C)(C)C)=O)([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59].N[C@H]([C@@H]1C[C@@H](C)C(=O)O1)CN1C(C)(C)CN(C2C=C(F)C=CC=2C)C(=O)C1>C(#N)C.[Cl-].[Na+].O.C(OCC)(=O)C.O>[C:61]([O:60][C:58](=[O:59])[NH:32][C@H:24]([C@@H:25]1[CH2:29][C@@H:28]([CH3:30])[C:27](=[O:31])[O:26]1)[CH2:23][N:9]1[CH2:10][C:11](=[O:22])[N:12]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[CH3:21])[CH2:13][C:8]1([CH3:7])[CH3:45])([CH3:64])([CH3:63])[CH3:62]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: Cc1ccc(F)cc1N1CC(C)(C)N(C[C@H](NS(=O)(=O)c2ccccc2[N+](=O)[O-])[C@@H]2C[C@@H](C)C(=O)O2)CC1=O
Agent: Cc1ccc(F)cc1N1CC(C)(C)N(C[C@H](N)[C@@H]2C[C@@H](C)C(=O)O2)CC1=O
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Cc1ccc(F)cc1N1CC(C)(C)N(C[C@H](NC(=O)OC(C)(C)C)[C@@H]2C[C@@H](C)C(=O)O2)CC1=O
Reaction time: 2 h
Yield: 82.1 %

Procedure:
966 mg of cesium carbonate (2.96 mmol) was added to a solution of 1.39 g of N-{(S)-2-[2,2-dimethyl-4-(5-fluoro-2-methylphenyl)-5-oxopiperazin-1-yl]-1-[(2S,4R)-4-methyl-5-oxotetrahydrofuran-2-yl]ethyl}-2-nitrobenzenesulfonamide obtained in Example (101a) (2.47 mmol) and 0.53 ml of thiophenol (content: 95%) (4.94 mmol) in acetonitrile (12 ml) under a nitrogen atmosphere at room temperature, and the mixture was stirred at the same temperature for two hours. Brine was added to the reaction mixture, followed by extraction with methylene chloride. Then, the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:methylene chloride/methanol=20/1-10/1). 213 mg of sodium bicarbonate (2.53 mmol) and 553 mg of di-t-butyl dicarbonate (2.53 mmol) were added to a solution of the resulting 4-{(S)-2-amino-2-[(2S,4R)-4-methyl-5-oxotetrahydrofuran-2-yl]ethyl}-5,5-dimethyl-1-(5-fluoro-2-methylphenyl)piperazin-2-one in ethyl acetate (10 ml)-water (10 ml), and the mixture was stirred at room temperature for 2.5 hours. Brine was added to the reaction mixture, followed by extraction with ethyl acetate. Then, the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:methylene chloride/ethyl acetate=2/1) to obtain 968 mg of the title compound (yield: 82%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([S:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][C:25]([C:32]([O:34]CC)=[O:33])([CH3:31])[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:18]([Cl:37])[CH:17]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].Cl>C(O)C.O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([S:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])([CH3:31])[C:32]([OH:34])=[O:33])=[C:18]([Cl:37])[CH:17]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C)(CCCc1ccc(Sc2cccc(OCc3ccccc3)c2)cc1Cl)C(=O)OCC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(C)(CCCc1ccc(Sc2cccc(OCc3ccccc3)c2)cc1Cl)C(=O)O
Temperature: 50 °C
Reaction time: 8 h
Yield: 91.6 %

Procedure:
The compound of Example 152 (2.74 g) was dissolved in ethanol (10 mL). To this solution, potassium hydroxide (330 mg) was added and the mixture was stirred at 50° C. overnight. Subsequently, the reaction mixture was diluted with water. 2 mol/L hydrochloric acid was then added and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride and the organic phase was dried over anhydrous magnesium sulfate and was concentrated. The residue was purified on a silica gel column chromatography (hexane:ethyl acetate=10:1 shifted to 2:1) to give the desired product as a yellow oil (2.38 g).
Reaction SMILES: CO.Cl.[NH2:4][C:5]1[N:17]=[C:8]2[CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=[CH:12][N:7]2[N:6]=1.[H][H]>[Pt](=O)=O.C(Cl)Cl>[NH2:4][C:5]1[N:17]=[C:8]2[CH2:9][CH:10]([C:13]([O:15][CH3:16])=[O:14])[CH2:11][CH2:12][N:7]2[N:6]=1
Reactant: COC(=O)c1ccn2nc(N)nc2c1
Reactant: [H][H]
Agent: O=[Pt]=O
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: COC(=O)C1CCn2nc(N)nc2C1
Yield: 107.7 %

Procedure:
Platinum(IV) oxide (3 g) was added to a mixed solution of methanol (200 ml), methylene chloride (200 ml), and concentrated hydrochloric acid (3.9 ml) containing the methyl 2-amino-[1,2,4]triazolo[1,5-a]pyridine-7-carboxylate (3.0 g) obtained in (Example 5.16) <Step 1>. The obtained mixture was stirred in a hydrogen atmosphere for 66 hours at room temperature. Thereafter, the reaction solution was filtered with Celite, and was then washed with methanol (80 ml). The filtrate was combined with the washing solution, and the thus mixed solution was then concentrated under reduced pressure. The obtained residue was subjected to azeotropy with methanol (20 ml) four times, so as to obtain the title compound (3.3 g) in the form of a light brown solid.
Reaction SMILES: NC1SC2C=CC=CC=2C=1C(OCC)=O.ClC1C=CC(Cl)=CC=1[N+]([O-])=O.[Cl:27][C:28]1[CH:48]=[CH:47][C:31]([NH:32][C:33]2[S:37][C:36]3[CH:38]=[CH:39][CH:40]=[CH:41][C:35]=3[C:34]=2[C:42]([O:44][CH2:45][CH3:46])=[O:43])=[C:30]([N+:49]([O-])=O)[CH:29]=1.Cl.O.O.[Sn](Cl)Cl>C(O)C.CS(C)=O>[NH2:49][C:30]1[CH:29]=[C:28]([Cl:27])[CH:48]=[CH:47][C:31]=1[NH:32][C:33]1[S:37][C:36]2[CH:38]=[CH:39][CH:40]=[CH:41][C:35]=2[C:34]=1[C:42]([O:44][CH2:45][CH3:46])=[O:43]
Reactant: CCOC(=O)c1c(Nc2ccc(Cl)cc2[N+](=O)[O-])sc2ccccc12
Agent: CCOC(=O)c1c(N)sc2ccccc12
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CS(C)=O
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1c(Nc2ccc(Cl)cc2N)sc2ccccc12

Procedure:
In the same manner as in Starting Material Synthesis Example 4 and using ethyl 2-aminobenzo[b]thiophene-3-carboxylate (6.0 g), 2,5-dichloronitrobenzene (5.8 g) and dimethyl sulfoxide (70 ml), crude crystals (9.5 g) of ethyl 2-(4-chloro-2-nitroanilino)benzo[b]thiophene-3-carboxylate were obtained. Without purification, in the same manner as in Starting Material Synthesis Example 21 and using ethanol (100 ml), 18% hydrochloric acid (100 ml) and tin(II) chloride dihydrate (22.5 g), ethyl 2-(2-amino-4-chloroanilino)benzo[b]thiophene-3-carboxylate (3.0 g) was obtained.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:15])=[C:5]([C:11]([Cl:14])=[CH:12][CH:13]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7].[C:16](Cl)(=[O:20])[CH:17]([CH3:19])[CH3:18].CCN(C(C)C)C(C)C>C1COCC1>[Cl:14][C:11]1[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([F:15])[C:3]([CH2:2][NH:1][C:16](=[O:20])[CH:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=1
Reactant: CCOC(=O)c1c(Cl)ccc(CN)c1F
Reactant: CC(C)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1c(Cl)ccc(CNC(=O)C(C)C)c1F
Yield: 76.7 %

Procedure:
The title compound was prepared following the procedure described in Intermediate-2, step-2 using ethyl 3-(aminomethyl)-6-chloro-2-fluorobenzoate (Intermediate-2, step-1, 1.00 g, 4.32 mmol), isobutyryl chloride (690 mg, 6.48 mmol) and DIPEA (1.67 g, 12.96 mmol) in THF (30 mL) to afford 1.0 g of the title product.
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]1([CH3:20])[CH2:11][O:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:13]=2[CH3:19])=[N:8]1.Cl[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([CH3:31])[CH:24]=1>C1COCC1>[CH3:30][O:29][C:26]1[CH:27]=[CH:28][C:23]([CH2:22][CH2:19][C:13]2[CH:14]=[C:15]([CH3:18])[CH:16]=[CH:17][C:12]=2[C:9]2[O:10][CH2:11][C:7]([CH3:20])([CH3:6])[N:8]=2)=[CH:24][C:25]=1[CH3:31]
Reactant: COc1ccc(CCl)cc1C
Reactant: Cc1ccc(C2=NC(C)(C)CO2)c(C)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(CCc2cc(C)ccc2C2=NC(C)(C)CO2)cc1C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
n-Butyllithium (14.4 ml, 2.5M solution in hexane) was added dropwise to a stirred solution of the product from step (i) (6.9 g) in THF (100 ml) at 0° C. The solution was stirred at 0° C. for 1 hour and then transferred by cannula into a solution of 4-chloromethyl-1-methoxy-2-methylbenzene (J. Chem. Soc. 1956, 2455) (5.86 g) in THF (60 ml) at -30° C. The mixture was stirred for 1 hour and allowed to warm to room temperature. After 30 minutes the reaction was quenched with water. The mixture was partitioned between ethyl acetate and water. The organic phase was washed with water, dried (MgSO4) and evaporated. Purification was by chromatography eluting with 5% ethyl acetate in isohexane. Yield 2.16 g.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:9][C:10]([C:12]2[C:17]([NH:18]C3C=NC=CC=3)=[CH:16][CH:15]=[C:14]([CH3:25])[N:13]=2)=[O:11])=[N:6][C:7]=1[CH3:8].Br[C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[C:29]([F:34])[CH:28]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:9][C:10]([C:12]2[C:17]([NH:18][C:27]3[CH:32]=[C:31]([F:33])[CH:30]=[C:29]([F:34])[CH:28]=3)=[CH:16][CH:15]=[C:14]([CH3:25])[N:13]=2)=[O:11])=[N:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(Nc2cccnc2)c(C(=O)Nc2ccc(F)c(C)n2)n1
Reactant: Fc1cc(F)cc(Br)c1
Product: Cc1ccc(Nc2cc(F)cc(F)c2)c(C(=O)Nc2ccc(F)c(C)n2)n1

Procedure:
The title compound, was prepared from 3-Amino-6-methyl-pyridine-2-carboxylic acid (5-fluoro-6-methyl-pyridin-2-yl)-amide (example 11) in accordance with the general method of example 20 using 1-Bromo-3,5-difluorobenzene instead of 3-Bromo-4-methylpyridine to yield the final compound as a light yellow crystalline solid, MS (ISP): m/e=373.1 (M+H+).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:32])[CH2:15][NH:16][C:17](=[O:31])[C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:20][CH:19]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[O:32]=[C:14]([N:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)[CH2:15][NH:16][C:17](=[O:31])[C:18]1[CH:19]=[CH:20][C:21]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:22][CH:23]=1
Reactant: O=C(NCC(=O)N1CCN(Cc2ccccc2)CC1)c1ccc(Oc2ccccc2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: O=C(NCC(=O)N1CCNCC1)c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.8 %

Procedure:
Under an inert atmosphere, 10% Pd/C (111 mg) was added to a stirred solution of N-[2-(4-benzyl-piperazin-1-yl)-2-oxo-ethyl]-4-phenoxy-benzamide (490 mg, 1.14 mmol) in MeOH (90 mL). Hydrogen gas was then passed into the reaction mixture by means of a hydrogen filled bladder and the mixture was stirred at room temperature overnight. The mixture was filtered over celite and the celite was washed with MeOH. The filtrate was collected and concentrated under reduced pressure to afford 390 mg (quantitative yield) of N-(2-Oxo-2-piperazin-1-yl-ethyl)-4-phenoxy-benzamide as a solid. LC-MS purity: 88.65, 1H NMR (CDCl3): δ 7.8 (d, 2H), 7.38 (m, 2H), 7.26 (bs, 1H), 7.18 (tt, 1H), 7.08-7.0 (m, 4H), 4.24 (d, 2H), 3.66 (t, 2H), 3.5 (s, 1H), 3.44 (t, 2H), 2.9 (q, 4H), 2.5-2.6 (m, 1H).