Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[O:3]1.[H][H].Cl>[Pd]>[C:4]1([C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:2][O:3]1)=[O:5]
Reactant: [H][H]
Reactant: O=C1OC(Cl)c2ccccc21
Agent: [Pd]
Agent: Cl
Product: O=C1OCc2ccccc21

Procedure:
824.5 weight parts of 3-chlorophthalide were melted at 85° C. in an autoclave, 25.3 parts of catalyst (5% Pd on BaSo4), and a hydrogen stream of 180 l/h was introduced with vigorous agitation. The excess hydrogen and the hydrogen chloride that evolved were removed as in the above examples. After 81/2 hours, the evolution of hydrogen chloride ceased. The melt was separated from the catalyst. In the distillation that followed, 608 weight-parts of phthalide were obtained (90.7% of the theory) having a content of 99.6% phthalide.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:13]2[O:12][C:11]([NH:14][C:15]([C:17]3[N:18]=[CH:19][C:20]4[C:25]([CH:26]=3)=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:16])=[N:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4].[Li+].[OH-].C1COCC1>CO>[CH:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:26]=[C:17]([C:15]([NH:14][C:11]2[O:12][C:13]3[C:5]([C:3]([OH:4])=[O:2])=[CH:6][CH:7]=[CH:8][C:9]=3[N:10]=2)=[O:16])[N:18]=1
Reactant: COC(=O)c1cccc2nc(NC(=O)c3cc4ccccc4cn3)oc12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(Nc1nc2cccc(C(=O)O)c2o1)c1cc2ccccc2cn1

Procedure:
2-[(Isoquinoline-3-carbonyl)-amino]-benzooxazole-7-carboxylic acid was synthesized according to General Procedure B using 417 mg (1.2 mmol) 2-[(isoquinoline-3-carbonyl)-amino]-benzooxazole-7-carboxylic acid methyl ester, 2.4 mL of 2 N aq. LiOH, 12 mL of THF and 3 mL of methanol at 40° C. for 4 h. 141 mg (0.423 mmol, 35%) of the product was obtained. LCMS: 334 (M+1)+.
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1)([CH3:5])[C:3]#[CH:4].[C:14]1(I)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>N(CC)CC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[C:14]1([C:4]#[C:3][C:2]([C:6]2[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=2)([CH3:1])[CH3:5])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: C#CC(C)(C)c1ccc(OC)cc1
Reactant: Ic1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCNCC
Product: COc1ccc(C(C)(C)C#Cc2ccccc2)cc1
Reaction time: 18 h
Yield: 83.6 %

Procedure:
To a stirred solution of Compound 21 (299 mg, 1.72 mmol), PhI (385 mg, 1.89 mmol), and (PPh3)2PdCl2 (60 mg, 0.086 mmol) in Et2NH (10 ml) was added CuI (33 mg, 0.17 mmol) at r.t. under N2, and stirred for 18 h. The mixture was quenched by the addition of H2O, and extracted with Et2O. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. This was purified by SiO2 chromatography to give Compound 67 (360 mg, 84%) as a colorless oil.
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(O)C.Cl>O>[N+:11]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:2]=1[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:6]([OH:8])=[O:7])([O-:13])=[O:12]
Reactant: O=C(O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: Nc1ccccc1
Agent: Cl
Solvent: O
Solvent: CCO
Product: O=C(O)c1ccc(Nc2ccccc2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 96.8 %

Procedure:
An eggplant flask was charged with 4-fluoro-3-nitrobenzoic acid (2.51 g, 13.56 mmol), aniline (2.52 g, 27.12 mmol), and ethanol (9.5 mL), and this was heated to reflux with stirring for 16 hours. After cooling to room temperature, the mixture was poured into dilute hydrochloric acid (1 M, 50 mL), diluted with distilled water (100 mL), was left to stir as is at room temperature for 30 minutes. The precipitated crystals were filtered off, and washed successively with dilute hydrochloric acid (1 M, with approx. 3 mL 3 times), distilled water (approx. 5 mL 2 times), and with diethyl ether (approx. 3 mL). The crystals obtained were dried at reduced pressure with heating to yield the title compound (3.39 g, quant.) as a reddish-orange solid.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]([N:13]1[CH2:17][CH2:16][CH2:15][C@@H:14]1[CH2:18][OH:19])([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].C(N(CC)CC)C>ClCCl>[CH3:1][S:2]([O:19][CH2:18][C@H:14]1[CH2:15][CH2:16][CH2:17][N:13]1[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])(=[O:4])=[O:3]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1CO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COS(C)(=O)=O
Reaction time: 1 h

Procedure:
Methanesulfonyl chloride (0.06 mL, 0.77 mmol) was added to a solution of (R)-N-Boc-pyrrolidine-2-methanol (125.3 mg, 0.62 mmol) and triethylamine (0.22 mL, 1.6 mmol) in dichloromethane at 0° C. under argon. After stirring for 1 h, the reaction mixture was partitioned between dichloromethane (50 mL) and sodium hydrogen sulfate (15 mL). The organic layer was sequentially washed with water (15 mL) and brine (15 mL), dried over anhydrous sodium sulfate and the solvent was removed in vacuo to yield (R)-N-Boc-pyrrolidine-2-methanol methanesulfonate, which was used crude.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:12])=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.Cl[C:14]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:15]>C(Cl)Cl>[CH3:12][C:3]1[C:2]([NH:1][C:14](=[O:15])[O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: Cc1nc2ccccc2cc1N
Reactant: O=C(Cl)Oc1ccccc1
Solvent: ClCCl
Product: Cc1nc2ccccc2cc1NC(=O)Oc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
3-amino-2-methylquinoline(4 g, 25 mmol) and phenyl chloroformate(4.04 g, 25 mmol) were dissolved in methylene chloride and then was stirred at room temperature for 2 hrs. The mixture solution was concentrated under the reduced pressure to remove methylene chloride and purified by column chromatography(ethylacetate:hexane=1:10) to obtain the titled compound.
Reaction SMILES: [CH:1]1([CH2:7][NH2:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].[C:11](Cl)(Cl)=[O:12]>C1(C)C=CC=CC=1>[CH:1]1([CH2:7][NH:8][C:11]([NH:8][CH2:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:12])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)Cl
Reactant: NCC1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: O=C(NCC1CCCCC1)NCC1CCCCC1
Yield: 95 %

Procedure:
A mixture of cyclohexanemethylamine (Aldrich, 68.66 g) and 5 N sodium hydroxide (Fisher, 200 ml) was stirred vigorously with cooling (−10° C.) while a solution of phosgene (30.0 g) in toluene (600 ml) was added rapidly. After stirring for 20 minutes, the resulting mixture was filtered and the precipitated solid was washed with water and dried (0.5 Torr) to give 1,3-bis(cyclohexylmethyl)urea as white powder (72.72 g, 95%), m.p. 150-152° C.; 1H-NMR (DMSO-d6) δ: 5.74 (br t, J=5.8 Hz, 2, 2 NH), 2.81 (t, J=6.3 Hz, 4, 2 NCH2), 1.62, 1.25, and 0.85 (all m, 22, 2 cyclohexyl).
Reaction SMILES: Cl.[F:2][C:3]([F:14])([F:13])[O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11]N)=[CH:7][CH:6]=1.[N:15]12[CH2:23][CH2:22][CH:19]([CH2:20][CH2:21]1)[C:18](=O)[CH2:17][CH2:16]2.Cl.O1CCOCC1>C(O)(=O)C>[F:2][C:3]([F:14])([F:13])[O:4][C:5]1[CH:10]=[CH:9][C:8]2[NH:11][C:18]3[CH:19]4[CH2:22][CH2:23][N:15]([CH2:16][C:17]=3[C:7]=2[CH:6]=1)[CH2:21][CH2:20]4
Reactant: NNc1ccc(OC(F)(F)F)cc1
Reactant: O=C1CCN2CCC1CC2
Agent: Cl
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: FC(F)(F)Oc1ccc2[nH]c3c(c2c1)CN1CCC3CC1
Temperature: 150 °C

Procedure:
In a 30 ml, microwave reaction tube were combined 4-(trifluoromethoxy)phenyl-hydrazine hydrochloride (1143 mg, 5.0 mmol; Alfa Aesar), 1-azabicyclo[3.2.2]nonan-4-one (696 mg, 5.0 mmol; Example 2A), 4 N HCl in dioxane (2.5 mL, 10.0 mmol; Aldrich), and acetic acid (15 mL). The reaction mixture was heated in a microwave to 150° C. (Biotage Personal Chemistry, maximum 300 W) for 15 minutes, then cooled to room temperature. The solvent was removed, and the residue was basified with 5 N sodium hydroxide and extracted with ethyl acetate (3×50 mL). The combined organic phases were concentrated in vacuo and purified by reverse-phase HPLC [Waters XBridge RP18 column, 5 μm, 30×100 mm, flow rate 40 mL/minute, 20-99% gradient of methanol in buffer (0.1 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide) over 20 minutes] to afford the title compound: 1H NMR (300 MHz, methanol-d4) δ ppm 2.08 (td, J=7, 4 Hz, 4H), 2.99-3.13 (m, 3H), 3.23 (dd, J=14, 7 Hz, 2H), 4.21 (s, 2H), 6.92 (ddd, J=9, 2, 1 Hz, 1H), 7.16 (d, J=1 Hz, 1H), 7.28 (d, J=8 Hz, 1H); MS (DCI/NH3) m/z 297 (M+H)+.
Reaction SMILES: C(O)C.[CH2:4]([O:11][C:12]1[C:13]([O:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:14][C:15]([N+:23]([O-])=O)=[C:16]([CH:22]=1)[CH:17]=[CH:18][N+]([O-])=O)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>[Fe].C(O)(=O)C>[CH2:4]([O:11][C:12]1[CH:22]=[C:16]2[C:15](=[CH:14][C:13]=1[O:26][CH2:27][CH2:28][CH2:29][CH3:30])[NH:23][CH:18]=[CH:17]2)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CCCCOc1cc([N+](=O)[O-])c(C=C[N+](=O)[O-])cc1OCc1ccccc1
Agent: [Fe]
Solvent: CCO
Solvent: CC(=O)O
Product: CCCCOc1cc2[nH]ccc2cc1OCc1ccccc1
Reaction time: 0.25 h
Yield: 40 %

Procedure:
8.6 g of activated iron are added at 60° C. to a solution of 28 ml of absolute ethanol and 14 ml of acetic acid. The mixture is kept for 15 minutes at 80° C. and 5-benzyloxy-4-butoxy-2,β-dinitrostyrene (1.6 g; 0.0043 mole) is added. The mixture is left at 80° C. for 1 hour, and the ferric sludge is filtered off and rinsed with 40 ml of ethanol and 40 ml of acetic acid. The filtrate is diluted with 100 ml of ice-cold water. After extraction of the solution with methylene chloride and drying of the organic phase over sodium sulphate, the organic phase is concentrated and chromatographed on silica 60 (eluent: toluene/CH2Cl2, 50:50). 0.5 g (40% yield) of the expected derivative is obtained.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[N:7]([C:9]([C:12]([NH:14][C:15]3[CH:20]=[C:19]([C:21]4[N:25]=[C:24]([CH:26]5[CH2:29][C:28]([F:31])([F:30])[CH2:27]5)[O:23][N:22]=4)[CH:18]=[CH:17][C:16]=3[F:32])=[O:13])=[CH:10][N:11]=2)[CH:8]=1)#[N:2].C([O-])([O-])=O.[Cs+].[Cs+].Cl.[C:40](=[NH:43])([NH2:42])[CH3:41]>CS(C)=O>[F:30][C:28]1([F:31])[CH2:27][CH:26]([C:24]2[O:23][N:22]=[C:21]([C:19]3[CH:18]=[CH:17][C:16]([F:32])=[C:15]([NH:14][C:12]([C:9]4[N:7]5[CH:8]=[C:3]([C:1]6[NH:43][C:40]([CH3:41])=[N:42][N:2]=6)[CH:4]=[CH:5][C:6]5=[N:11][CH:10]=4)=[O:13])[CH:20]=3)[N:25]=2)[CH2:29]1
Reactant: CC(=N)N
Reactant: N#Cc1ccc2ncc(C(=O)Nc3cc(-c4noc(C5CC(F)(F)C5)n4)ccc3F)n2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: Cc1nnc(-c2ccc3ncc(C(=O)Nc4cc(-c5noc(C6CC(F)(F)C6)n5)ccc4F)n3c2)[nH]1
Temperature: 120 °C

Procedure:
A mixture of 6-cyano-N-(5-(5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazol-3-yl)-2-fluorophenyl)imidazo[1,2-a]pyridine-3-carboxamide (42h) (15.0 mg, 0.034 mmol), CuBr (9.2 mg, 0.007 mmol), Cs2CO3(39 mg, 0.12 mmol), and acetimidamide hydrochloride (6.6 mg, 0.07 mmol) in DMSO (1 mL) was heated at 120° C. overnight. The reaction mixture was purified by HPLC to give N-(5-(5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazol-3-yl)-2-fluorophenyl)-6-(5-methyl-4H-1,2,4-triazol-3-yl)imidazo[1,2-a]pyridine-3-carboxamide (F61). MS m/z 495.1 (M+1)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[CH:2]1.Cl[C:11]1([C:17]([O:19][CH3:20])=[O:18])[C:15](=[O:16])[CH:14]=[CH:13][S:12]1>C(Cl)(Cl)Cl>[CH3:20][O:19][C:17]([C:11]1[S:12][C:13]([N:3]2[C:4]3=[N:5][CH:6]=[CH:7][CH:8]=[C:9]3[N:1]=[CH:2]2)=[CH:14][C:15]=1[OH:16])=[O:18]
Reactant: c1cnc2nc[nH]c2c1
Reactant: COC(=O)C1(Cl)SC=CC1=O
Solvent: ClC(Cl)Cl
Product: COC(=O)c1sc(-n2cnc3cccnc32)cc1O

Procedure:
In a similar manner as described for example C6, 30.0 g of 1H-imidazo[4,5-b]pyridine and 19.26 g of methyl 2-chloro-3-oxo-2,3-dihydrothiophene-2-carboxylate in 2 l chloroform give 3-hydroxy-5-imidazo[4,5-b]pyridin-3-yl-thiophene-2-carboxylic acid methyl ester (compound C8b) and the crude title compounds as an isomeric mixture which was used for the next step without further purification (example B5). The structural assignment of compound C8b was unequivocally established by two-dimensional 1H NMR experiment (NOESY, COSY).
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[F:21][C:22]([F:34])([F:33])[CH2:23][O:24][C:25]1[CH:32]=[CH:31][C:28]([CH:29]=O)=[CH:27][CH:26]=1>>[CH3:18][O:17][C:16]1[CH:15]=[CH:14][CH:13]=[C:12]([O:19][CH3:20])[C:11]=1[CH:2]1[N:1]([CH2:29][C:28]2[CH:31]=[CH:32][C:25]([O:24][CH2:23][C:22]([F:21])([F:33])[F:34])=[CH:26][CH:27]=2)[C:5](=[O:7])[CH:4]([CH3:10])[CH2:3]1
Reactant: O=Cc1ccc(OCC(F)(F)F)cc1
Reactant: CCOC(=O)C(C)CC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CC(C)C(=O)N1Cc1ccc(OCC(F)(F)F)cc1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2,6-dimethoxyphenyl)-2-methylbutanoate with 4-(2,2,2-trifluoroethoxy)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.89 min.; [M+H]+: 424.45 g/mol.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([Cl:12])[CH:8]=[CH:9][CH:10]=2)[C:5]([O:13][C:14]2[CH:15]=[CH:16][C:17]([F:24])=[C:18]([CH:23]=2)[C:19]([O:21][CH3:22])=[O:20])=[N:4][N:3]=1.C(O)(=[O:27])C.C([O-])(=O)C.[Na+]>C(OCC)(=O)C>[Cl:12][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[C:5]([O:13][C:14]1[CH:15]=[CH:16][C:17]([F:24])=[C:18]([CH:23]=1)[C:19]([O:21][CH3:22])=[O:20])=[N:4][NH:3][C:2]2=[O:27]
Reactant: CC(=O)O
Reactant: COC(=O)c1cc(Oc2nnc(Cl)c3cccc(Cl)c23)ccc1F
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(Oc2n[nH]c(=O)c3cccc(Cl)c23)ccc1F

Procedure:
Methyl 5-((4,8-dichlorophthalazin-1-yl)loxy)-2-fluorobenzoate (5d) (700 mg, 1.9 mmol), acetic acid (20 mL) and sodium acetate (420 mg, 3 mmol) were added into a reaction flask successively, the mixture was refluxed for one hour, and diluted with 50 mL ethyl acetate. The reaction solution was washed with 50 mL saturated sodium bicarbonate solution and saturated sodium chloride solution successively for three times, the organic layers were combined, concentrated and dried to give methyl 5-((8-chloro-4-oxo-3,4-dihydrophthalazin-1-yl)oxy)-2-fluorobenzoate (5e), 650 mg white solid (yield 95%). 1H NMR (600 MHZ, DMSO-d6): δ 12.12 (s, 1H), 8.13 (d, J=8.0 Hz, 1H), 7.95-8.00 (m, 1H), 7.83-7.87 (m, 1H), 7.74-7.77 (m, 1H), 7.61-7.64 (m, 1H), 7.42-7.47 (m, 1H), 3.86 (s, 3H); ESI-MS m/z; calculated for 348.0. found 371.6 [M+Na]+.
Reaction SMILES: [NH2:1]C(OCC)=O.C[O-].[Na+].[CH3:10][O:11][CH2:12][CH:13]1[CH2:17][O:16][C:15](=O)[O:14]1>CN(C)C=O>[CH3:10][O:11][CH2:12][CH:13]1[O:14][C:15](=[O:16])[NH:1][CH2:17]1
Reactant: CCOC(N)=O
Reactant: COCC1COC(=O)O1
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCC1CNC(=O)O1
Temperature: 140 °C
Reaction time: 80 h
Yield: 43.3 %

Procedure:
Urethane (10.0 g, 113 mmol) was dissolved in N,N-dimethylformamide (40 ml), and thereto were added sodium methoxide (409 mg, 7.57 mmol) and 4-methoxymethyl-1,3-dioxolan-2-one (10.0 g, 75.7 mmol), in order. The mixture was stirred for 80 hours at 140° C. under an atmosphere of argon. After filtering off the insoluble materials, the filtrate was condensed in vacuo, and the residue was purified by silica gel chromatography to give the subject 5-methoxymethyloxazolidin-2-one (4.3 g, yield 43.3%).
Reaction SMILES: I[CH2:2][C@H:3]1[O:15][C@H:14]([CH2:16][OH:17])[C@@H:5]([O:6][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:4]1.[OH-].[Na+].[H][H]>[Pd].C(O)C>[C:8]1([CH2:7][O:6][C@@H:5]2[C@@H:14]([CH2:16][OH:17])[O:15][C@@H:3]([CH3:2])[CH2:4]2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: [H][H]
Reactant: OC[C@H]1O[C@H](CI)C[C@@H]1OCc1ccccc1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C[C@H]1C[C@H](OCc2ccccc2)[C@@H](CO)O1
Yield: 75.7 %

Procedure:
A mixture of 6.0 g of product from Example 334, Isomer A, 34 ml of ethyl alcohol, 17.2 ml of 1N sodium hydroxide and 7.8 g of 10% palladium on carbon is hydrogenated in a Parr apparatus at 45 psi of hydrogen for 15 hours. The reaction mixture is filtered, diluted with ethyl acetate, washed with saturated sodium chloride, dried and concentrated in vacuo to give 2.9 g of the desired product.
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[CH3:13][O:14][C:15](=[O:24])[C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[C:18]([Cl:23])[CH:17]=1.CCN(CC)CC>C(Cl)Cl>[CH3:13][O:14][C:15](=[O:24])[C:16]1[CH:21]=[CH:20][C:19]([N:22]=[C:2]=[O:4])=[C:18]([Cl:23])[CH:17]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COC(=O)c1ccc(N)c(Cl)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(N=C=O)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 260 %

Procedure:
To an ice cold solution of triphosgene (59 mg, 200 μmol) in CH2Cl2 (1.5 ml) was added 4-amino-3-chloro-benzoic acid methyl ester (100 mg, 540 μmol; [84228-44-4]) and a solution of Et3N (150 μl, 1.1 mmol) in CH2Cl2 (0.5 ml) under an argon atmosphere. The reaction mixture was stirred at ambient temperature for 30 min. The solvent was removed under reduced pressure. The residue was triturated with EtOAc, the solid was filtered off and the filtrate was evaporated to dryness under reduced pressure to give the title compound (111 mg, 520 μmol; 97%) as brown solid which was used in the next step without further purification. MS: m/e=228.9 [M+H+].
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][N:6]=[C:5]([NH:9][C:10](=[O:35])[C:11]2[CH:16]=[C:15]([CH2:17][C:18]3[C:19](=[O:30])[C:20]([O:28][CH3:29])=[C:21]([O:26][CH3:27])[C:22](=[O:25])[C:23]=3[CH3:24])[CH:14]=[CH:13][C:12]=2[O:31]C(=O)C)[CH:4]=1.C(=O)([O-])O.[Na+]>CO.O>[CH3:1][O:2][C:3]1[N:8]=[CH:7][N:6]=[C:5]([NH:9][C:10](=[O:35])[C:11]2[CH:16]=[C:15]([CH2:17][C:18]3[C:19](=[O:30])[C:20]([O:28][CH3:29])=[C:21]([O:26][CH3:27])[C:22](=[O:25])[C:23]=3[CH3:24])[CH:14]=[CH:13][C:12]=2[OH:31])[CH:4]=1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)Nc3cc(OC)ncn3)c2)=C(C)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC1=C(OC)C(=O)C(Cc2ccc(O)c(C(=O)Nc3cc(OC)ncn3)c2)=C(C)C1=O
Yield: 72.8 %

Procedure:
N-(6-Methoxypyrimidin-4-yl)-5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzamide (0.060 g, 0.125 mmol) was dissolved in methanol (3 ml) and after adding thereto an aqueous saturated sodium hydrogencarbonate solution (3 ml), the solution was stirred at room temperature for 3 hours. After the completion of reaction, the reaction solution was diluted with water and then extracted with ethyl acetate. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=10:1) and then recrystallized from ether to obtain the titled compound (0.040 g, 0.0910 mmol, 73%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([N:8]=[C:9]([NH:11][C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])[N:10]=2)[CH:7]=1.[F:17][C:18]1[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[CH:21]=[C:20](F)[CH:19]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[F:17][C:18]1[CH:19]=[C:20]([CH:21]=[C:22]([N+:24]([O-:26])=[O:25])[CH:23]=1)[O:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([N:8]=[C:9]([NH:11][C:12]([CH:14]3[CH2:15][CH2:16]3)=[O:13])[N:10]=2)[CH:7]=1
Reactant: O=C(Nc1nc2ccc(O)cn2n1)C1CC1
Reactant: O=[N+]([O-])c1cc(F)cc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1nc2ccc(Oc3cc(F)cc([N+](=O)[O-])c3)cn2n1)C1CC1
Temperature: 140 °C
Reaction time: 6 h
Yield: 485.3 %

Procedure:
A mixture of N-(6-hydroxy[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide (200 mg, 0.917 mmol), 1,3-difluoro-5-nitrobenzene (437 mg, 2.75 mmol), potassium carbonate (380 mg, 2.75 mmol) and N,N-dimethylformamide (6 mL) was stirred at 140° C. for 6 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was collected by filtration and washed with ethyl acetate-hexane to give the title compound (1.59 g, 89%) as a yellow solid.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[C:5]([O:11][C:12]3[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:19])[CH:6]=[CH:7][CH:8]=2)[NH:3]1.[OH-:20].[Na+:21].O>O1CCOCC1>[NH2:3][C:4]1[C:5]([O:11][C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:19])=[CH:6][CH:7]=[CH:8][C:9]=1[CH2:10][C:2]([O-:20])=[O:1].[Na+:21]
Reactant: [OH-]
Reactant: O=C1Cc2cccc(Oc3c(Cl)cccc3Cl)c2N1
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Nc1c(CC(=O)[O-])cccc1Oc1c(Cl)cccc1Cl

Procedure:
A mixture of 2-oxo-7-(2,6-dichlorophenoxy)indoline (3.4 g.), sodium hydroxide (1.86 g.) and water (50 ml.) was refluxed under heating for 120 hours with stirring. Insoluble starting material (2.5 g.) was recovered by filtration and the filtrate was cooled. The precipitates were collected by filtration and washed with a small amount of water and diethyl ether in turn to give the captioned compound (1.35 g.). Further, to the above obtained insoluble material (2.5 g.) were added sodium hydroxide (2 g.) and 50% dioxane (50 ml.), and the mixture was stirred for 70 hours and filtered. After cooling, the precipitates were collected by filtration and washed with water and diethyl ether in turn to give the same captioned compound (1.3 g.). Total yield (2.65 g.). mp>230° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([O:13][C:14]1[CH:18]=[C:17]([N:19]2[C:27]3[CH:26]=[C:25]([CH2:28][OH:29])[N:24]=[CH:23][C:22]=3[N:21]=[CH:20]2)[S:16][C:15]=1[C:30]([NH2:32])=[O:31])[C:9]([F:12])([F:11])[F:10].[CH3:33][S:34](Cl)(=[O:36])=[O:35].C(N(CC)CC)C>ClCCl>[CH3:33][S:34]([O:29][CH2:28][C:25]1[N:24]=[CH:23][C:22]2[N:21]=[CH:20][N:19]([C:17]3[S:16][C:15]([C:30](=[O:31])[NH2:32])=[C:14]([O:13][CH:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])[C:9]([F:12])([F:11])[F:10])[CH:18]=3)[C:27]=2[CH:26]=1)(=[O:36])=[O:35]
Reactant: CS(=O)(=O)Cl
Reactant: NC(=O)c1sc(-n2cnc3cnc(CO)cc32)cc1OC(c1ccccc1Cl)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCc1cc2c(cn1)ncn2-c1cc(OC(c2ccccc2Cl)C(F)(F)F)c(C(N)=O)s1

Procedure:
In a similar manner as described for example 49 (step 1), 170 mg of 3-[1-(2-chlorophenyl)-2,2,2-trifluoroethoxy]-5-[6-(hydroxymethyl)-1H-imidazo[4,5-c]pyridin-1-yl]thiophene-2-carboxamide, 76.7 mg of methanesulfonyl chloride, and 70.8 mg of triethylamine in 3 ml dichloromethane give (1-{5-carbamoyl-4-[1-(2-chlorophenyl)-2,2,2-trifluoroethoxy]-2-thienyl}-1H-imidazo[4,5-c]pyridin-6-yl)methyl methanesulfonate as crude material that is used for step 2 without further purification.