Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[CH2:2]([N:9]([CH2:12][CH2:13][CH2:14][C:15]1([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[O:19][CH2:18][CH2:17][O:16]1)CC)[C:3]1C=CC=CC=1.Cl.CO.[H][H]>[Pd].CO>[ClH:1].[CH2:2]([NH:9][CH2:12][CH2:13][CH2:14][C:15]1([C:20]2[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=2)[O:16][CH2:17][CH2:18][O:19]1)[CH3:3]
Reactant: CCN(CCCC1(c2ccc(F)cc2)OCCO1)Cc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CCNCCCC1(c2ccc(F)cc2)OCCO1
Temperature: 25 °C
Yield: 96849.9 %

Procedure:
A suspension prepared from 47.2 g (0.124 mmol) of 2-[3-(N-benzyl-N-ethylamino)propyl]-2-(4-fluorophenyl)-1,3-dioxolane hydrochloride, 0.035 ml of saturated HCl/methanol, 350 ml of methanol, and 4 g of 5% palladium on carbon was shaken at 50° under 50 psi hydrogen for 5 hours. The mixture was allowed to cool to room temperature and filtered. Evaporation of the solvent followed by trituration with ether provided 34.8 g (96%) of product. Recrystallization from ether/isopropyl alcohol provided analytically pure material.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:16]([C:17]4[CH:22]=[CH:21][C:20]([C:23](=[O:25])[NH2:24])=[CH:19][C:18]=4[CH3:26])[C:15]([CH2:27][CH2:28][C:29]([O-:31])=[O:30])=[CH:14][CH:13]=3)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.O[Li].O>C1COCC1.O>[N:1]1([C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:16]([C:17]4[CH:22]=[CH:21][C:20]([C:23](=[O:25])[NH2:24])=[CH:19][C:18]=4[CH3:26])[C:15]([CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[CH:14][CH:13]=3)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: Cc1cc(C(N)=O)ccc1-n1c(CCC(=O)[O-])ccc1-c1ccc(-n2ccnc2)cc1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C(N)=O)ccc1-n1c(CCC(=O)O)ccc1-c1ccc(-n2ccnc2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 56.7 %

Procedure:
To a solution of compound 3-(5-(4-(1H-imidazol-1-yl)phenyl)-1-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-2-yl)propanoate (22.0 g, 48.3 mmol) in THF/H2O (v/v=1/1, 220 mL) was added LiOH.H2O (4.15 g, 96.6 mmol). The reaction solution was stirred at room temperature for 5 h. The THF was removed under reduced pressure and the aqueous solution was acidified with 10% HCl to pH=5. The solid was filtered and recrystallized from THF and water [1:1(v/v)] to afford 3-(5-(4-(1H-imidazol-1-yl)phenyl)-1-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-2-yl)propanoic acid as a yellow solid (11.35 g, 55%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:9][C@H:10]2[CH2:14][O:13][C@@H:12]([CH2:15][OH:16])[CH2:11]2)=[N:4][CH:5]=[N:6][C:7]=1[Cl:8].[CH2:17](OC(OC(=O)C)OCC)C>>[Cl:8][C:7]1[N:6]=[CH:5][N:4]=[C:3]2[C:2]=1[N:1]=[CH:17][N:9]2[C@H:10]1[CH2:14][O:13][C@@H:12]([CH2:15][OH:16])[CH2:11]1
Reactant: CCOC(OCC)OC(C)=O
Reactant: Nc1c(Cl)ncnc1N[C@H]1CO[C@@H](CO)C1
Product: OC[C@H]1C[C@@H](n2cnc3c(Cl)ncnc32)CO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48 %

Procedure:
A solution of (2R-cis)-4-[(5-amino-6-chloro-4-pyrimidinyl)amino]tetrahydro-2-furanmethanol, Compound IX, (220 mg, 0.90 mmole) and diethoxymethylacetate (5 mL) in a 10 mL round bottom flask fitted with a reflux condenser was heated to 100° for 120 hours. The volatile materials were removed via rotary evaporation, and the residue was recombined with toluene (5 mL) and p-toluenesulphonic acid (5 mg). After stirring at room temperature for one hour and by flash column chromatography (10% MeOH/90% CH2Cl2) to afford 109 mg (48%) of Compound X as a white solid:
Reaction SMILES: [Na].[C:2]([CH2:4][C:5]([NH2:7])=[O:6])#[N:3].[Cl:8][C:9]1[CH:10]=[C:11]([CH:16]=[C:17]([CH3:28])[C:18]=1[C:19](=[O:27])[C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)[CH2:12][N:13]=[N+:14]=[N-:15].C(O)(=O)C>C(O)C>[NH2:3][C:2]1[N:13]([CH2:12][C:11]2[CH:16]=[C:17]([CH3:28])[C:18]([C:19](=[O:27])[C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)=[C:9]([Cl:8])[CH:10]=2)[N:14]=[N:15][C:4]=1[C:5]([NH2:7])=[O:6]
Reactant: N#CCC(N)=O
Reactant: Cc1cc(CN=[N+]=[N-])cc(Cl)c1C(=O)c1ccc(Cl)cc1
Agent: [Na]
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1cc(Cn2nnc(C(N)=O)c2N)cc(Cl)c1C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 67.3 %

Procedure:
A stirred, 60° C. solution of sodium (88.7 mg, 3.84 mmol) in absolute ethanol (9.6 ml) was treated with 2-cyanoacetamide (323 mg, 3.84 mmol), kept 5 min., and treated with 3-chloro-4-(4-chlorobenzoyl)-5-methylbenzyl azide (1.03 g, 3.20 mmol). The mixture was refluxed 1 hour, cooled to ambient temperature, acidified with glacial acetic acid (487 μl, 511 mg, 7.68 mmol), and evaporated to dryness at 30° C. under vacuum. The residue was chromatographed on a column of silica gel (150 g) eluted in 17 ml fractions with 19:1 (v/v) dichloromethane-methanol. Fractions 22-38 were combined and evaporated to dryness. The residual glass was kept 18 hours at ambient temperature with diethyl ether (25 ml), filtered, washed with diethyl ether, and dried to provide 870 mg (67%) crystalline 5-amino-1-(3-chloro-4-[4-chlorobenzoyl]-5-methylbenzyl)-1,2,3-triazole-4 -carboxamide, m.p. 205°-206° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][N:3]=1.[CH3:11][NH:12][CH3:13]>CS(C)=O.ClCCl>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:12]([CH3:13])[CH3:11])=[O:7])=[CH:4][N:3]=1
Reactant: CNC
Reactant: O=C(O)c1ccc(Br)nc1
Solvent: CS(C)=O
Solvent: ClCCl
Product: CN(C)C(=O)c1ccc(Br)nc1
Reaction time: 24 h
Yield: 46 %

Procedure:
N,N′-Carbonyldiimidazole (1 g, 6.17 mmol) was added to a solution of 6-bromonicotinic acid (1 g, 4.95 mmol) in dimethylsulfoxide (4.16 mL) and the mixture was stirred for 24 hours. Dimethylamine (40% in water, 8.3 mL, 37 mmol) was then added and the mixture was stirred for a further 18 hours. The reaction mixture was then diluted with dichloromethane (20 mL) and washed with water (10 mL). The organic layer was dried over sodium sulphate and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with ethyl acetate to afford the title compound in 46% yield, 520 mg.
Reaction SMILES: C([O:5][C:6](=[O:35])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][N:18]([CH2:27][C:28]2[CH:33]=[CH:32][C:31](Br)=[CH:30][CH:29]=2)[C:19]2[N:24]=[CH:23][C:22]([CH2:25][CH3:26])=[CH:21][N:20]=2)[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.[C:36]([C:38]1[CH:39]=[C:40](OB(O)O)[CH:41]=[CH:42][CH:43]=1)#[N:37].[ClH:48].C(OCC)(=O)C>C(OCC)C>[ClH:48].[C:36]([C:38]1[CH:43]=[C:42]([C:31]2[CH:32]=[CH:33][C:28]([CH2:27][N:18]([C:19]3[N:20]=[CH:21][C:22]([CH2:25][CH3:26])=[CH:23][N:24]=3)[CH2:17][CH2:16][C:14]3[N:15]=[C:11]([S:10][C:7]([CH3:8])([CH3:9])[C:6]([OH:5])=[O:35])[S:12][CH:13]=3)=[CH:29][CH:30]=2)[CH:41]=[CH:40][CH:39]=1)#[N:37]
Reactant: N#Cc1cccc(OB(O)O)c1
Reactant: CCc1cnc(N(CCc2csc(SC(C)(C)C(=O)OC(C)(C)C)n2)Cc2ccc(Br)cc2)nc1
Agent: Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CCc1cnc(N(CCc2csc(SC(C)(C)C(=O)O)n2)Cc2ccc(-c3cccc(C#N)c3)cc2)nc1

Procedure:
A compound obtained using 2-[(4-{2-[(4-bromobenzyl)(5-ethylpyrimidin-2-yl)amino]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester synthesized in Example 402-1 and 3-cyanophenylboric acid as starting materials and by an operation similar to that of Example 407 was dissolved in diethyl ether, and reacted with 4 mol/L hydrochloric acid-ethyl acetate to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=O)[C:7]3[C:12]([S:13][C:14]=2[CH:15]=1)=[C:11]([O:16][CH3:17])[CH:10]=[CH:9][CH:8]=3.B#B>O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:6][C:7]3[C:12]([S:13][C:14]=2[CH:15]=1)=[C:11]([O:16][CH3:17])[CH:10]=[CH:9][CH:8]=3
Reactant: COc1cccc2c(=O)c3ccc(Cl)cc3sc12
Agent: B#B
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc2c1Sc1cc(Cl)ccc1C2

Procedure:
A stirred suspension of 3-chloro-5-methoxythioxanth-9-one (13.8 g.) in dry tetrahydrofuran (140 ml.) is treated dropwise with a solution of diborane in tetrahydrofuran (1M, 40 ml.) at ambient temperature and in an atmosphere of argon. The mixture is heated at reflux for 1.25 hours, cooled, diluted carefully with water and extracted with ether (× 3). The combined ether extracts are washed with brine, dried over MgSO4 and then evaporated, to give 3-chloro-5-methoxythioxanthene, m.p. 72°-74° C. on recrystallisation from methanol.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([CH2:8][C:9]([C:11]1[CH:12]=[C:13]([CH2:19][CH:20]([CH2:26][CH3:27])[C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:14]=[CH:15][C:16]=1[O:17][CH3:18])=[O:10])=[O:7])[CH3:4].[F:28][C:29]([F:39])([F:38])[C:30]1[CH:37]=[CH:36][C:33]([CH2:34]Br)=[CH:32][CH:31]=1.Cl>O1CCCC1>[CH2:3]([O:5][C:6]([CH:8]([CH2:34][C:33]1[CH:32]=[CH:31][C:30]([C:29]([F:28])([F:38])[F:39])=[CH:37][CH:36]=1)[C:9]([C:11]1[CH:12]=[C:13]([CH2:19][CH:20]([CH2:26][CH3:27])[C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:14]=[CH:15][C:16]=1[O:17][CH3:18])=[O:10])=[O:7])[CH3:4]
Reactant: CCOC(=O)CC(=O)c1cc(CC(CC)C(=O)OCC)ccc1OC
Reactant: FC(F)(F)c1ccc(CBr)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(CC)Cc1ccc(OC)c(C(=O)C(Cc2ccc(C(F)(F)F)cc2)C(=O)OCC)c1
Temperature: 25 °C
Yield: 98.5 %

Procedure:
Under an argon atmosphere, stirring and cooling with ice, sodium hydride (60% oil dispersion, 296 mg, 7.40 mmol) was added little by little to a solution of ethyl 3-[3-(2-ethoxycarbonylacetyl)-4-methoxyphenyl]-2-ethylpropanoate (2.59 g, 7.39 mmol) in anhydrous tetrahydrofuran (30 mL), and then the mixture was stirred for 20 minutes under cooling with ice and for 30 minutes at room temperature. Following this, a solution of 4-(trifluoromethyl)benzylbromide (1.77 g, 7.40 mmol) in anhydrous tetrahydrofuran (10 mL) was added dropwise. After completion of the dropwise addition, the mixture was refluxed for 6 hours. After cooling, a mixture of 1 mol/L hydrochloric acid (15 mL) with ice water (100 mL) was added thereto, which was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and then concentrated. The residue was purified by silica gel column chromatography (eluent n-hexane:ethyl acetate=8:1 v/v) to afford 3.70 g (98%) of the title compound as a pale yellow oil.
Reaction SMILES: Cl.[C:2]([C:4]([C:17](=[O:30])[N:18]([CH3:29])[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=1)=[CH:5][NH:6][C:7](=[NH:16])[N:8]1[CH2:12][C:11]([CH3:14])([CH3:13])[NH:10][C:9]1=[O:15])#[N:3].[OH-].[Na+].C(OCC)C.C(OC(C)C)(C)C>>[CH3:29][N:18]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:26])([F:27])[F:28])[CH:20]=1)[C:17]([C:4]1[C:2]([NH2:3])=[N:16][C:7]([N:8]2[CH2:12][C:11]([CH3:14])([CH3:13])[NH:10][C:9]2=[O:15])=[N:6][CH:5]=1)=[O:30]
Reactant: CN(C(=O)C(C#N)=CNC(=N)N1CC(C)(C)NC1=O)c1cccc(C(F)(F)F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CC(C)OC(C)C
Product: CN(C(=O)c1cnc(N2CC(C)(C)NC2=O)nc1N)c1cccc(C(F)(F)F)c1
Yield: 32.6 %

Procedure:
2.67 g (6 mmol) of 1-cyano-1-[N-methyl-N-(3-trifluoromethylphenyl)carbamoyl]-2-[imino(4,4-dimethyl-2-oxo-1-imidazolidinyl)methylamino]ethene hydrochloride are heated at 187°-189° C. under vacuum (4-6 mbar) for 10 min in a bath preheated to 190° C. After cooling, the solidified melt was mixed with 5 ml of 2N sodium hydroxide solution. 12 ml of diethyl ether/diisopropyl ether 5:1 were added. Stirring resulted in initial formation of two clear phases, from which crystals separated out. The mixture was stirred while cooling in ice for 1 hour, and the crystals were filtered off with suction, washed with water and taken up in 50 ml of CH2Cl2. The solution which formed was extracted successively three times with 5 ml of 0.5N NaOH each time and twice with 5 ml of water each time, dried over Na2SO4, filtered and evaporated. The residue was triturated with diisopropyl ether, filtered off with suction and dried as in Example 13. 0.82 g (=32.6% yield) of the compound I was obtained, melting point 209°-210° C.
Reaction SMILES: [C@@H:1]1(C(O)=O)[CH2:6][CH2:5][CH2:4][CH2:3][C@H:2]1[C:7]([OH:9])=[O:8].C(Cl)(Cl)Cl.[N-:17]=[N+]=[N-].[Na+].CCOCC>S(=O)(=O)(O)O>[NH2:17][C@@H:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C@H:2]1[C:7]([OH:9])=[O:8]
Reactant: O=C(O)[C@@H]1CCCC[C@H]1C(=O)O
Reactant: [N-]=[N+]=[N-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: N[C@@H]1CCCC[C@H]1C(=O)O
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
Trans-cyclohexane-1,2-dicarboxylic acid (8.105 g; racemic modification) is dissolved in conc. sulfuric acid (25 ml) and chloroform (50 ml) and kept at a temperature of 45° C., to which is added sodium azide (3.6 g) in one hour. After this, the solution is stirred for 90 minutes, added with ice water (25 ml) and is added with ether to remove chloroform. Barium carbonate (90 g) is added to the water layer of the solution to effect the neutralization. Barium sulfate is removed from the solution by filtration and the filtrate is concentrated to dryness to result in needle crystals of rac-trans-2-aminocyclohexanecarboxylic acid (referred to as A) having the following characteristics. When a corresponding rac-cis-compound is used as starting material, there is obtained the corresponding cis-compound i.e. rac-cis-aminocyclohexanecarboxylic acid, referred to as B).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]1[N:13]=[C:14]([C:30]2[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=2)[S:15][C:16]=1[CH2:17][O:18][C:19]1[CH:28]=[CH:27][C:22]([C:23]([NH:25][OH:26])=[NH:24])=[C:21]([F:29])[CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl[C:47](OC1C=CC=CC=1)=[O:48]>ClCCl>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]1[N:13]=[C:14]([C:30]2[CH:31]=[CH:32][C:33]([C:36]([F:38])([F:37])[F:39])=[CH:34][CH:35]=2)[S:15][C:16]=1[CH2:17][O:18][C:19]1[CH:28]=[CH:27][C:22]([C:23]2[NH:24][C:47](=[O:48])[O:26][N:25]=2)=[C:21]([F:29])[CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: N=C(NO)c1ccc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2CCCOCc2ccccc2)cc1F
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=c1[nH]c(-c2ccc(OCc3sc(-c4ccc(C(F)(F)F)cc4)nc3CCCOCc3ccccc3)cc2F)no1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a stirred suspension of 0.62 g of 4-[4-(3-benzyloxy-propyl)-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-2-fluoro-N-hydroxy-benzamidine in 17 mL of dichloromethane at 0° C., under argon, were added 0.23 mL of pyridine and 154 μL of phenyl chloroformate. The reaction mixture was stirred for 10 min at 0° C. followed by 1 h at room temperature. The reaction mixture was concentrated under reduced pressure and the resulting residue was taken up into 10 mL of acetonitrile under argon and 0.165 mL of 1,4-diazabicyclo[5.4.0]undec-7-ene (DBU) was added. The reaction mixture was stirred at room temperature overnight then warmed to 40° C. for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was taken up into dichloromethane and a 1M aqueous solution of NaH2PO4 was added. The aqueous layer was separated and extracted three times with dichloromethane. The combined organic layers were washed with water, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give 770 mg of crude product as a yellow powder. Purification by column chromatography on silica gel (heptane 1/ethyl acetate 1) gave 150 mg followed by column washing with 100% MeOH gave 320 mg of the title compound. In total, 470 mg of 3-{4-[4-(3-benzyloxy-propyl)-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-2-fluoro-phenyl}-4H-[1,2,4]oxadiazol-5-one as white powder was obtained.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:4]=1N.Cl.[N+:12]([O-:15])([O-])=[O:13].[Na+].S([O-])([O-])(=O)=O>O>[Cl:2][C:3]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:4]=1[N+:12]([O-:15])=[O:13]
Reactant: O=[N+]([O-])[O-]
Reactant: Nc1c(F)cccc1Cl
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1c(F)cccc1Cl
Reaction time: 1 h

Procedure:
To a solution of 17.2 g. of 2-chloro-6-fluoroaniline hydrochloride and 12.5 ml. of concentrated hydrochloric acid in 150 ml. of water is added slowly a solution of 9 g. of sodium nitrate in 25 ml. of water. The temperature of the solution of kept below 5° at all times. This solution is then added to a stirred suspension of 18 g. of cuprocupric sulfate and 60 g. of sodium nitrate in 300 ml. of water at room temperature. The mixture is stirred for 1 hour then steam distilled until no trace of product is noted condensing in the distillate. The distillate is extracted with ether, dried (magnesium sulfate) concentrated and distilled to give 7.8 g. of product, b.p. 148°-152° at 30 mm. Gas chromatography analysis shows this to be greater than 95% pure.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[C:5](Cl)(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=1[O:23][CH3:24].Cl>ClCCCl>[CH3:24][O:23][C:17]1[C:16]([O:15][CH3:14])=[CH:21][C:20]([C:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:12])=[C:19]([F:22])[CH:18]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COc1ccc(F)cc1OC
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: COc1cc(F)c(C(=O)c2ccccc2)cc1OC
Temperature: 0 °C
Reaction time: 3 h

Procedure:
12.7 g (95 mmol) of aluminium trichloride in 80 ml of 1,2-dichloroethane are stirred under nitrogen and cooled to 3°. 13.35 g (95 mmol) of benzoyl chloride are added. At 30°, this red solution is added dropwise over a period of 25 minutes to a solution of 12.55 g (80.3 mmol) of 1,2-dimethoxy-4-fluorobenzene (4-fluoroveratrole) in 80 ml of 1,2-dichloroethane. The reaction mixture is stirred for a further 3 hours at 3°, then for 31/2 hours at room temperature and then poured onto a mixture of 250 ml of ice and 20 ml of concentrated hydrochloric acid. The organic phase is separated off and the aqueous phase is extracted several times with ether. Organic phase and ether solutions are combined, washed with 1N sodium hydroxide solution, water and with saturated sodium chloride solution, dried over magnesium sulphate and concentrated by evaporation. The resulting yellow oil is stirred with 50 ml of ether in an ice bath until crystallisation takes place, yielding the desired (4,5-dimethoxy-2-fluorophenyl)-phenylmethanone in the form of white crystals having a melting point of 102°-103°.
Reaction SMILES: F[C:2]1[CH:19]=[CH:18][C:5]([C:6]([C:8]2[C:13]([O:14][CH2:15][CH2:16][CH3:17])=[CH:12][CH:11]=[CH:10][N:9]=2)=[O:7])=[CH:4][CH:3]=1.[N-:20]=[N+]=[N-].[Na+].CS(C)=O>O>[NH2:20][C:2]1[CH:19]=[CH:18][C:5]([CH:6]([C:8]2[C:13]([O:14][CH2:15][CH2:16][CH3:17])=[CH:12][CH:11]=[CH:10][N:9]=2)[OH:7])=[CH:4][CH:3]=1
Reactant: CCCOc1cccnc1C(=O)c1ccc(F)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCCOc1cccnc1C(O)c1ccc(N)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.5 %

Procedure:
A solution of 2-(4-fluorobenzoyl)-3-propoxypyridine (4.46 g) and sodium azide (3.34 g) in. DMSO (50 ml) was stirred for 22 hours at 90° C. To the reaction mixture was added water, and the mixture was extracted with diethylether. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure, and a solution of the residue (4.8 g) in THF (50 ml) was added dropwise to a suspension of aluminum lithium hydride (1.3 g) in. THF (40 ml) at 0° C. The mixture was stirred at room temperature for 30 minutes, water (1.3 ml), 15% aqueous solution of sodium hydroxide (1.3 ml) and water (3.9 ml) were sequentially and slowly added dropwise to the solution at 0° C. The mixture was stirred at room temperature for 2 hours, magnesium sulfate was added to the mixture, and the precipitates were removed by filtration (Celite). The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from ethyl acetate to give (4-aminophenyl)(3-propoxypyridin-2-yl)methanol (2.82 g) as pale yellow crystals.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[NH2:11].[C:13](Cl)([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14].Cl.O>N1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[NH:11][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COC(=O)c1cc(Cl)ccc1N
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: COC(=O)c1cc(Cl)ccc1NC(=O)OCc1ccccc1
Yield: 69.5 %

Procedure:
2-Amino-5-chlorobenzoic acid methyl ester (5 g, 27 mmol) was dissolved in 36 mL pyridine. CBz-Cl (4.2 mL, 29.6 mmol) was then added and the resultant solution was stirred at 60° C. overnight. The following day, LCMS analysis indicated the reaction was complete. The reaction mixture was subsequently poured in a slow stream into 200 mL of rapidly stirring 2 M HCl/H2O. The mixture was transferred to a separatory funnel and extracted with 2×50 mL of EtOAc. The aqueous phase was discarded and the combined organics were dried over sodium sulfate and concentrated in vacuo to provide 6 g of 2-benzyloxycarbonylamino-5-chloro-benzoic acid methyl ester (pale yellow oil, 70% yield): HPLC retention time=3.15 minutes; MS (ES) M+H expected 320.0, found 320.0.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([F:26])[C:23]([O:27][CH3:28])=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.Cl[C:35]([C@@H:37]([O:39]C(=O)C)[CH3:38])=[O:36]>>[OH:39][C@@H:37]([CH3:38])[C:35]([N:2]1[CH2:3][CH2:4][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([F:26])[C:23]([O:27][CH3:28])=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:6][CH2:7]1)=[O:36]
Reactant: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCNCC4)c[nH]c23)cc1F
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Agent: Cl
Product: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCN(C(=O)[C@H](C)O)CC4)c[nH]c23)cc1F

Procedure:
Starting from 4-(2-cyclopropylmethoxy-5-fluoro-4-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide hydrochloride (example A166) and acetic acid (S)-1-chlorocarbonyl-ethyl ester the title compound is obtained as colorless solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][OH:21])=[CH:15][CH:14]=1>>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][OH:21])=[CH:15][CH:14]=2)=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Cl
Reactant: Nc1ccc(CCO)cc1
Product: O=[N+]([O-])c1cc(Cl)ccc1Nc1ccc(CCO)cc1

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 1 from 2,5-dichloronitrobenzene and 4-aminophenylethyl alcohol.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:12]([OH:14])=[O:13])[N:6]2[CH3:11].C(N(CC)CC)C.[C:22](Cl)(=[O:24])[CH3:23]>ClCCl>[C:22]([O:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:12]([OH:14])=[O:13])[N:6]2[CH3:11])(=[O:24])[CH3:23]
Reactant: Cn1c(C(=O)O)cc2c(O)cccc21
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Oc1cccc2c1cc(C(=O)O)n2C
Temperature: 25 °C
Reaction time: 1 h
Yield: 109.6 %

Procedure:
To 4-hydroxy-1-methyl-1H-indole-2-carboxylic acid (0.262 mmol, 50 mg) in dichloromethane (1 ml) and triethylamine (2.62 mmol, 365 μl) at 0° C. was added acetyl chloride (0.266 mmol, 19 μl) and the reaction mixture stirred at room temperature for one hour. The reaction was quenched with saturated aqueous sodium hydrogencarbonate and extracted twice with dichloromethane. The organic layers were combined, dried (Na2SO4) and concentrated under reduced pressure to yield 4-acetoxy-1-methyl-1H-indole-2-carboxylic acid (67 mg).