Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][S:10]([NH:13][C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[NH:19][C:18]([C:23]([O:25]CC)=[O:24])=[CH:17]3)(=[O:12])=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[K+].Cl>O1CCOCC1.O>[N:1]1([CH2:7][CH2:8][CH2:9][S:10]([NH:13][C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[NH:19][C:18]([C:23]([OH:25])=[O:24])=[CH:17]3)(=[O:12])=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)c1cc2cc(NS(=O)(=O)CCCN3CCCCC3)ccc2[nH]1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1cc2cc(NS(=O)(=O)CCCN3CCCCC3)ccc2[nH]1
Reaction time: 24 h

Procedure:
Ethyl 5-[(3-(piperadin-1-yl)propyl)sulfonamido]indole-2- carboxylate (PREPARATION 83, 1.63 g) is dissolved in 10 ml of dioxane and 5 ml of water. Then 0.59 g of solid potassium hydroxide pellets are added and the reaction is stirred at 20°-25° for 24 hr. Then 8.91 ml of 1N hydrochloric acid is added after diluting the reaction with 100 ml of water. The mixture is extracted with n-butanol (3×50 ml) and the organic layer is separated and evaporated under reduced pressure to provide the title compound, NMR (300 MHz, d6 -DMSO) 7.37, 7.27, 7.00, 6.90, 2.91, 2.25, 1.75, 1.31, (peak at 4.3 ppm obscured by DMSO).
Reaction SMILES: C([O:3][C:4](=[O:34])[CH:5](C(OCC)=O)[CH:6]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH2:23][CH:24]([CH2:27][CH3:28])[CH2:25][CH3:26])[CH:15]=1)[CH:7]([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])C.C(OC(=O)C(C(OCC)=O)C(C1C=CC(OC)=C(OC)C=1)C(OCC)OCC)C>>[CH2:9]([O:8][CH:7]([O:11][CH2:12][CH3:13])[CH:6]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH2:23][CH:24]([CH2:27][CH3:28])[CH2:25][CH3:26])[CH:15]=1)[CH2:5][C:4]([OH:34])=[O:3])[CH3:10]
Reactant: CCOC(=O)C(C(=O)OCC)C(c1ccc(OC)c(OCC(CC)CC)c1)C(OCC)OCC
Agent: CCOC(=O)C(C(=O)OCC)C(c1ccc(OC)c(OC)c1)C(OCC)OCC
Product: CCOC(OCC)C(CC(=O)O)c1ccc(OC)c(OCC(CC)CC)c1
Yield: 36.9 %

Procedure:
Using the same procedure as in Example 1(3), 4,4-diethoxy-2-ethoxycarbonyl-3-[3-(2-ethylbutoxy)-4-methoxyphenyl]butyric acid ethyl ester, instead of 3-(3,4-dimethoxyphenyl)-4,4-diethoxy-2-ethoxycarbonylbutyric acid ethyl ester, was used to obtain a yellow solid of the above-described compound via 4,4-diethoxy-3-[3-(2-ethylbutoxy)-4-methoxyphenyl] butyric acid (yield 36.9%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][C:10]=1[CH2:11][N:12]([C:15]1[CH:20]=[CH:19][C:18]([C:21]([OH:23])=O)=[CH:17][N:16]=1)[CH2:13][CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:29]([S:32]([NH2:35])(=[O:34])=[O:33])[CH2:30][CH3:31].CN(C1N=CC=CN=1)C.Cl.CN(C)CCCC(N=C=N)C.Cl>ClCCl>[CH2:1]([O:8][C:9]1[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][C:10]=1[CH2:11][N:12]([C:15]1[CH:20]=[CH:19][C:18]([C:21]([NH:35][S:32]([CH2:29][CH2:30][CH3:31])(=[O:34])=[O:33])=[O:23])=[CH:17][N:16]=1)[CH2:13][CH3:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCS(N)(=O)=O
Reactant: CCN(Cc1cc(Br)ccc1OCc1ccccc1)c1ccc(C(=O)O)cn1
Agent: CC(CCCN(C)C)N=C=N
Agent: CN(C)c1ncccn1
Agent: Cl
Solvent: ClCCl
Product: CCCS(=O)(=O)NC(=O)c1ccc(N(CC)Cc2cc(Br)ccc2OCc2ccccc2)nc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 24.6 %

Procedure:
To a solution of 2-(N-(2-benzyloxy-5-bromobenzyl)-N-ethylamino]pyridine-5-carboxylic acid (0.89 g) in dichloromethane (50 ml) was added propanesulphonamide (0.3 g), dimethylaminopyrimidine (0.493 g) and 1-(3-dimethylaminopropyl)ethylcarbodiimide hydrochloride (0.58 g). The mixture was stirred at ambient temperature for 18 hours, and poured into 2N HCl. The organic layer was separated and washed with water and brine, then dried (MgSO4), filtered and evaporated. The resulting oil was purified by chromatography on silica gel (eluting with 5% ethylacetate/dichloromethane to give N-(2-[N-(2-benzyloxy-5-bromobenzyl)-N-ethylamino]pyridine-5-carbonyl)propanesulphonamide (271 mg) as a white foam.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:19].[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29](O)=[O:30])=[CH:24][CH:23]=1>>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3](=[O:19])[N:2]([NH:1][C:29](=[O:30])[CH2:28][C:25]3[CH:26]=[CH:27][C:22]([O:21][CH3:20])=[CH:23][CH:24]=3)[N:11]=2)=[CH:13][CH:14]=1
Reactant: COc1ccc(CC(=O)O)cc1
Reactant: Nn1nc(-c2ccc(Cl)cc2)c2ccccc2c1=O
Product: COc1ccc(CC(=O)Nn2nc(-c3ccc(Cl)cc3)c3ccccc3c2=O)cc1

Procedure:
The product of Example 86A and 2-(4-methoxyphenyl)acetic acid were treated using a method similar to that described in Example 57 to give the title compound. 1H NMR (500 MHz, DMSO-d6/Deuterium Oxide) δ ppm 8.40-8.42 (m, 1H), 7.88-8.03 (m, 2H), 7.71-7.74 (m, 1H), 7.58-7.68 (m, 4H), 7.29-7.31 (m, 2H), 6.90-6.93 (m, 2H), 3.74 (s, 3H), 3.62 (s, 2H); MS (APCI+) M/Z 420 (M+H)+.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][O:17][CH3:18])[CH:12]=[CH:11][C:10]=1/[CH:19]=[CH:20]/[C:21]([O:23][CH2:24][CH3:25])=[O:22])C1C=CC=CC=1>[C].[Pd].C(O)C>[OH:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][O:17][CH3:18])[CH:12]=[CH:11][C:10]=1[CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC(=O)/C=C/c1ccc(OCOC)cc1OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCc1ccc(OCOC)cc1O
Yield: 83.4 %

Procedure:
A mixture of ethyl (E)-3-(2-benzyloxy-4-methoxymethoxyphenyl)-2-propenoate (14.80 g), 5% palladium carbon (20.0 g) and ethanol (300 mL) was subjected to catalytic hydrogenation at room temperature and 1 atm. After filtering off the catalyst, the solvent was evaporated under reduced pressure to give ethyl 3-(2-hydroxy-4-methoxymethoxyphenyl)propionate as a colorless oil (9.17 g, 84%).
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[CH2:14][CH2:13]2)=[N:9][C:8]2[C:3]1=[N:4][C:5]([C:30]1[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[N:32](S(C3C=CC=CC=3)(=O)=O)[CH:31]=1)=[N:6][C:7]=2[N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1.[OH-].[Na+]>C(O)C>[NH:32]1[C:33]2[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:30]([C:5]2[N:4]=[C:3]3[C:8]([N:9]=[C:10]([CH2:11][N:12]4[CH2:13][CH2:14][CH:15]([N:18]5[CH2:23][CH2:22][O:21][CH2:20][CH2:19]5)[CH2:16][CH2:17]4)[N:2]3[CH3:1])=[C:7]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[N:6]=2)=[CH:31]1
Reactant: Cn1c(CN2CCC(N3CCOCC3)CC2)nc2c(N3CCOCC3)nc(-c3cn(S(=O)(=O)c4ccccc4)c4ccccc34)nc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cn1c(CN2CCC(N3CCOCC3)CC2)nc2c(N3CCOCC3)nc(-c3c[nH]c4ccccc34)nc21
Reaction time: 18 h
Yield: 57.6 %

Procedure:
To a solution of 4-(1-((9-methyl-6-morpholino-2-(1-(phenylsulfonyl)-1H-indol-3-yl)-9H-purin-8-yl)methyl)piperidin-4-yl)morpholine (357 mg, 0.544 mmol) in ethanol (5 mL) was added a 1 M aqueous solution of NaOH (4 mL, 4 mmol). After 18 hours of stirring, the reaction mixture was concentrated and purified by RP-HPLC to give 104 (162 mg, 57.7%). LCMS: M+H+=517.3. 1H-NMR (400 MHz, DMSO-d6): δ 11.46 (s, 1H), 8.60 (m, 1H), 8.13 (s, 1H), 7.43 (m, 1H), 7.14 (m, 2H), 4.16 (s, 4H), 3.84, (s, 3H), 3.76 (t, 4H), 3.71 (s, 2H), 3.54 (t, 4H), 2.85 (d, 2H), 2.43 (t, 4H), 2.07 (m, 3H), 1.75 (d, 2H), 1.38 (m, 2H)
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][S:7][CH2:8][CH2:9][C:10]([NH:12][NH:13][C:14]([N:16]1[CH2:22][C:21]2[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=2[O:19][C:18]2[CH:27]=[CH:28][C:29]([Cl:31])=[CH:30][C:17]1=2)=[O:15])=[O:11].[OH:32]O>CC(O)=O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][S:7]([CH2:8][CH2:9][C:10]([NH:12][NH:13][C:14]([N:16]1[CH2:22][C:21]2[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=2[O:19][C:18]2[CH:27]=[CH:28][C:29]([Cl:31])=[CH:30][C:17]1=2)=[O:15])=[O:11])=[O:32]
Reactant: OO
Reactant: O=C(CCSCc1ccco1)NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Solvent: CC(=O)O
Product: O=C(CCS(=O)Cc1ccco1)NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Reaction time: 1 h

Procedure:
To a stirring solution of 0.69 g (1.5 mmol) of 8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid, 2-[3-[(2-furanylmethyl)thio]-1-oxopropyl]hydrazide (13), prepared as described above in Example 13, in 5 mL of HOAc was added 0.13 mL (1.5 mmol) of a 30% hydrogen peroxide solution. After one hour, the reaction mixture was lyophilized. The product was recrystallized from EtOAc-hexanes. The yield of 8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid, 2-[3-[(2-furanylmethyl)sulfinyl]-1-oxopropyl]hydrazide (60) was 0.56 g (79%). Analysis calculated for C22H20N3O5SCl (M.W. 473.93): C, 55.76; H, 4.25; N, 8.87; Cl, 7.48; S, 6.77. Found: C, 55.67; H, 4.30; N, 8.79; Cl, 7.47; S, 6.56.
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:17])[C:4]1[CH:9]=[CH:8][C:7]([S:10](=[O:16])(=[O:15])NCCO)=[CH:6][CH:5]=1.C(C1C=CC(S(Cl)(=O)=O)=CC=1)#N.Cl.[CH2:31]([O:33][C:34](=[O:37])[CH2:35][NH2:36])[CH3:32]>>[CH2:31]([O:33][C:34](=[O:37])[CH2:35][NH:36][S:10]([C:7]1[CH:6]=[CH:5][C:4]([C:3](=[NH:17])[NH:2][OH:1])=[CH:9][CH:8]=1)(=[O:16])=[O:15])[CH3:32]
Reactant: CCOC(=O)CN
Reactant: N=C(NO)c1ccc(S(=O)(=O)NCCO)cc1
Agent: Cl
Agent: N#Cc1ccc(S(=O)(=O)Cl)cc1
Product: CCOC(=O)CNS(=O)(=O)c1ccc(C(=N)NO)cc1

Procedure:
The title compound is prepared in analogy to N-hydroxy-4-(2-hydroxy-ethylsulfamoyl)-benzamidine starting from 4-cyano-benzenesulfonyl chloride and glycine ethyl ester hydrochloride; LC-MS: tR=0.27 min; [M+1]+=302.03;
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:17]=[CH:16][C:8]([O:9][CH2:10][C:11]2[NH:15][N:14]=[N:13][N:12]=2)=[CH:7][CH:6]=1)=[O:4].[N:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:20][CH:19]=1>C(#N)C>[N:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:25][CH2:26][N:27]([CH2:2][C:3]([C:5]3[CH:17]=[CH:16][C:8]([O:9][CH2:10][C:11]4[NH:15][N:14]=[N:13][N:12]=4)=[CH:7][CH:6]=3)=[O:4])[CH2:28][CH2:29]2)=[CH:20][CH:19]=1
Reactant: O=C(CCl)c1ccc(OCc2nnn[nH]2)cc1
Reactant: c1cc(N2CCNCC2)ccn1
Solvent: CC#N
Product: O=C(CN1CCN(c2ccncc2)CC1)c1ccc(OCc2nnn[nH]2)cc1
Reaction time: 8 h

Procedure:
A mixture of 5-(4-chloroacetylphenoxymethyl)tetrazole (166 mg) and 1-(4-pyridyl)piperazine (214 mg) in acetonitrile (10 ml) was stirred overnight. The precipitate was collected, washed with acetonitrile and dried. A solution of this material in a small volume of 50% v/v acetic acid/water was transfered to a 1 inch preparative reverse phase hplc column (DYNAMAX (Trade Mark) C18 83-221-C) and eluted with water/acetonitrile/ trifluoroacetic acid in a gradient from 98:2:0.1 v/v/v to 60:40:0.1 v/v/v. The pure fractions, on freeze-drying, gave the title compound, 8.1 mg, as a white powder: NMR (D2O) δ8.39 (2H,d), 8.18(2H,d), 7.40(4H,m), 5.84(2H,s), 5.20(2H,s), 4.31(4H,bt), 3.87(4H,bt); m/e 380 (M+H)+
Reaction SMILES: [CH:1]([C:5]1[CH:6]=[C:7]([S:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([CH3:27])([CH3:26])[CH3:25])=[C:20](C=CCC)[CH:19]=2)(=[O:17])=[O:16])C=CC=1C(C)(C)C)=CCC.[CH3:32][SnH:33]([CH3:35])[CH3:34]>[Hg]>[C:24]([C:21]1[CH:22]=[CH:23][C:18]([S:15]([CH2:7][CH2:6][CH2:5][CH2:1][Sn:33]([CH3:35])([CH3:34])[CH3:32])(=[O:17])=[O:16])=[CH:19][CH:20]=1)([CH3:27])([CH3:26])[CH3:25]
Reactant: C[SnH](C)C
Reactant: CCC=Cc1cc(S(=O)(=O)c2ccc(C(C)(C)C)c(C=CCC)c2)ccc1C(C)(C)C
Agent: [Hg]
Product: CC(C)(C)c1ccc(S(=O)(=O)CCCC[Sn](C)(C)C)cc1
Yield: 20.3 %

Procedure:
An 80 ml, two-necked, pyrex glass Schlenk reaction tube containing a Teflon coated magnetic stir bar was swept thoroughly with nitrogen and maintained in an air-free condition. The tube was charged with 10.7 g (42.5 mmoles) of 3-butenyl-4-t-butylphenyl sulfone and 7.0 g (42.5 mmoles) of trimethyltin hydride, stoppered, and placed in a 20° C. water bath. The tube was irradiated for 70 hours by a 100 watt mercury vapor lamp which was situated in a large test tube and placed in the same bath 5-10 cm. from the reaction tube. Recrystallization of the solid product from petroleum ether afforded 3.6 g of 4-(4-t-butylphenylsulfonyl)butyltrimethylstannane, m.p. 80°-81.8° C. The presence of both the sulfonyl and trimethyltin moieties was indicated by strong infrared absorption bands at 1300 cm-1, 1282 cm-1, 1147 cm-1 (--SO2 --) and 780 cm-1 [(CH3)3Sn--] employing a KBR disc. Nuclear magnetic resonance spectroscopy (NMR) showed the following:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][C:11]([O:14]C)=[CH:10][C:8]=2[CH:9]=1)=[O:4].B(Br)(Br)Br>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][C:8]=2[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc2cc(OC)ccc2o1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: COC(=O)c1cc2cc(O)ccc2o1
Reaction time: 3 h
Yield: 43.4 %

Procedure:
A solution of 5-methoxy-benzofuran-2-carboxylic acid methyl ester (5.0 g, 24 mmol) in 50 mL DCM at 0° C. was treated portionwise with boron tribromide (4.4 mL of a 1 M solution in DCM). After 3 hours, the reaction mixture was carefully quenched with 50% NH4OH. The organic layer was separated and washed 1×50 mL brine, dried (Na2SO4), and concentrated in vacuo to give 2 g (43%) of the title compound pure enough for subsequent use. 400 MHz 1H NMR (DMSO-d6) δ 9.47 (s, 1H), 7.56 (s, 1H), 7.45 (d, 1H, J=8.8 Hz), 7.00 (s, 1H), 6.91 (d, 1H,J=8.8 Hz), 3.81 (s, 3H).
Reaction SMILES: [CH2:1]([N:8]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:9]1[N:10]=[CH:11][CH:12]=[C:13]2[CH:17]=[C:16]([CH:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[OH:19])[NH:15][C:14]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(Cl)Cl.O=[Mn]=O>[CH2:26]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:9]1[N:10]=[CH:11][CH:12]=[C:13]2[CH:17]=[C:16]([C:18]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[O:19])[NH:15][C:14]=12)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: OC(c1ccccc1)c1cc2ccnc(N(Cc3ccccc3)Cc3ccccc3)c2[nH]1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: O=C(c1ccccc1)c1cc2ccnc(N(Cc3ccccc3)Cc3ccccc3)c2[nH]1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A mixture of [7-(dibenzylamino)-1H-pyrrolo[2,3-c]pyridin-2-yl](phenyl)methanol (Example 46) (1.13 g, 2.69 mmol) and MnO2 (2.35 g, 27.0 mmol) in methylene chloride (75 mL) was stirred under a nitrogen atmosphere at room temperature overnight (17 h). The crude reaction mixture was filtered through diatomaceous earth, rinsing with methylene chloride. The filtrate was concentrated to give a dark oil. Purification by Biotage chromatography (10-30% ethyl acetate in hexanes) provided [7-(dibenzylamino)-1H-pyrrolo[2,3-c]pyridin-2-yl](phenyl)methanone as a yellow solid: mp 122-124° C.; 1H NMR (300 MHz, CD3OD) δ4.76 (4H, s), 5.49 (1H, s), 6.25 (1H, s), 7.11 (1H, s) 7.15-7.30 (10H, m), 7.56-7.72 (4H, m), 7.94-7.97 (2H, m); ESI MS m/z 418 [C28H23N3O+H]+; HPLC (Method A) >99% (AUC), tR=20.2 min.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5]([CH2:7][C:8]1[S:12][C:11]([N:13]=[C:14]2[N:18]3[CH2:19][C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=4[CH2:26][C@H:17]3[CH2:16][S:15]2)=[N:10][C:9]=1[CH3:27])=[O:6].[ClH:28]>C(O)C>[ClH:28].[C:5]([CH2:7][C:8]1[S:12][C:11]([N:13]=[C:14]2[N:18]3[CH2:19][C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=4[CH2:26][C@H:17]3[CH2:16][S:15]2)=[N:10][C:9]=1[CH3:27])([OH:6])=[O:4]
Reactant: COC(=O)Cc1sc(N=C2SC[C@@H]3Cc4ccccc4CN23)nc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nc(N=C2SC[C@@H]3Cc4ccccc4CN23)sc1CC(=O)O
Temperature: 20 °C

Procedure:
5 N Aqueous sodium hydroxide (20 cc) is added to a solution of (S)-3-[(5-methoxycarbonylmethyl-4-methylthiazol-2-yl)imino]-1,5,10,10a-tetrahydrothiazolo[3,4-b]isoquinoline (8.1 g) in ethanol (60 cc). The mixture is heated under reflux for two hours. After cooling to 20° C., it is acidified by adding 12 N hydrochloric acid (d=1.19; 10 cc). The resulting precipitate is filtered off, washed with water (5×25 cc), ethanol (3×15 cc) and diethyl ether (2×25 cc) and recrystallised by dissolving it in dimethylformamide (80 cc) at 150° C. and cooling to 0° C. The resulting crystals are filtered off, washed with dimethylformamide (10 cc), ethanol (4×15 cc) and diethyl ether (3×15 cc) and dried at 45° C. under reduced pressure (0.1 mm Hg; 0.013 kPa) to yield (S)-3-[(5-carboxymethyl-4-methylthiazol-2-yl)imino]-1,5,10,10a-tetrahydrothiazolo[3,4-b]-isoquinoline hydrochloride (4.8 g), as a white solid melting at about 250° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]2=[N:19]N(C)C)=[O:12])[CH2:7][CH2:6]1)=[O:4].C([O-])(=O)C.[Na+].Cl.NO>CO>[CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]2[O:12][N:19]=[C:14]3[CH2:15][CH2:16][CH2:17][CH2:18][C:13]=23)[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)[C@H]1CC[C@H](C(=O)C2CCCCC2=NN(C)C)CC1
Agent: CC(=O)[O-]
Agent: Cl
Agent: NO
Solvent: CO
Product: COC(=O)[C@H]1CC[C@H](c2onc3c2CCCC3)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of trans-4-[2-(dimethyl-hydrazono)-cyclohexanecarbonyl]-cyclohexanecarboxylic acid methyl ester (0.95 g, 3.1 mmol), sodium acetate (0.28 g, 3.4 mmol) and hydroxylamine hydrochloride (0.24 g, 3.4 mmol) in methanol (15 ml) was stirred at room temperature for 16 h. The reaction mixture was partitioned between ethyl acetate (100 ml) and water (50 ml). The layers were separated. The aqueous layer was extracted with two 100-ml portions of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue (0.88 g) was dissolved in toluene (15 ml). After addition of a catalytic amount of toluene-4-sulfonic acid monohydrate the mixture was heated at reflux for 3 h. The solvent was evaporated. Purification with n-heptane/ethyl acetate as eluent gave the title compound (0.58 g, 72%) with a regioisomeric purity of approx. 90% according to 13C-NMR. MS m/e: 264 ([M+H]+)
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][N:8]=[C:9]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH3:20])[C:15]2[N:21]([CH3:34])[C:22](=[O:33])[C:23]([C:25]4[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=4[Cl:32])=[CH:24][C:14]3=2)[CH:10]=1)=[O:5])[CH3:2].I[CH3:36]>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:36])[N:8]=[C:9]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH3:20])[C:15]2[N:21]([CH3:34])[C:22](=[O:33])[C:23]([C:25]4[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=4[Cl:32])=[CH:24][C:14]3=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(-c2ccc3c(c2)c2cc(-c4ccc(Cl)cc4Cl)c(=O)n(C)c2n3C)n[nH]1
Reactant: CI
Product: CCOC(=O)c1cc(-c2ccc3c(c2)c2cc(-c4ccc(Cl)cc4Cl)c(=O)n(C)c2n3C)nn1C

Procedure:
The process is carried out as in Example 36 above, with 5-[3-(2,4-dichlorophenyl)-1,9-dimethyl-2-oxo-2,9-dihydro-1H-pyrido[2,3-b]indol-6-yl]-2H-pyrazole-3-carboxylic acid ethyl ester from Example 43 above and iodomethane.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:13][CH2:12][CH:11]([C:14]3[NH:18][N:17]=[N:16][N:15]=3)[O:10][C:9]=2[C:19]=1[NH:20][C:21](=[O:37])[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[CH:24][CH:23]=1)=[O:4].[OH-].[Na+].Cl>CO>[CH2:29]([O:28][C:25]1[CH:26]=[CH:27][C:22]([C:21]([NH:20][C:19]2[C:9]3[O:10][CH:11]([C:14]4[NH:18][N:17]=[N:16][N:15]=4)[CH2:12][O:13][C:8]=3[CH:7]=[CH:6][C:5]=2[C:3]([OH:4])=[O:2])=[O:37])=[CH:23][CH:24]=1)[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: CCCCCCCCOc1ccc(C(=O)Nc2c(C(=O)OC)ccc3c2OC(c2nnn[nH]2)CO3)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCCCOc1ccc(C(=O)Nc2c(C(=O)O)ccc3c2OC(c2nnn[nH]2)CO3)cc1

Procedure:
8-(p-octyloxybenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane-7-carboxylic acid methyl ester (332 mg; synthesized in example 2 (107) was dissolved in methanol (1.5 ml). To the solution, a 1N aqueous solution of sodium hydroxide (1.36 ml), and the mixture was stirred for 50 min at room temperature and for 2 hrs at 40° C. After cooling, 1N hydrochloric acid (2 ml) was added to the solution. The mixture was extracted with ethyl acetate. The extract was dried and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (chloroform: methanol=9:1) to give the title compound (263 mg) having the following physical data:
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@H:8]([NH:13]C(=O)OC(C)(C)C)[C:9]([NH:11][CH3:12])=[O:10])=[CH:3][CH:2]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:13][C@@H:8]([CH2:7][C:4]1[CH:5]=[CH:6][C:1]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:2][CH:3]=1)[C:9]([NH:11][CH3:12])=[O:10]
Reactant: CNC(=O)[C@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)[C@@H](N)Cc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (S)-tert-butyl 3-(biphenyl-4-yl)-1-(methylamino)-1-oxopropan-2-ylcarbamate (111 mg, 0.31 mmol) in DCM (4 mL) was added TFA (2 mL). The mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated and azeotroped (three times) with toluene and dried under high vacuum. The obtained (S)-2-amino-3-(biphenyl-4-yl)-N,N-methylpropanamide TFA salt (80 mg) was used for next step without further purification. HPLC retention time=1.21 minutes (condition B); MS (m+1)=255.0; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.48 (d, J=1.8 Hz, 3H) 2.90-3.24 (m, 2H) 4.04-4.48 (m, 1H) 7.10 (d, J=8.3 Hz, 2H) 7.20 (d, J=7.3 Hz, 1H) 7.26 (t, J=7.5 Hz, 2H) 7.37 (d, J=7.6 Hz, 4H) 8.16 (br. s., 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10](OCC)[CH:11]=C=O)=[CH:4][C:3]=1[N:17]1[C:25](=[O:26])[N:20]2[CH2:21][CH2:22][CH2:23][CH2:24][C:19]2=[N:18]1.Cl.O1CCOCC1.[C:34](=[O:37])(O)[O-:35].[Na+]>O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]([C:34]([OH:35])=[O:37])[CH3:11])=[CH:4][C:3]=1[N:17]1[C:25](=[O:26])[N:20]2[CH2:21][CH2:22][CH2:23][CH2:24][C:19]2=[N:18]1
Reactant: CCOC(C=C=O)Oc1cc(-n2nc3n(c2=O)CCCC3)c(Cl)cc1Cl
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(Oc1cc(-n2nc3n(c2=O)CCCC3)c(Cl)cc1Cl)C(=O)O

Procedure:
10.8 Parts of 2-[2,4-dichloro-5-(1-ethoxy-carbonylethoxy)-phenyl]-5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-A]pyridin-3(2H)-one, 20.6 parts of concentrated hydrochloric acid (38%) and 175 parts of dioxane were combined and heated to 80° for 30 hours. After cooling the solution was poured into 750 parts of water. The pH of the solution was raised to 8-9 by addition of solid sodium bicarbonate. The aqueous solution of the product was then extracted three times with 250 parts of methylene chloride. The organic extracts were discarded. The aqueous solution of the product was then acidified to pH 1 by addition at concentrated hydrochloric acid (38%). The aqueous solution of product was extracted three times with 250 parts of methylene chloride. The solution of product was dried with anhydrous sodium sulfate. The solvent was removed on a rotary evaporator at reduced pressure. The glassy residue was triturated with ether. 4.4 Parts of white solid with m.p. 183°-185° were obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(O)C.[Cl-].[NH4+]>[Fe].O>[C:1]([O:5][C:6](=[O:26])[NH:7][CH:8]1[CH2:9][CH2:10][N:11]([S:14]([C:17]2[CH:18]=[CH:19][C:20]([NH2:23])=[CH:21][CH:22]=2)(=[O:16])=[O:15])[CH2:12][CH2:13]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CCN(S(=O)(=O)c2ccc([N+](=O)[O-])cc2)CC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)NC1CCN(S(=O)(=O)c2ccc(N)cc2)CC1
Temperature: 80 °C
Yield: 82.2 %

Procedure:
[1-(4-Nitro-benzenesulfonyl)-piperidin-4-yl]-carbamic acid tert-butyl ester (0.5 g, 1.3 mmol) was suspended in a 5:1 mixture of ethanol and water (20 ml). To this solution was added iron powder (0.22 g, 3.4 mmol) followed by saturated ammonium chloride solution (3 ml) and the mixture was heated to 80° C. for three hours. After this time, the reaction mixture was cooled to room temperature and filtered through a pad of celite, the celite was washed with ethanol (10 ml) and EtOAc (50 ml) and the solution was concentrated under vacuum. The resulting residue was suspended in water (10 ml) and the solid precipitate collected by filtration and dried under vacuum to give the title compound (0.38 g, 78% yield) as a white solid. Tr=1.84 min, m/z (ES+) (M+Na)+ 378.