Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C(OC([NH:15][C@H:16]([C@@H:36]([OH:49])[CH2:37][C@H:38]([C:42](=[O:48])[NH:43][CH2:44][CH2:45][CH2:46][CH3:47])[CH:39]([CH3:41])[CH3:40])[CH2:17][C@@H:18]([CH:33]([CH3:35])[CH3:34])[CH2:19][NH:20][C:21](=[O:32])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[O:28]COC)=O)(C)(C)C.C1(C)C=CC=CC=1>ClCCl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:15][C@H:16]([C@@H:36]([OH:49])[CH2:37][C@H:38]([C:42](=[O:48])[NH:43][CH2:44][CH2:45][CH2:46][CH3:47])[CH:39]([CH3:40])[CH3:41])[CH2:17][C@@H:18]([CH:33]([CH3:34])[CH3:35])[CH2:19][NH:20][C:21](=[O:32])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[OH:28]
Reactant: CCCCNC(=O)[C@@H](C[C@H](O)[C@H](C[C@H](CNC(=O)c1ccccc1OCOC)C(C)C)NC(=O)OC(C)(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCCCNC(=O)[C@@H](C[C@H](O)[C@@H](N)C[C@H](CNC(=O)c1ccccc1O)C(C)C)C(C)C

Procedure:
Trifluoroacetic acid (0.5 ml) is added at 0° C., with stirring, to a solution of (2S,4S,5S,7S)-N-[4-(tert-butoxycarbonyl)amino-7-butylcarbamoyl-5-hydroxy-2-isopropyl-8-methyl-nonyl]-2-(methoxymethoxy)-benzamide (46 mg) in dichloromethane (2 ml). When the reaction is complete (after approximately 30 minutes), toluene (2 ml) is added and the reaction mixture is concentrated. The crude product obtained after briefly drying under a high vacuum is purified by FC on 6 g of silica gel (eluant Q), and (2S,4S,5S,7S)-N-(4-amino-7-butylcarbamoyl-5-hydroxy-2-isopropyl-8-methyl-nonyl)-2-hydroxy-benzamide trifluoroacetate is obtained: Rf (W)=0.34. HPLC Rt =12.1 min. MS(FAB) m/e 450 (M+ +1).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]2[NH:6][C:7](=[S:9])[NH:8][C:4]=2[CH:3]=1.Cl.[CH:13]([N:16]([CH:20]([CH3:22])[CH3:21])[CH2:17][CH2:18]Cl)([CH3:15])[CH3:14].C(=O)([O-])O.[Na+]>C(O)C>[CH:13]([N:16]([CH:20]([CH3:22])[CH3:21])[CH2:17][CH2:18][S:9][C:7]1[NH:8][C:4]2[CH:3]=[C:2]([CH3:1])[CH:11]=[CH:10][C:5]=2[N:6]=1)([CH3:15])[CH3:14]
Reactant: Cc1ccc2[nH]c(=S)[nH]c2c1
Reactant: CC(C)N(CCCl)C(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Cc1ccc2nc(SCCN(C(C)C)C(C)C)[nH]c2c1

Procedure:
6.16 g (37.5 mmoles) of 5-methyl-benzimidazoline-2-thione, 9 g (45 mmoles) of 2-(diisopropylamino)-ethylchloride hydrochloride and 3.52 g (41.9 mmoles) of sodium hydrogencarbonate are refluxed in 60 ml of ethanol for 6 hours. After the filtration of the salt and concentration of the filtrate the residue is extracted with dichloromethane and aqueous sodium hydroxide solution as described in Example 2. The aqueous phase is further extracted with dichloromethane, the combined organic phases are concentrated, the residue is recrystallized from 47 ml of ethylacetate. The title product thus obtained weights 6.65 g (61%) and melts at 109°-110° C.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH:7]([CH3:26])[N:8]([C:12]3[CH:17]=[C:16]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[N:15]=[C:14]([NH2:25])[N:13]=3)[CH2:9]2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:35]2[CH2:36][CH2:37][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:39][CH:40]=2)O1.ClCCl.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[NH2:25][C:14]1[N:13]=[C:12]([N:8]2[CH:7]([CH3:26])[CH2:6][C:5]3[C:10](=[CH:11][C:2]([C:35]4[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][CH:36]=4)=[CH:3][CH:4]=3)[CH2:9]2)[CH:17]=[C:16]([N:18]2[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]2)[N:15]=1
Reactant: CC1Cc2ccc(Br)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC1Cc2ccc(C3=CCN(C(=O)OC(C)(C)C)CC3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Temperature: 120 °C
Yield: 59.6 %

Procedure:
A mixture of 4-(7-bromo-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine (0.350 g, 0.839 mmol) (Peak 1, Example 49, Step 7), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (0.311 g, 1.01 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (41.1 mg, 0.0503 mmol), potassium carbonate (0.464 g, 3.35 mmol) in 1,4-dioxane (5.0 mL) and water (2.5 mL) was degassed and recharged with nitrogen three times, and heated at 120° C. for 2 h. The reaction was diluted with ethyl acetate and then washed with water and brine, dried over NaSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column eluted with methanol in DCM (0-10%) to afford the desired product (260 mg, 59.7%). LCMS (M+H)+: m/z=520.4.
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]([O:13]C)=O)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:15][NH2:16]>>[C:1]1([S:7]([CH2:10][C:11]([NH:16][CH3:15])=[O:13])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CN
Reactant: COC(=O)CS(=O)(=O)c1ccccc1
Product: CNC(=O)CS(=O)(=O)c1ccccc1

Procedure:
reacting methyl phenylsulfonylacetate with methylamine to yield 2-benzenesulfonyl-N-methylacetamide;
Reaction SMILES: C([O:8][C:9](=[O:32])[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15](=[O:31])[C@H:16]([CH3:30])[NH:17][C:18](=[O:29])[C@H:19]([CH3:28])[NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])C1C=CC=CC=1.[H][H].C(O)C>C(O)(C)(C)C>[C:21]([NH:20][C@H:19]([C:18]([NH:17][C@H:16]([C:15]([N:11]1[CH2:12][CH2:13][CH2:14][C@H:10]1[C:9]([OH:32])=[O:8])=[O:31])[CH3:30])=[O:29])[CH3:28])([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22]
Reactant: [H][H]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Solvent: CC(C)(C)O
Solvent: CCO
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)O
Temperature: 25 °C
Yield: 97.5 %

Procedure:
A Parr flask was flushed with argon and charged with 10% palladium on charcoal (0.74 g), followed by the addition of Boc-L-alanyl-L-alanyl-L-proline benzyl ester (1.8 g, 4.0 mmol) dissolved in tert-butanol (300 ml). The reaction mixture shaken under 30 psi of hydrogen at 35° C. for 5 hr. After cooling to room temperature, ethanol (50 ml) was added and the solution was filtered through celite and the filtrate concentrated on a rotary evaporator. The residue was azeotroped with chloroform-hexane to remove the last traces of tert-butanol and then dried under high vacuum to give Boc-L-alanyl-L-alanyl-L-proline (1.40 g, 3.9mmol) in 98% yield.
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[N:11][C:10]2[N:9]([CH2:13][CH3:14])[C:8]3[N:15]=[CH:16][C:17]([C:19]#[C:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[CH:18][C:7]=3[C:6](=[O:27])[N:5]([CH3:28])[C:4]=2[C:3]=1[CH3:29]>[Pt]=O>[CH3:1][C:2]1[CH:12]=[N:11][C:10]2[N:9]([CH2:13][CH3:14])[C:8]3[N:15]=[CH:16][C:17]([CH2:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[CH:18][C:7]=3[C:6](=[O:27])[N:5]([CH3:28])[C:4]=2[C:3]=1[CH3:29]
Reactant: CCN1c2ncc(C#Cc3ccccc3)cc2C(=O)N(C)c2c1ncc(C)c2C
Agent: O=[Pt]
Product: CCN1c2ncc(CCc3ccccc3)cc2C(=O)N(C)c2c1ncc(C)c2C

Procedure:
The title compound was prepared by hydrogenation of 5,11-dihydro-3,4-dimethyl-11-ethyl-5-methyl-8-(phenylethynyl)-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one over platinum oxide, as described in Example 42b. The product crystallized from ether/petroleum ether, m.p. 187°-188° C.
Reaction SMILES: CN1C2=NC=C(C[N:12]3[CH2:17][CH2:16][N:15]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH2:14][CH2:13]3)C=C2OC1=O.[CH3:25][N:26]1[C:30]2=[N:31][CH:32]=[C:33]([C:35](=[O:38])[CH2:36]Br)[CH:34]=[C:29]2[O:28][C:27]1=[O:39].CN1C2=NC=C(CBr)C=C2OC1=O>>[CH3:25][N:26]1[C:30]2=[N:31][CH:32]=[C:33]([C:35](=[O:38])[CH2:36][N:12]3[CH2:17][CH2:16][N:15]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH2:14][CH2:13]3)[CH:34]=[C:29]2[O:28][C:27]1=[O:39]
Reactant: Cn1c(=O)oc2cc(C(=O)CBr)cnc21
Reactant: Cn1c(=O)oc2cc(CN3CCN(c4ccccc4)CC3)cnc21
Agent: Cn1c(=O)oc2cc(CBr)cnc21
Product: Cn1c(=O)oc2cc(C(=O)CN3CCN(c4ccccc4)CC3)cnc21

Procedure:
The method of operation is the same as that used for the synthesis of the compound of Example 16, 3-methyl-6-(bromoacetyl)oxazolo[4,5-b]pyridin-2(3H)-one from Preparation 17 being used instead of 3-methyl-6-(bromomethyl)oxazolo[4,5-b]pyridin-2(3H)-one. The yield obtained is 84%. ##STR70##
Reaction SMILES: [N:1]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7][CH2:6][C@@H:2]1[C:3]([OH:5])=[O:4].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)CC)C>CN(C=O)C>[N:1]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7][CH2:6][C@@H:2]1[C:3]([O:5][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:4]
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)OCc1ccccc1

Procedure:
While cooling on ice, Boc-D-Pro-OH (17.2 g, 80 mmol) and benzyl bromide (14.3 ml, 120 mmol) were reacted in DMF (160 ml) in the presence of triethylamine (16.8 ml, 120 mmol) to obtain Boc-D-Pro-OBzl as an oily product. This product was reacted with 2 N HCl/dioxane (5 eq.) for 3 hours to obtain H-D-Pro-OBzl-HCl.
Reaction SMILES: [NH2:1][CH2:2][C:3]([CH3:6])([OH:5])[CH3:4].C[O:8][C:9]([C:11]1[C:15]([NH:16][C:17]([C:19]2[C:24]([NH:25][C:26]3[CH:27]=[N:28][CH:29]=[N:30][CH:31]=3)=[CH:23][CH:22]=[C:21]([CH:32]3[CH2:34][CH2:33]3)[N:20]=2)=[O:18])=[CH:14][N:13]([CH3:35])[N:12]=1)=O>>[OH:5][C:3]([CH3:6])([CH3:4])[CH2:2][NH:1][C:9]([C:11]1[C:15]([NH:16][C:17]([C:19]2[C:24]([NH:25][C:26]3[CH:27]=[N:28][CH:29]=[N:30][CH:31]=3)=[CH:23][CH:22]=[C:21]([CH:32]3[CH2:34][CH2:33]3)[N:20]=2)=[O:18])=[CH:14][N:13]([CH3:35])[N:12]=1)=[O:8]
Reactant: CC(C)(O)CN
Reactant: COC(=O)c1nn(C)cc1NC(=O)c1nc(C2CC2)ccc1Nc1cncnc1
Product: Cn1cc(NC(=O)c2nc(C3CC3)ccc2Nc2cncnc2)c(C(=O)NCC(C)(C)O)n1
Yield: 27 %

Procedure:
According to the general method described in step 5 of example 27, reaction of 1-amino-2-methyl-propan-2-ol with 4-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyridine-2-carbonyl]-amino}-1-methyl-1H-pyrazole-3-carboxylic acid methyl ester provided the title compound (27%) as amorphous yellow solid.
Reaction SMILES: F[C:2]1[CH:8]=[C:7]([I:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[C:10]([S-:15])(=[S:14])OCC.[Na+]>CN(C=O)C.O.Cl>[I:9][C:7]1[CH:6]=[CH:5][C:3]2[N:4]=[C:10]([SH:15])[S:14][C:2]=2[CH:8]=1
Reactant: CCOC(=S)[S-]
Reactant: Nc1ccc(I)cc1F
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Sc1nc2ccc(I)cc2s1
Temperature: 95 °C
Reaction time: 5 h
Yield: 112.6 %

Procedure:
A mixture of 2-fluoro-4-iodoaniline (2.4 g, 10 mmol) and sodium O-ethyl carbonodithioate (3.2 g, 20 mmol) in DMF (8 mL) was stirred at 95° C. for 5 h. The reaction mixture was cooled to rt then diluted with water (25 mL) and 1 N aqueous HCl (20 mL). The mixture was stirred at room temperature for 1 h. The resulting precipitate was collected by filtration and washed with water. The solid was dried to afford 6-iodobenzo[d]thiazole-2-thiol as a light yellow solid (3.3 g, 100%). 1H NMR (300 MHz, CD3OD) δ 7.89 (d, J=1.2 Hz, 1H), 7.67 (dd, J=1.8, 8.7 Hz, 1H), 7.05 (d, J=8.4 Hz, 1H). LCMS (ESI) m/z 294 (M+H)+.
Reaction SMILES: N[C:2]1[CH:6]=[CH:5][NH:4]N=1.C[O:8][C:9](=O)[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1.[H-].[Na+].C(#N)CC>>[CH3:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([C:9](=[O:8])[CH:6]([CH3:2])[C:5]#[N:4])=[CH:11][CH:12]=1
Reactant: COC(=O)c1ccc(OC)cc1
Reactant: Nc1cc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CCC#N
Product: COc1ccc(C(=O)C(C)C#N)cc1
Yield: 62 %

Procedure:
The product was prepared according to the general procedure for aminopyrazole synthesis (route A1) from 4-methoxy-benzoic acid methyl ester (3.0 mL, 18.0 mmol, 1.0 eq), NaH (1.4 g, 36.0 mmol, 2.0 eq) and propionitrile (6.1 mL, 84.9 mmol, 4.7 eq). The crude was purified through Si-column (eluent exane/ethyl acetate) to give 2.1 g of title product (yield: 62%).
Reaction SMILES: C([O-])C.[Na+].[F:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.Cl[CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]>C(O)C>[CH2:20]([O:19][C:17](=[O:18])[CH2:16][CH2:15][CH2:14][O:12][C:9]1[CH:10]=[CH:11][C:6]([F:5])=[CH:7][CH:8]=1)[CH3:21]
Reactant: CCOC(=O)CCCCl
Reactant: Oc1ccc(F)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CCCOc1ccc(F)cc1

Procedure:
Under cooling (0° C.), sodium ethanolate (2.18 g, 32 mmol) was added to a mixture of 4-fluorophenol ([371-41-5], 3.00 g, 27 mmol), ethyl 4-chlorobutyrate ([3153-36-4], 4.84 g, 32 mmol) and ethanol (15 ml), and the reaction mixture was then refluxed overnight. The solvent was evaporated, the residue was taken up in ethyl ester and was washed with water. After drying (Na2SO4), the solvent was evaporated, and 4-(4-fluoro-phenoxy)-butyric acid ethyl ester was isolated from the residue by column chromatography (silica gel, ethyl acetate/heptane). 1H NMR (d6-DMSO): 1.29 (t, 3H), 2.11 (tt, 2H), 2.51 (t, 2H), 3.96 (t, 2H), 4.13 (q, 2H), 6.79-6.85 (m, 2H), 6.92-6.99 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:20])[C:5]([NH2:19])=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1.O.C(=O)(O)[O-].[Na+]>FC(F)(F)C(O)=O.Cl>[Cl:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:16])[F:17])=[CH:11][CH:10]=2)=[CH:6][C:5]2[NH:19][C:12]([C:15]([F:18])([F:17])[F:16])=[N:20][C:4]=2[CH:3]=1
Reactant: Nc1cc(Cl)c(Oc2ccc(C(F)(F)F)cc2)cc1N
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: FC(F)(F)c1ccc(Oc2cc3[nH]c(C(F)(F)F)nc3cc2Cl)cc1
Yield: 124.5 %

Procedure:
To a solution of 4,5-dichloro-2-nitroaniline (5 g, 24.15 mmol) in DMSO (15 ml) was added potassium carbonate (6.62 g, 47.90 mmol) and 4-(trifluoromethyl)phenol (6.6 g, 40.71 mmol) in several batches. The resulting solution was stirred for 8 h at 90° C. in an oil bath maintained with an inert atmosphere of nitrogen. The reaction mixture was then quenched by the addition of water (200 ml), extracted with ethyl acetate (5×100 ml) and the organic layers combined. The resulting mixture was washed with sodium chloride (3×100 m), dried over anhydrous sodium sulfate and concentrated under vacuum to give a residue, which was purified by a silica gel column with 2% to 10% ethyl acetate in petroleum ether to produce 4-chloro-2-nitro-5-[4-(trifluoromethyl)phenoxy]aniline as a yellow solid (1.43 g, 18%). Next, to a solution of 4-chloro-2-nitro-5-[4-(trifluoromethyl)phenoxy]aniline (499 mg, 1.50 mmol) in ethanol (30 ml) was added hydrogen chloride (conc) (0.4 mL) and Zn powder (586 mg) in several bacthes. The resulting solution was stirred for 1.5 h at 85° C. in an oil bath and then concentrated under vacuum. The residue was dissolved in ethyl acetate (150 ml), washed with saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by a silica gel column with 2% to 10% ethyl acetate in petroleum ether to afford 4-chloro-5-[4-(trifluoromethyl)phenoxy]benzene-1,2-diamine as a red solid (359 mg, 79%). Finally, a solution of 4-chloro-5-[4-(trifluoromethyl)phenoxy]benzene-1,2-diamine (100 mg, 0.33 mmol) in trifluoroacetic acid (5 ml) and HCl ((conc), 1 ml) was stirred for 4.5 h at 80° C. in an oil bath. The solution was poured into water (100 ml), adjusted pH value of the solution to 8 with sodium bicarbonate (sat) and extracted with ethyl acetate (3×50 ml). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum to give a residue, which was purified by Pre-TLC with 11% ethyl acetate in petroleum ether to produce 5-chloro-2-(trifluoromethyl)-6-[4-(trifluoromethyl)phenoxy]-1H-1,3-benzodiazole as a white solid (78.2 mg, 62%).
Reaction SMILES: [NH:1]1[C:5]2=[N+:6]([O-])[CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.O=P(Cl)(Cl)[Cl:13].[OH-].[Na+]>>[Cl:13][C:9]1[CH:8]=[CH:7][N:6]=[C:5]2[NH:1][CH:2]=[CH:3][C:4]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: [O-][n+]1cccc2cc[nH]c21
Agent: [Na+]
Agent: [OH-]
Product: Clc1ccnc2[nH]ccc12
Temperature: 106 °C

Procedure:
The m-CBA salt of 1H-Pyrrolo[2,3-b]pyridine 7-oxide (9 g) was taken into POCl3 (46 mL, 7.5 eq.). The mixture was heated at 90° C. for 15 hours and to 106° C. for another 4 hours. The mixture was cooled to room temperature, and most of the POCl3 was distilled off under high vacuum. The residue was dissolved in CH3CN (10 mL). Water (20 mL) was added slowly to quench the reaction. The resulted mixture was adjusted to pH 9 using 10 N NaOH. The solid was filtered. The crude solid was redissolved in several ml of THF and combiflashed using 0-10% MeOH in DCM to give 4-Chloro-1H-pyrrolo[2,3-b]pyridine as a slightly yellowish solid. (4 g). MS: m/z 154.9 [MH+].
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[CH:10]=[C:9]([CH:11](OCC)[O:12]CC)[N:8]([CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[C:6]=2[N:7]=1.Cl.[OH-].[Na+].C([O-])(O)=O.[Na+]>O1CCOCC1>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[CH:10]=[C:9]([CH:11]=[O:12])[N:8]([CH:18]3[CH2:19][CH2:20][CH2:21][CH2:22]3)[C:6]=2[N:7]=1
Reactant: CCOC(OCC)c1cc2cnc(Cl)nc2n1C1CCCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: O=Cc1cc2cnc(Cl)nc2n1C1CCCC1
Reaction time: 0.5 h
Yield: 123.2 %

Procedure:
To a stirred solution of 2-chloro-7-cyclopentyl-6-diethoxymethyl-7H-pyrrolo[2,3-d]pyrimidine (6.29 g, 19.5 mmol) in 1,4-dioxane (68 mL) is added conc. HCl (19 mL) at room temperature. The reaction mixture is stirred for 30 minutes, then neutralized with 2N NaOH aqueous solution and saturated NaHCO3 aqueous solution. The mixture extracted into EtOAc (×3), combined organic extracts are dried (MgSO4), filtered and concentrated to give 6 g of the crude 2-chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carbaldehyde as a beige solid. To a stirred suspension of the crude 2-chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carbaldehyde in MeCN (125 mL) and H2O (125 mL) is added H2N—SO3H (6.62 g, 58.5 mmol) at room temperature. The reaction mixture is stirred for 3 hours before the pH is made >10 with 2N NaOH aqueous solution and the reaction stirred for 1 hour. The mixture extracted into dichloromethane (×3), combined organic extracts are dried (MgSO4), filtered and concentrated. The residue is purified by SiO2 chromatography, eluting with a gradient of 5% EtOAc/petrol to 20% EtOAc/petrol providing 4.00 g of 2-chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile as a white solid, 83% yield.
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:23])[NH:6][C:7]2[C:12]([C:13]=1C)=[C:11](OS(O)(=O)=O)[CH:10]=[CH:9][C:8]=2[CH:20]([CH3:22])[CH3:21])(=[O:3])[CH3:2].[CH:24]([NH2:28])([CH2:26][CH3:27])[CH3:25]>>[C:1]([C:4]1[C:5](=[O:23])[NH:6][C:7]2[C:12]([C:13]=1[NH:28][CH:24]([CH2:26][CH3:27])[CH3:25])=[CH:11][CH:10]=[CH:9][C:8]=2[CH:20]([CH3:21])[CH3:22])(=[O:3])[CH3:2]
Reactant: CC(=O)c1c(C)c2c(OS(=O)(=O)O)ccc(C(C)C)c2[nH]c1=O
Reactant: CCC(C)N
Product: CCC(C)Nc1c(C(C)=O)c(=O)[nH]c2c(C(C)C)cccc12
Yield: 89.9 %

Procedure:
3-Acetyl-4-methylsulfoxy-8-isopropyl-2-quinolinone (2.91g, 0.01 mol) and sec-butylamine (0.73g, 0.01 mol) were used, but the reaction was carried out as the above process of example 37 to obtain the desired product (2.7g, yield: 90%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[CH:9]=2)[CH:5]=[CH:4][C:3]=1[CH2:15][N:16]1[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[CH:9]=2)[CH:5]=[CH:4][C:3]=1[CH2:15][N:16]1[CH2:17][CH2:18][NH:19][CH2:20][CH2:21]1
Reactant: Cc1cccc(-c2ccc(CN3CCN(C(=O)OC(C)(C)C)CC3)c(C)c2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cccc(-c2ccc(CN3CCNCC3)c(C)c2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.7 %

Procedure:
A 100 mL round-bottom flask was charged with tert-butyl 4-[[2-methyl-4-(3-methylphenyl)phenyl]methyl]piperazine-1-carboxylate (2.00 g, 5.26 mmol, 1.00 equiv), trifluoroacetic acid (8 mL), dichloromethane (40 mL). The resulting solution was stirred for 1 h at room temperature and concentrated under reduced pressure to yield 1.50 g (crude) of 1-[[2-methyl-4-(3-methylphenyl)phenyl]methyl]piperazine as light yellow oil. LCMS (ESI, m/z): 281 [M+H]+.
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:22]=[CH:21][C:8]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH2:17][C:18]([OH:20])=[O:19])=O)=[CH:7][CH:6]=1)([OH:3])=[O:2].Cl.O.[OH-].[Na+]>CO>[C:1]([CH2:4][C:5]1[CH:22]=[CH:21][C:8]([CH2:9][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH2:17][C:18]([OH:20])=[O:19])=[CH:7][CH:6]=1)([OH:3])=[O:2]
Reactant: O=C(O)Cc1ccc(C(=O)c2ccccc2CC(=O)O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)Cc1ccc(Cc2ccccc2CC(=O)O)cc1
Yield: 46.1 %

Procedure:
A solution of 3.8 g of 2-(4-carboxymethylbenzoyl)phenylacetic acid in 15 ml of methanol was added to 9.0 g of zinc amalgam, 17.5 ml of conc. hydrochloric acid and 7.5 ml of water. The mixture was heated under reflux for 5 hours with stirring. After the reaction, the reaction mixture was cooled, and the zinc amalgam was removed by decantation. Water (100 ml) was added, and the mixture was extracted with ether. The ethereal layer was washed with a saturated aqueous solution of sodium chloride. The ether was distilled off to afford a yellow oily product. Methanol (20 ml) was added to dissolve it. Then, 60 ml of a 10% sodium hydroxide solution was added to the solution, and the solution was heated under reflux for 3 hours with stirring. After the reaction, the reaction mixture was cooled, acidified with conc. hydrochloric acid, and extracted with ether. The ethereal layer was washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. The ether was then distilled off. The residue was chromatographed on a silica gel column using a mixture of chloroform and methanol (95:5) as an eluent. A solid was obtained from the eluate. Recrystallization from ether afforded 1.67 g of 2-(4-carboxymethylbenzyl)phenylacetic acid as colorless plate-like crystals having a melting point of 155° to 156° C.
Reaction SMILES: [CH2:1]([N:5]=[C:6]=[O:7])[CH2:2][CH2:3][CH3:4].[CH2:8]([O:15][C:16]1[CH:21]=[C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:19]=[CH:18][C:17]=1[CH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>O1CCCC1.C(N(CC)C(C)C)(C)C>[CH2:1]([NH:5][C:6]([N:33]1[CH2:32][CH2:31][CH:30]([C:17]2[CH:18]=[CH:19][C:20]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:21][C:16]=2[O:15][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:35][CH2:34]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: c1ccc(COc2ccc(C3CCNCC3)c(OCc3ccccc3)c2)cc1
Reactant: CCCCN=C=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCCCNC(=O)N1CCC(c2ccc(OCc3ccccc3)cc2OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 78 %

Procedure:
In a 10 ml round-bottomed flask, 0.25 g of 4-(2,4-bis(benzyloxy)phenyl)piperidine is dissolved in 5 ml of tetrahydrofuran in the presence of 0.23 ml of N,N-diisopropylethylamine. 0.08 ml of butyl isocyanate is added and the reaction mixture is then stirred for 20 minutes at ambient temperature. The reaction mixture is extracted with ethyl acetate, and then the organic phases are combined and dried over magnesium sulphate. The residue is chromatographed on silica gel (8/2 heptane/ethyl acetate). 0.25 g of 4-(2,4-bis(benzyloxy)phenyl)piperidine-1-carboxylic acid butylamide is obtained. Yield=78%.