Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:10]([C:11](=O)/[CH:12]=[CH:13]/N(C)C)=[CH:9][N:8]([CH2:18][CH3:19])[C:7]=12.Cl.[OH:21][C:22]1[CH:23]=[C:24]([NH:28][C:29]([NH2:31])=[NH:30])[CH:25]=[CH:26][CH:27]=1>>[Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:10]([C:11]3[CH:12]=[CH:13][N:31]=[C:29]([NH:28][C:24]4[CH:23]=[C:22]([OH:21])[CH:27]=[CH:26][CH:25]=4)[N:30]=3)=[CH:9][N:8]([CH2:18][CH3:19])[C:7]=12
Reactant: N=C(N)Nc1cccc(O)c1
Reactant: CCn1cc(C(=O)/C=C/N(C)C)c2ccnc(Cl)c21
Agent: Cl
Product: CCn1cc(-c2ccnc(Nc3cccc(O)c3)n2)c2ccnc(Cl)c21

Procedure:
Prepared by treatment of (E)-1-(7-chloro-1-ethyl-1H-pyrrolo[2,3-c]pyridin-3-yl)-3-(dimethylamino)prop-2-en-1-one with 1-(3-hydroxyphenyl)guanidine hydrochloride. 1H-NMR (DMSO-d6) δ: 1.46 (m, 3H, CH3), 4.49 (m, 2H, CH2), 6.39 (m, 1H, Ph-H), 7.07 (m, 1H, Ph-H), 7.20 (m, 2H, Ph-H and Ar—H), 7.77 (d, 1H, J=5.6 Hz, Pyrimidin-H), 8.18 (d, 1H, J=5.6 Hz, Ar—H), 8.37 (d, 1H, J=5.6 Hz, Pyrimidin-H), 8.41 (s, 1H, Ar—H), 9.23 (s, 1H, OH), 9.32 (s, 1H, NH). MS (ESI+) m/z 362.1670 (M+H)+
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-])=O)[C:3]=1[C:4]([NH:6][C:7]1[NH:11][N:10]=[N:9][N:8]=1)=[O:5].[OH-].[Na+].[H][H]>[Pd]>[NH2:16][C:12]1[CH:13]=[CH:14][CH:15]=[C:2]([CH3:1])[C:3]=1[C:4]([NH:6][C:7]1[NH:11][N:10]=[N:9][N:8]=1)=[O:5]
Reactant: [H][H]
Reactant: Cc1cccc([N+](=O)[O-])c1C(=O)Nc1nnn[nH]1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Product: Cc1cccc(N)c1C(=O)Nc1nnn[nH]1

Procedure:
A solution was prepared from 7.5 g of 2-methyl-6-nitro-N-(1H-tetrazol-5-yl)benzamide in 100 ml of aqueous 1N sodium hydroxide. A 0.5-g quantity of 5% Pd/C was added and the mixture was hydrogenated in a Parr apparatus at 3.3 atmospheres until uptake of hydrogen stopped (75 minutes). The catalyst was removed by filtration and the filtrate was treated with 100 ml of aqueous 1N hydrochloric acid. The white solid which formed was separated by filtration and air dried to give 2-amino-6-methyl-N-(1H-tetrazol-5-yl)benzamide melting at about 248° C. with decomposition.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:12]([CH:13]=O)[CH2:11][S:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:15][O:16][C:17](=[O:39])[C@H:18]([CH2:35][CH2:36][S:37][CH3:38])[NH:19][C:20](=[O:34])[C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][C:22]=1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH3:15][O:16][C:17](=[O:39])[C@H:18]([CH2:35][CH2:36][S:37][CH3:38])[NH:19][C:20](=[O:34])[C:21]1[CH:26]=[CH:25][C:24]([NH:27][CH2:13][C@@H:12]2[CH2:11][S:10][CH2:9][N:8]2[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[CH:23][C:22]=1[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1ccc(N)cc1-c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CSC[C@H]1C=O
Product: COC(=O)[C@H](CCSC)NC(=O)c1ccc(NC[C@@H]2CSCN2C(=O)OC(C)(C)C)cc1-c1ccccc1

Procedure:
N-tert-butoxycarbonyl-(R)-(−)thiazolidine-4-carboxaldehyde was reductively aminated with 4-amino-2-phenylbenzoyl methionine methyl ester (compound 8) according to the procedure of Example 158B.
Reaction SMILES: CO[C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:15]([OH:17])=[O:16])[CH:11]=2)[CH:6]=1)=[O:4].[CH2:18]([CH2:20][NH2:21])[OH:19]>>[OH:19][CH2:18][CH2:20][NH:21][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[C:10]([C:15]([OH:17])=[O:16])[CH:9]=[CH:8]2)=[O:4]
Reactant: NCCO
Reactant: COC(=O)c1ccc2cc(C(=O)O)ccc2c1
Product: O=C(O)c1ccc2cc(C(=O)NCCO)ccc2c1

Procedure:
2.1 g of naphthalene-2,6-dicarboxylic acid monomethyl ester and 25 ml of ethanolamine are heated at 150° C. for 3 h. The excess ethanolamine is distilled off in vacuo, and the residue is dissolved in water and the mixture is extracted with ethyl acetate. After acidifying the aqueous phase, the product which is deposited is filtered off with suction and recrystallized from ethanol. 1.2 g of 6-(2-hydroxyethyl-aminocarbonyl)-2-naphthoic acid are obtained.
Reaction SMILES: [I-].[CH:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([CH3:4])[CH3:3].C([Li])CCC.[CH3:29][N:30]1[C:34]([CH3:35])=[CH:33][C:32]([CH:36]=O)=[N:31]1.[Cl-].[NH4+]>C1COCC1>[CH3:29][N:30]1[C:34]([CH3:35])=[CH:33][C:32]([CH:36]=[C:2]([CH3:4])[CH3:3])=[N:31]1
Reactant: CC(C)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1cc(C=O)nn1C
Agent: [Cl-]
Agent: [I-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)=Cc1cc(C)n(C)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 100 %

Procedure:
A suspension of isopropyltriphenylphosphonium iodide (5.23 g, 12.1 mmol) in THF (35 ml) at −20° C. was treated dropwise with a 1.6 M solution of butyllithium in hexanes (7.5 ml, 12 mmol). The mixture was stirred at −20° C. for 45 minutes before a solution of 1,5-dimethyl-1H-pyrazole-3-carboxaldehyde (1.20 g, 9.68 mmol) in THF (50 ml) was added. The thick suspension was allowed to warm to room temperature and stirred for 24 hours. The reaction mixture was treated with saturated aqueous ammonium chloride (150 ml) and the phases separated. The aqueous phase was back-extracted with ethyl acetate (3×50 ml) and the combined organic phases were dried (Na2SO4) and concentrated. The residue was extracted with petroleum ether (2×100 ml) and the combined extracts were concentrated to afford a yellow oil which was purified by chromatography (SiO2, 0-100% EtOAc-petroleum ether) to give the title compound as a colourless solid (1.56 g, 9.68 mmol). δH (CDCl3, 300K) 6.15 (1H, m), 6.01 (1H, s), 3.75 (3H, s), 2.26 (3H, s), 1.96 (3H, d J 0.8 Hz), 1.89 (3H, d J 1.2 Hz). m/z (ES+, 70V) 151.1 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([C:12]2[CH2:16][CH2:15][CH2:14][C:13]=2Br)[CH:6]=1)[CH3:2].[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)=[C:24](B(O)O)[CH:25]=1>>[CH2:1]([O:3][C:4](=[O:18])[C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([C:12]2[CH2:16][CH2:15][CH2:14][C:13]=2[C:22]2[CH:21]=[C:20]([Cl:19])[CH:25]=[CH:24][C:23]=2[O:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[CH:6]=1)[CH3:2]
Reactant: OB(O)c1cc(Cl)ccc1OCc1ccc(F)cc1
Reactant: CCOC(=O)c1cc(C)cc(C2=C(Br)CCC2)c1
Product: CCOC(=O)c1cc(C)cc(C2=C(c3cc(Cl)ccc3OCc3ccc(F)cc3)CCC2)c1

Procedure:
Prepared by general procedure B(iii) but using 3-(2-bromocyclopent-1-enyl)-5-methylbenzoic acid ethyl ester instead of 3-(2-bromo-cyclopent-1-enyl)-6-methyl benzoic acid ethyl ester and using [5-chloro-2-(4-fluorobenzyloxy)phenyl]boronic acid instead of (5-chloro-2-benzyloxyphenyl)boronic acid.
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([N:9]3[C:13]4[CH:14]=[C:15]([NH:20][C@H:21]([C:23]5[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=5)[CH3:22])[C:16]([C:18]#[N:19])=[CH:17][C:12]=4[N:11]=[CH:10]3)[CH:5]=2)[CH2:3][CH2:2]1.[OH-:30].[K+]>CO.OO.O>[CH:1]1([C:4]2[NH:8][N:7]=[C:6]([N:9]3[C:13]4[CH:14]=[C:15]([NH:20][C@H:21]([C:23]5[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=5)[CH3:22])[C:16]([C:18]([NH2:19])=[O:30])=[CH:17][C:12]=4[N:11]=[CH:10]3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: [OH-]
Reactant: C[C@H](Nc1cc2c(cc1C#N)ncn2-c1cc(C2CC2)[nH]n1)c1ccc(F)cc1
Agent: OO
Agent: [K+]
Solvent: CO
Solvent: O
Product: C[C@H](Nc1cc2c(cc1C(N)=O)ncn2-c1cc(C2CC2)[nH]n1)c1ccc(F)cc1
Temperature: 75 °C
Yield: 44 %

Procedure:
1-(5-Cyclopropyl-1H-pyrazol-3-yl)-6-[(S)-1-(4-fluorophenyl)ethylamino]-1H-benzo[d]imidazol-5-carbonitrile (Example 33; 0.30 g, 0.77 mmol) was dissolved in MeOH (10 ml), followed by addition of 25% aqueous KOH solution (0.87 ml, 3.88 mol) and 15 drops of 30% H2O2 solution. The reaction was heated at 75° C. for 48 hours. After cooling, the reaction was diluted with H2O (5 ml). The resulted solid was collected by filtration and dried under vacuum to give the title compound (0.137 g, 44%) as a white solid. NMR (400 MHz) 12.70 (s, 1H), 8.66 (d, J=4.8 Hz, 1H), 8.30 (s, 1H), 8.06 (s, 1H), 8.03 (br, 1H), 7.42 (m, 2H), 7.24 (br, 1H), 7.13 (m, 1H), 6.80 (s, 1H), 6.00 (s, 1H), 4.57 (m, 1H), 1.95 (m, 1H), 1.47 (d, J=6.0 Hz, 3H), 1.02 (m, 2H), 0.74 (m, 2H). MS: Calcd.: 404; Found: [M+H]+ 405.
Reaction SMILES: [CH:1]([N:3]1[C:9]2[CH:10]=[CH:11][C:12]([C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[CH:16][CH:15]=3)=[CH:13][C:8]=2[CH:7]=[C:6]([C:26]([O:28]C)=[O:27])[CH2:5][CH2:4]1)=[O:2].[OH-].[Na+]>CO.C1COCC1>[CH:1]([N:3]1[C:9]2[CH:10]=[CH:11][C:12]([C:14]3[CH:15]=[CH:16][C:17]([N:20]4[CH2:21][CH2:22][O:23][CH2:24][CH2:25]4)=[CH:18][CH:19]=3)=[CH:13][C:8]=2[CH:7]=[C:6]([C:26]([OH:28])=[O:27])[CH2:5][CH2:4]1)=[O:2]
Reactant: COC(=O)C1=Cc2cc(-c3ccc(N4CCOCC4)cc3)ccc2N(C=O)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=CN1CCC(C(=O)O)=Cc2cc(-c3ccc(N4CCOCC4)cc3)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.7 %

Procedure:
In methanol (250 ml) and THF (250 ml) was dissolved methyl 1-formyl-7-(4-morpholinophenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (3.54 g). To the solution was added 1N sodium hydroxide solution (90 ml), and the mixture was stirred at room temperature overnight and concentrated. To the mixture was added water, and the mixture was neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was dried with anhydrous magnesium sulfate, and the solvent was evaporated to give 1-formyl-7-(4-morpholinophenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (3.30 g) as colorless crystals.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5](O)=[O:6].B(OC)(OC)OC.B(F)(F)F.CCOCC.CO>ClCCCl>[OH:6][CH2:5][C:4]1[CH:8]=[CH:9][C:10]([N+:11]([O-:13])=[O:12])=[C:2]([OH:1])[CH:3]=1
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(O)c1
Agent: COB(OC)OC
Agent: FB(F)F
Solvent: CCOCC
Solvent: CO
Solvent: ClCCCl
Product: O=[N+]([O-])c1ccc(CO)cc1O
Temperature: 4 °C
Reaction time: 2.5 h
Yield: 90.2 %

Procedure:
To a magnetically stirred suspension of 3-hydroxy-4-nitro-benzoic acid (75 g, 0.41 mol) in 1,2-dichloroethane (1.5 L), under an argon blanket, was added trimethyl borate (69 g, 0.66 mol) and boron trifluoride diethyl etherate (94 g, 0.66 mol) at 20 □C. Borane-pyridine complex (57 g, 0.61 mol) was slowly added drop-wise over 2.5 hrs (exotherm to 44° C.). After addition was complete, the solution was stirred for 2.5 hrs then cooled in an ice bath to 4° C. Methanol (150 ml) was added over 15–20 min. to quench the reaction. The mixture was stirred for 45 min. while warming to 20 □C then concentrated in vacuo to a yellow solid residue. The solid was partitioned between 1N NaOH (450 ml) and toluene (600 ml). The phases were separated, and the organic portion was extracted with 1N NaOH (2×450 mL). The aqueous portions were combined and acidified to below pH 2 with the slow addition of conc. HCl (100 ml). The resulting thick suspension was extracted with ethyl acetate (750 ml, 500 nm). The combined organic extract was washed with water (2×450 mL), brine (450 mL), dried (MgSO4), filtered then concentrated in vacuo to give 62 g brownish yellow solid 1 (0.37 mol, 90%). An additional 106 g of intermediate 1 was obtained from three other reactions.
Reaction SMILES: N#N.[CH3:3][C:4]1([C:9]2[S:13][C:12]([CH2:14][N:15]3[CH:19]=[C:18]([N+:20]([O-])=O)[CH:17]=[N:16]3)=[N:11][CH:10]=2)[O:8][CH2:7][CH2:6][O:5]1.[NH4+].[Cl-]>CCO.O.[Fe]>[CH3:3][C:4]1([C:9]2[S:13][C:12]([CH2:14][N:15]3[CH:19]=[C:18]([NH2:20])[CH:17]=[N:16]3)=[N:11][CH:10]=2)[O:8][CH2:7][CH2:6][O:5]1
Reactant: CC1(c2cnc(Cn3cc([N+](=O)[O-])cn3)s2)OCCO1
Agent: [Fe]
Agent: N#N
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: CC1(c2cnc(Cn3cc(N)cn3)s2)OCCO1
Temperature: 75 °C
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 5-(2-methyl-[1,3]dioxolan-2-yl)-2-(4-nitro-pyrazol-1-ylmethyl)-thiazole (490 mg, 1.65 mmol), iron powder (280 mg, 4.96 mmol) and NH4Cl (447 mg, 8.27 mmol) in a mixture of EtOH (3.0 mL) and water (1.5 mL) was stirred at 75° C. for 60 min. The reaction mixture was filtered while hot and concentrated under reduced pressure. CH2Cl2 (10 mL) was added followed by 1N NaOH (10 mL). The aq. layer was extracted with CH2Cl2 (2×10 mL) and the combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give the title compound as a brown oil. TLC: rf (19:1 CH2Cl2-MeOH)=0.20. LC-MS-conditions 02: tR=0.56 min; [M+H]+=267.29.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][S:5][C:6]1[CH:10]=[CH:9][S:8][C:7]=1[C:11]([O:13]C)=O.C[O-].[Na+]>C1(C)C=CC=CC=1.CO>[S:5]1[C:6]2[CH:10]=[CH:9][S:8][C:7]=2[C:11](=[O:13])[NH:2][CH2:3][CH2:4]1
Reactant: COC(=O)c1sccc1SCCN
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: O=C1NCCSc2ccsc21

Procedure:
1.0 g of methyl 3-[(2-aminoethyl)thio]-2-thiophenecarboxylate hydrochloride was suspended in 20 ml of toluene under argon, whereupon 9.4 ml of 1N sodium methylate solution in methanol were added. After the reaction finished, the mixture was evaporated in vacuo and the residue was treated with 20 ml of water. The crystals were removed by filtration, washed with water and dried. By recrystallization there was obtained 3,4-dihydrothieno-[2,3-f][1,4]thiazepin-5(2H)-one as white crystals of m.p. 186°-188°. The reaction can also be carried out with 1.1 mol equivalents of potassium tert-butylate solution in toluene.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH:10][CH2:11][C:12]2[S:16][C:15]([S:17](Cl)(=[O:19])=[O:18])=[CH:14][CH:13]=2)=[O:9])=[CH:4][CH:3]=1.O.Cl.[NH:23]1[CH2:28][CH2:27][C:26](=[O:29])[CH2:25][CH2:24]1>C(Cl)(Cl)Cl.[OH-].[Na+]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH:10][CH2:11][C:12]2[S:16][C:15]([S:17]([N:23]3[CH2:28][CH2:27][C:26](=[O:29])[CH2:25][CH2:24]3)(=[O:19])=[O:18])=[CH:14][CH:13]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: O=C1CCNCC1
Reactant: O=C(NCc1ccc(S(=O)(=O)Cl)s1)c1ccc(Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=C1CCN(S(=O)(=O)c2ccc(CNC(=O)c3ccc(Cl)cc3)s2)CC1

Procedure:
A solution of 5-({[1-(4-Chloro-phenyl)-methanoyl]-amino}-methyl)-thiophene-2-sulfonyl chloride (1b) (5.0 g, 14 mmol) in 100 ml chloroform and a solution of 4-piperidinone hydrochloride monohydrate (4.3 g, 28 mmol) in 21 ml of NaOH (2N) were stirred vigorously for 15 h. The reaction was quenched with HCl (2N) and the organic layer was extracted twice with HCl (2N) and twice with brine. The dried organic phase affords after evaporation of chloroform 5.8 g (99.5%) of (63c) as a colourless solid: 1H NMR (CDCl3) δ7.67 (d, J=8.7 Hz, 2H), 7.42-7.38 (m, 3H), 6.99 (d, J=3.8 Hz, 1H), 6.53 (t, J=5.3 Hz, 1H), 4.74 (d, J=6.0 Hz, 2H), 3.37 (d, J=6.2 Hz, 4H), 2.50 (d, H=6.2 Hz, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1[NH:27][C:28]([NH:30][CH:31]1[CH2:33][CH2:32]1)=[O:29])[O:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:19][CH2:20][CH2:21][O:22][CH3:23])=[C:13]([C:16]([OH:18])=O)[CH:14]=2)[N:9]=[CH:8][CH:7]=1.[CH3:34][O:35][CH2:36][CH2:37][NH2:38].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>C(OCC)(=O)C.O.CN(C)C=O>[CH3:34][O:35][CH2:36][CH2:37][NH:38][C:16]([C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][C:12]=1[O:19][CH2:20][CH2:21][O:22][CH3:23])[N:9]=[CH:8][CH:7]=[C:6]2[O:5][C:4]1[CH:24]=[CH:25][C:26]([NH:27][C:28]([NH:30][CH:31]2[CH2:32][CH2:33]2)=[O:29])=[C:2]([Cl:1])[CH:3]=1)=[O:18]
Reactant: COCCN
Reactant: COCCOc1cc2nccc(Oc3ccc(NC(=O)NC4CC4)c(Cl)c3)c2cc1C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: O
Product: COCCNC(=O)c1cc2c(Oc3ccc(NC(=O)NC4CC4)c(Cl)c3)ccnc2cc1OCCOC

Procedure:
4-(3-Chloro-4-{[(cyclopropylamino)carbonyl]amino}phenoxy)-7-(2-methoxyethoxy)-6-quinolinecarboxylic acid (200 mg), 2-methoxyethylamine (38 mg), benzotriazol-1-yloxytris (dimethylamino)phosphonium hexafluorophosphate (Bop reagent) (230 mg), triethylamine (0.12 ml) and dimethylformamide (5 ml) were stirred together at room temperature for 14 hours. Water and ethyl acetate were added to the reaction solution for extraction, NH type silica gel was added to the extract, the solvent was distilled off under reduced pressure and the reaction product was adsorbed onto the silica gel. The silica gel was charged into a dry column packed with NH type silica gel, and column purification was performed (ethyl acetate). The solvent was distilled off under reduced pressure to obtain 120 mg of the target substance as a solid.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([NH:14]C(=O)OC(C)(C)C)=[O:13])=[C:5]2[NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=1.[Si:31]([O:38][C:39]1[CH:44]=[CH:43][C:42]([SH:45])=[CH:41][CH:40]=1)([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32].O(C1C=CC=CC=1P(C1C=CC=CC=1)C1C=CC=CC=1)C1C=CC=CC=1P(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+]>C1(C)C=CC=CC=1.C(OCC)(=O)C.[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1>[Si:31]([O:38][C:39]1[CH:44]=[CH:43][C:42]([S:45][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12]([NH2:14])=[O:13])=[C:5]3[NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=2)=[CH:41][CH:40]=1)([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(S)cc1
Reactant: COc1cccc(Nc2c(C(=O)NC(=O)OC(C)(C)C)cnc3ccc(I)cc23)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1cccc(Nc2c(C(N)=O)cnc3ccc(Sc4ccc(O[Si](C)(C)C(C)(C)C)cc4)cc23)c1
Yield: 46.4 %

Procedure:
A stirred mixture of Intermediate 37 (0.8 g) and 4-{[tert-butyl(dimethyl)silyl]oxy} benzenethiol (0.74 g, EP465802A1), with (oxydi-2,1-phenylene)bis(diphenylphosphine) (0.05 g), potassium tert-butoxide (0.26 g) and tris(dibenzylideneacetone) dipalladium(0) (0.08 g) in toluene (30 ml) was heated at 106° C. for 18 h. The mixture was cooled, diluted with ethyl acetate (25 ml) and washed with a sodium carbonate solution (30 ml). The organic extracts were washed with water (30 ml) , dried (Na2SO4) and concentrated in vacuo. The residue was purified by chromatography on silica gel using ethyl acetate/diethyl ether (7:3) as the eluent. The appropriate fractions were concentrated in vacuo to give the title compound as a yellow foam (0.38 g).
Reaction SMILES: Br[C:2]1(Br)[C:4]2([CH2:8][C@@H:7]([C:9]([O:11][CH3:12])=[O:10])[N:6]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:5]2)[CH2:3]1.C[Si]([SiH]([Si](C)(C)C)[Si](C)(C)C)(C)C.CC(N=NC(C#N)(C)C)(C#N)C>C1(C)C=CC=CC=1>[CH2:3]1[C:4]2([CH2:8][C@@H:7]([C:9]([O:11][CH3:12])=[O:10])[N:6]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:5]2)[CH2:2]1
Reactant: COC(=O)[C@@H]1CC2(CN1C(=O)OC(C)(C)C)CC2(Br)Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: C[Si](C)(C)[SiH]([Si](C)(C)C)[Si](C)(C)C
Solvent: Cc1ccccc1
Product: COC(=O)[C@@H]1CC2(CC2)CN1C(=O)OC(C)(C)C
Temperature: 90 °C
Yield: 69 %

Procedure:
To a solution of (6S)-5-tert-butyl 6-methyl 1,1-dibromo-5-azaspiro[2.4]heptane-5,6-dicarboxylate (0.209 g, 0.506 mmol) in toluene (5 mL) was added tris(trimethylsilyl)-silane (0.47 mL, 1.518 mmol, 3.0 eq), followed by AIBN (8.3 mg, 0.0506 mmol, 0.1 eq). The mixture was degassed at 0° C. 3 times and then heated at 90° C. for 24 hours. The mixture was allowed to cool down and directly purified by flash column chromatography (silica, Hexanes-EtOAc) to afford the desired product as a colorless oil (89.1 mg, 69%). 1H NMR (500 MHz, CDCl3): 4.36 (dd, J=3.8, 8.4 Hz, 0.4H), 4.25 (dd, J=4.8, 8.3 Hz, 0.6H), 3.62 (s, 3H), 3.30-3.17 (m, 2H), 2.16-2.08 (m, 1H), 1.75 (dd, J=4.7, 12.7 Hz, 0.6H), 1.67 (dd, J=3.8, 12.7 Hz, 0.4H), 1.34/1.31 (two overlapping s, 9H), 0.54-0.39 (m, 4H).
Reaction SMILES: C[O:2][C:3](=[O:35])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]([S:24]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)(=[O:26])=[O:25])[CH:12]2[CH2:18][CH:17]([C:19]([F:22])([F:21])[F:20])[CH2:16][CH2:15][NH:14][C:13]2=[O:23])=[C:6]([F:34])[CH:5]=1.[OH-].[Na+]>C1COCC1>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([S:24]([N:11]([CH2:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:35])=[O:2])=[CH:5][C:6]=2[F:34])[CH:12]2[CH2:18][CH:17]([C:19]([F:21])([F:20])[F:22])[CH2:16][CH2:15][NH:14][C:13]2=[O:23])(=[O:26])=[O:25])=[CH:28][CH:29]=1
Reactant: COC(=O)c1ccc(CN(C2CC(C(F)(F)F)CCNC2=O)S(=O)(=O)c2ccc(Cl)cc2)c(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1ccc(CN(C2CC(C(F)(F)F)CCNC2=O)S(=O)(=O)c2ccc(Cl)cc2)c(F)c1
Reaction time: 6 h

Procedure:
4-{[(4-Chloro-benzenesulfonyl)-(2-oxo-5-trifluoromethyl-azepan-3-yl)-amino]-methyl}-3-fluoro-benzoic acid methyl ester (0.03 g, 0.06 mmol) was dissolved in THF (2 ml) and 1 N NaOH (4 ml) was added. The reaction mixture was stirred for 6 h at pH 10. A KHSO4/K2SO4 aqueous buffer was added to adjust the pH to 3. The mixture was extracted with ethyl acetate and the combined organic extracts were dried (Na2SO4) and concentrated under reduced pressure and lyophilised yielding a solid: 11 mg; MS: m/e=521.2 (MH−).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH:12]([F:14])[F:13])=[CH:8][C:7]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25](O)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1.Cl.[N:29]([C@@H:32]1[CH2:37][CH2:36][C@@H:35]([NH2:38])[CH2:34][C@H:33]1[CH3:39])=[N+:30]=[N-:31]>>[N:29]([C@H:32]1[CH2:37][CH2:36][C@H:35]([NH:38][C:25]([C:21]2[C:17]3[N:18]=[CH:19][N:20]=[C:15]([C:7]4[CH:8]=[C:9]([CH:12]([F:14])[F:13])[CH:10]=[CH:11][C:6]=4[O:5][CH2:4][CH:1]4[CH2:2][CH2:3]4)[C:16]=3[NH:23][C:22]=2[CH3:24])=[O:26])[CH2:34][C@@H:33]1[CH3:39])=[N+:30]=[N-:31]
Reactant: Cc1[nH]c2c(-c3cc(C(F)F)ccc3OCC3CC3)ncnc2c1C(=O)O
Reactant: C[C@@H]1C[C@H](N)CC[C@H]1N=[N+]=[N-]
Agent: Cl
Product: Cc1[nH]c2c(-c3cc(C(F)F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@H]1CC[C@H](N=[N+]=[N-])[C@@H](C)C1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-(difluoromethyl)phenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.g1) and (1R*,3R*,4R*)-4-azido-3-methylcyclohexanamine hydrochloride (example C12) the title compound is obtained as pale yellow foam.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[C:43]([F:49])[C:42]=3[F:50])[CH:34]=2)([O:31][CH3:32])[O:11][C@@H:10]1[CH:51]=[O:52])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:53]=[O:54].[OH-].[Na+]>O1CCOCC1>[CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[C:43]([F:49])[C:42]=3[F:50])[CH:34]=2)([O:31][CH3:32])[O:11][C@:10]1([CH2:53][OH:54])[CH:51]=[O:52])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=O
Reactant: COc1ccc(Cc2cc([C@]3(OC)O[C@H](C=O)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)c(F)c1F
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1ccc(Cc2cc([C@]3(OC)O[C@@](C=O)(CO)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)c(F)c1F
Temperature: 70 °C
Reaction time: 8 h
Yield: 99.4 %

Procedure:
(2S,3S,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[(2,3-difluoro-4-methoxy-phenyl)methyl]phenyl]-6-methoxy-tetrahydropyran-2-carbaldehyde 2k (1.24 g, 1.71 mmol) was dissolved in 15 mL 1,4-dioxane, followed by 37%-40% aqueous solution of formaldehyde (2.8 mL, 34.2 mmol) and 1.5 mL of sodium hydroxide solution (205 mg, 5.13 mmol). The reaction mixture was stirred overnight at 70° C. Thereafter, the reaction mixture was concentrated under reduced pressure and partitioned after 30 mL ethyl acetate and 15 mL saturated sodium chloride solution were added. The aqueous phase was extracted with ethyl acetate (15 mL×2) and the organic extract was combined, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (2S,3S,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[(2,3-difluoro-4-methoxy-phenyl)methyl]phenyl]-2-(hydroxymethyl)-6-methoxy-tetrahydropyran-2-carbaldehyde 2m (1.29 g, yellow grease), which was used directly in the next step without purification.