Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:22])[S:3]([C:6]1[CH:7]=[CH:8][C:9]2[O:15][C:14]3[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=3[NH:12][C:11](=O)[C:10]=2[CH:21]=1)(=[O:5])=[O:4].B.CSC>O1CCCC1.CO>[CH3:1][N:2]([CH3:22])[S:3]([C:6]1[CH:7]=[CH:8][C:9]2[O:15][C:14]3[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=3[NH:12][CH2:11][C:10]=2[CH:21]=1)(=[O:4])=[O:5]
Reactant: CN(C)S(=O)(=O)c1ccc2c(c1)C(=O)Nc1ccccc1O2
Agent: B
Solvent: CO
Solvent: C1CCOC1
Solvent: CSC
Product: CN(C)S(=O)(=O)c1ccc2c(c1)CNc1ccccc1O2
Reaction time: 8 h
Yield: 85.4 %

Procedure:
To 5.88 g of 10,11-dihydro-N,N-dimethyl-11-oxodibenz[b,f][1,4]oxazepine-2-sulfonamide in 5 ml of tetrahydrofuran is added 20 ml of a molar solution of borane-dimethylsulfide in tetrahydrofuran. The mixture is stirred overnight and then refluxed for 2 hours. The mixture is chilled, diluted with 10 ml of methanol and then concentrated, methanol added again and the mixture concentrated. To the mixture is added 20 ml of 2N NaOH and the mixture refluxed for 2 hours. The mixture is extracted with dichloromethane, the extract dried (MgSO4) and filtered. The filtrate is passed through a thin pad of hydrous magnesium silicate and the pad washed with dichloromethane. The filtrate is concentrated to give 4.8 g of crystals, m.p. 99°-102° C. Recrystallization from diisopropylether-dichloromethane gives 3.96 g of crystals, m.p. 109°-110° C. Mass Spectrum (FAB) 305(M+H). Anal. Calc'd for C15H16N2O3S: C,59.2; H,5.3; N,9.2; S,10.6. Found: C,57.6; H,5.2; N,8.9; S,10.1.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[CH:7]=O)[CH3:2].[CH:14]([NH:17][OH:18])([CH3:16])[CH3:15]>>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:7]=[N+:17]([CH:14]([CH3:16])[CH3:15])[O-:18])[CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[CH3:2]
Reactant: CC(C)NO
Reactant: CCOc1cc(C=O)ccc1OC
Product: CCOc1cc(C=[N+]([O-])C(C)C)ccc1OC

Procedure:
The title compound was prepared according to the procedures described in Examples 11 using 3-ethoxy-4-methoxybenzaldehyde and N-isopropylhydroxylamine. The title compound was isolated in 43.9% yield as a solid, m.p. 80.8° C. (Rf=0.15 on a silica gel plate using ethyl acetate as the eluant).
Reaction SMILES: [CH3:1][CH:2]1[O:6][C:5]2[CH:7]=[C:8]([N+:15]([O-:17])=[O:16])[C:9]([NH:11]C(C)=O)=[CH:10][C:4]=2[O:3]1.C[O-].[Na+].C(O)(=O)C>CO>[CH3:1][CH:2]1[O:6][C:5]2[CH:7]=[C:8]([N+:15]([O-:17])=[O:16])[C:9]([NH2:11])=[CH:10][C:4]=2[O:3]1
Reactant: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])OC(C)O2
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC1Oc2cc(N)c([N+](=O)[O-])cc2O1
Yield: 89.8 %

Procedure:
39.6 g of 2-methyl-5-acetamino-6-nitro-1,3-benzodioxole were boiled at reflux for 1 hour in 4 l of methanol with 4 g of sodium methoxide. After adding 5 ml of glacial acetic acid, the solution was evaporated in vacuo. The last traces of glacial acetic acid were removed by evaporation with toluene. The residue was dissolved in methylene chloride and filtered through a small amount of silicon dioxide. The evaporated filtrate was crystallized from isopropanol. There were obtained 29.3 g (90.1% of theory) of 2-methyl-5-amino-6-nitro-1,3-benzodioxole of melting point 139° C.
Reaction SMILES: [CH2:1]([CH2:10][NH:11][C:12]1[C:20]2[C:15](=[CH:16][C:17]([Cl:21])=[CH:18][CH:19]=2)[NH:14][C:13]=1[C:22]([O:24]C)=[O:23])[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3].[OH-].[Li+].C(OCC)(=O)C>O1CCCC1.O>[CH2:1]([CH2:10][NH:11][C:12]1[C:20]2[C:15](=[CH:16][C:17]([Cl:21])=[CH:18][CH:19]=2)[NH:14][C:13]=1[C:22]([OH:24])=[O:23])[C:2]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)=[O:3]
Reactant: COC(=O)c1[nH]c2cc(Cl)ccc2c1NCCC(=O)c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: O=C(CCNc1c(C(=O)O)[nH]c2cc(Cl)ccc12)c1ccccc1

Procedure:
Dissolve 3-[(phenacyl)methylamino]-2-carbmethoxy-6-chloroindole from above, in tetrahydrofuran (5 mL) and water (5 mL). Add lithium hydroxide and stir for 8 hours at 40° C. Dilute the reaction with water(10 mL) and ethyl acetate (10 mL). Separate the layers and acidify the aqueous layer. Extract the aqueous with ethyl acetate, dry the organic phase over magnesium sulfate, filter and concentrate in vacuo. Recrystallize from ethyl acetate/hexane to yield the title compound (75 mg); mp 250°-255° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)=[O:9])=[C:6]([CH3:19])[CH:5]=[C:4](Cl)[N:3]=1.[NH:21]1[CH2:26][CH2:25][S:24][CH2:23][CH2:22]1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[C:7]([C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)=[O:9])=[C:6]([CH3:19])[CH:5]=[C:4]([N:21]2[CH2:26][CH2:25][S:24][CH2:23][CH2:22]2)[N:3]=1
Reactant: Cc1cc(Cl)nc(Cl)c1C(=O)NCc1cccc(F)c1
Reactant: C1CSCCN1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: Cc1cc(N2CCSCC2)nc(Cl)c1C(=O)NCc1cccc(F)c1
Temperature: 120 °C
Yield: 49.1 %

Procedure:
A solution of 700 mg (2.24 mmol) 2,6-dichloro-N-(3-fluorobenzyl)-4-methyl-pyridine-3-carboxylic acid amide (synthesis is described in section a) of example 2), 280 μl (2.9 mmol) thiomorpholine and 3.95 g (12.1 mmol) Cs2CO3 in dioxane (60 ml) was degassed for 30 min followed by the addition of 285 mg (0.25 mmol) Pd(PPh3)4. Subsequently the reaction solution was heated to 120° C. for 16 h. Then the mixture was filtered through celite and concentrated in vacuo. Purification of the residue by CC (hexane/EtOAc 19:1) provided 420 mg (1.1 mmol, 49%) 2-chloro-N-(3-fluorobenzyl)-4-methyl-6-thiomorpholino-pyridine-3-carboxylic acid amide.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[CH:9]([CH2:11][CH2:12][C:13]([NH:15][C:16]1[CH:24]=[CH:23][C:19](C(O)=O)=[CH:18][N:17]=1)=[O:14])[N:8]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)[C:7]2=[O:33].[Br:34]C1C=CC(N)=NC=1>>[Br:34][C:19]1[CH:23]=[CH:24][C:16]([NH:15][C:13](=[O:14])[CH2:12][CH2:11][CH:9]2[C:10]3[C:6](=[CH:5][CH:4]=[CH:3][C:2]=3[F:1])[C:7](=[O:33])[N:8]2[CH2:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)=[N:17][CH:18]=1
Reactant: Nc1ccc(Br)cn1
Reactant: O=C(CCC1c2c(F)cccc2C(=O)N1Cc1ccc(F)cc1)Nc1ccc(C(=O)O)cn1
Product: O=C(CCC1c2c(F)cccc2C(=O)N1Cc1ccc(F)cc1)Nc1ccc(Br)cn1

Procedure:
The product from Example 11, Part D (150 mg, 0.45 mmol) and 5-bromopyridin-2-ylamine (78 mg, 0.45 mmol) were converted to the title compound in a manner analogous to the method described in Example 27 (151 mg, 69%). 1H NMR (300 MHz, DMSO) δ 8.18 (d, J=2 Hz, 1H), 8.05 (m, 2H), 7.76 (dd, J=9 Hz, 3 Hz, 1H), 7.66 (d, J=7 Hz, 1H), 7.44 (m, 1H), 7.30 (m, 2H), 7.18 (t, J=9, 1H), 7.01 (t, J=7 Hz, 2H), 5.26 (d, J=15 Hz, 1H), 4.69 (m, 1H), 4.23 (d, J=15 Hz, 1H), 2.54 (m, 2H), 1.95 (m, 2H). MS: m/z (MH+) 486 (MH+ 2) 488.
Reaction SMILES: O=O.[C:3]([OH:11])(=[O:10])[C:4]([CH2:6][C:7]([OH:9])=[O:8])=[CH2:5].C1(C)C=CC=CC=1.C(N(CC)CC)C>CC(OC(N1[C@H](CP(C2C=CC=CC=2)C2C=CC=CC=2)C[C@H](P(C2C=CC=CC=2)C2C=CC=CC=2)C1)=O)(C)C.FC(F)(F)C([O-])=O.C([N+](CCCC)(CCCC)CCCC)CCC.CO>[CH3:5][CH:4]([CH2:6][C:7]([OH:9])=[O:8])[C:3]([OH:11])=[O:10]
Reactant: C=C(CC(=O)O)C(=O)O
Agent: CC(C)(C)OC(=O)N1C[C@@H](P(c2ccccc2)c2ccccc2)C[C@H]1CP(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CO
Solvent: Cc1ccccc1
Product: CC(CC(=O)O)C(=O)O
Yield: 90.8 %

Procedure:
A 500 ml steel autoclave was loaded in a glove box (O2 -content less than 1 ppm) with 2.6 g (20 mmol) of itaconic acid, 150 ml of toluene, 50 ml of methanol, 2.02 g (20 mmol) of triethylamine, 36.0 mg (0.0886 mmol) of [Rh(COD)2 ]BF4, 49 mg (0.0886 mmol) of BPPM and 31.5 mg (0.0886 mmol) of tetrabutylammonium trifluoroacetate. the hydrogenation was carried out at a constant pressure of 6 bar of H2, at 30° C. and with intensive stirring. After a total hydrogenation time of 3 hours the reaction solution was evaporated and the residue was dissolved in 40 ml of 2N sodium hydroxide solution. The aqueous phase was washed with toluene, adjusted to pH 2 with conc. hydrochloric acid, saturated with NaCl and extracted with 3×100 ml of ether. The combined ether phases were dried over Na2SO4 and evaporated. There were obtained 2.4 g (92.3%) of methylsuccinic acid as white crystals. M.p. 111°-112° C. [α]D20 =-16.2° (c=5, EtOH). Optical purity 95.4%.
Reaction SMILES: BrC1C=NC=C(Cl)C=1COC1CCCCO1.C(OC=O)C.[Cl:22][C:23]1[C:24]([CH2:34][O:35][CH:36]2[CH2:41][CH2:40][CH2:39][CH2:38][O:37]2)=[C:25]([C:29](=[O:33])COC)[CH:26]=[N:27][CH:28]=1>>[Cl:22][C:23]1[C:24]([CH2:34][O:35][CH:36]2[CH2:41][CH2:40][CH2:39][CH2:38][O:37]2)=[C:25]([CH:29]=[O:33])[CH:26]=[N:27][CH:28]=1
Reactant: COCC(=O)c1cncc(Cl)c1COC1CCCCO1
Agent: Clc1cncc(Br)c1COC1CCCCO1
Solvent: CCOC=O
Product: O=Cc1cncc(Cl)c1COC1CCCCO1

Procedure:
Reaction of 3-bromo-5-chloro-4-(tetrahydro-pyran-2-yloxymethyl)-pyridine (0.36 g, 1.0 mmol) with formic acid ethyl ester (1.6 mL, 20 mmol) according to the synthesis of 1-[5-chloro-4-(tetrahydro-pyran-2-yloxymethyl)-pyridin-3-yl]-2-methoxy-ethanone yielded the title compound. MS (m/z): 256.0 [M+H+].
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[CH3:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][C:20]=1[N+:21]([O-:23])=[O:22])[NH2:17].C([BH3-])#N.[Na+].C(O)(=O)C>CC1C=CC=CC=1C.C(OCC)(=O)C>[CH3:13][C:14]1[CH:15]=[C:16]([NH:17][CH2:7][C:6]2[CH:9]=[CH:10][C:3]([C:2]([F:12])([F:11])[F:1])=[CH:4][CH:5]=2)[CH:18]=[CH:19][C:20]=1[N+:21]([O-:23])=[O:22]
Reactant: Cc1cc(N)ccc1[N+](=O)[O-]
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: Cc1ccccc1C
Product: Cc1cc(NCc2ccc(C(F)(F)F)cc2)ccc1[N+](=O)[O-]
Temperature: 140 °C
Yield: 82.2 %

Procedure:
A suspension of 4-trifluoromethylbenzaldehyde (819 μL, 6.00 mmol), 3-methyl-4-nitroaniline (609 mg, 4.00 mmol), and Amberlite IRC-84 (200 mg, H+ form) in o-xylene (4 mL) was heated under nitrogen at 140° C. for 6 hours. It was then cooled to room temperature, diluted with ethyl acetate (5 mL), dried over sodium sulfate, filtered, and volatiles were evaporated. The residue was dissolved in acetonitrile (20 mL) and sodium cyanoborohydride (503 mg, 8.00 mmol) was added in one portion, followed by acetic acid (1 mL) in several portions over 15 minutes. After a further 30 minutes solvents were evaporated and the residue was partitioned between ethyl acetate (50 mL), brine (25 mL), and 10% aqueous potassium carbonate (25 mL). The organic layer was dried over sodium sulfate, solvents were evaporated, and the residue was purified on a FlashMaster system (silica, eluted with heptane/ethyl acetate mixtures) to yield the title compound as a yellow powder (1.02 g, 82%).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([C:11]([F:14])([F:13])[F:12])=[CH:4][N:3]=1>CO.[Pd]>[F:14][C:11]([F:12])([F:13])[C:5]1[CH:6]=[C:7]([NH2:8])[CH:2]=[N:3][CH:4]=1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cnc1Cl
Agent: [Pd]
Solvent: CO
Product: Nc1cncc(C(F)(F)F)c1
Reaction time: 1.5 h
Yield: 120.7 %

Procedure:
To a solution of 2-chloro-3-nitro-5-(trifluoromethyl)pyridine (1.25 g, 5.518 mmol) in methanol (25.0 mL) under N2 was added palladium (1.17 g, 1.10 mmol) (10% dry weight on wet activated carbon). The reaction mixture was placed on a Parr apparatus and hydrogenated at 50 psi for 90 min. The catalyst was filtered off through a celite pad. The filtrate was concentrated to give a crude product (1.08 g) which was pure (>98% by HPLC) enough without further purification. LC-MS calculated for C6H5F3N2: (M+H) 163; found 163.1.
Reaction SMILES: C1(C[O:8][C:9](=[O:34])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]2[CH:20]([C:21]([OH:23])=[O:22])[CH2:19][CH2:18][N:17]2C(OCC2C=CC=CC=2)=O)C=CC=CC=1.C(N1CCCC1C(O)=O)(OC[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=O>>[CH2:43]([O:23][C:21]([CH:20]1[CH2:19][CH2:18][NH:17][CH:16]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:9]([OH:8])=[O:34])=[O:22])[CH2:44][CH2:39][CH2:40][CH2:41][CH3:42]
Reactant: O=C(CCCCCCC1C(C(=O)O)CCN1C(=O)OCc1ccccc1)OCc1ccccc1
Reactant: O=C(O)C1CCCN1C(=O)OCc1ccccc1
Product: CCCCCCOC(=O)C1CCNC1CCCCCCC(=O)O

Procedure:
By substituting 3-carboxy-1-[(phenylmethyloxy)carbonyl]-2-pyrrolidineheptanoic acid phenylmethyl ester (Example 18) for the N-carbobenzoxy-DL-proline in the procedure of Example 1, 3-[(hexyloxy)carbonyl]-2-pyrrolidineheptanoic acid is obtained.
Reaction SMILES: [C:1]([OH:12])(=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH2:13]([SH:19])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>>[C:1](=[O:12])([S:19][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCC/C=C/C(=O)O
Reactant: CCCCCCS
Product: CCCCCCC/C=C/C(=O)SCCCCCC

Procedure:
The same operation as in Example 1-1 or 1-2 was carried out using trans-2-decenoic acid and n-hexylmercaptan as starting materials to give the aimed compound.
Reaction SMILES: C[O:2][C:3]([CH:5]([N:13]1[CH:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:15]([NH:23][C:24](=[O:26])[CH3:25])[C:14]1=[O:27])[CH2:6]C1C=CC=CC=1)=[O:4]>CO.[Pd]>[C:24]([NH:23][C@H:15]([C:14]([NH:13][C@H:5]([C:3]([OH:4])=[O:2])[CH3:6])=[O:27])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:26])[CH3:25]
Reactant: COC(=O)C(Cc1ccccc1)N1C(=O)C(NC(C)=O)C1c1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](C)C(=O)O
Reaction time: 18 h
Yield: 122.9 %

Procedure:
According to the same procedure as in Example 1, 1-(1-methoxycarbonyl-2-phenylethyl)-3-acetylamino-4-phenylazetidin-2-one (300 mg.) was subjected to hydrogenolysis at 50° C. in methanol (30 ml.) under a hydrogen pressure of one atmosphere in the presence of a 10% Pd-C (350 mg.). The reaction completed in 18 hours. The same after-treatment as in Example 1 was followed to give methyl ester of N-acetylphenylalanylalanine (280 mg., yield: 92.8%) melting at 128.0°-132.0° C.
Reaction SMILES: [OH:1][CH:2]([CH3:17])[CH2:3][S:4]([C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:8]=1Cl)(=[O:6])=[O:5].[CH2:18]([NH2:21])[CH2:19][NH2:20]>C(O)(C)C.O>[OH:1][CH:2]([CH3:17])[CH2:3][S:4]([C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:8]=1[NH:20][CH2:19][CH2:18][NH2:21])(=[O:6])=[O:5]
Reactant: NCCN
Reactant: CC(O)CS(=O)(=O)c1cc([N+](=O)[O-])ccc1Cl
Solvent: CC(C)O
Solvent: O
Product: CC(O)CS(=O)(=O)c1cc([N+](=O)[O-])ccc1NCCN

Procedure:
28 g (0.1 mol) of 2-chloro-5-nitrophenyl 2-hydroxypropyl sulphone are refluxed in 100 ml of isopropanol. To this are added gradually 15 ml of ethylenediamine, and heating is continued with stirring for a further hour. The cold reaction solution is diluted with 300 ml of water and stirred at 20° C. for two hours. The precipitated yellowish crystals are filtered off with suction, washed with 100 ml of water and dried. This gives 28 g of uniform 2-(2-aminoethylamino)-5-nitrophenyl 2-hydroxypropyl sulphone.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:19]=[CH:20][C:21]4[O:25][C:24]([CH:26]([OH:28])C)=[CH:23][C:22]=4[CH:29]=3)[N:14]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2]>O1CCOCC1.O=[Mn]=O>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:19]=[CH:20][C:21]4[O:25][C:24]([CH:26]=[O:28])=[CH:23][C:22]=4[CH:29]=3)[N:14]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2]
Reactant: CCOc1ccc(-c2nc(-c3ccc4oc(C(C)O)cc4c3)no2)cc1OCC
Agent: O=[Mn]=O
Solvent: C1COCCO1
Product: CCOc1ccc(-c2nc(-c3ccc4oc(C=O)cc4c3)no2)cc1OCC
Temperature: 25 °C
Yield: 101.1 %

Procedure:
A suspension of the product of Step D (0.13 g; 0.34 mmol) and MnO2 (0.15 g; 1.7 mmol) in dioxane (4 ml) was refluxed for 1 h with stirring. After cooling to room temperature, the insoluble material was removed by filtration, washed with EtOAc (20 ml) and combined filtrates were evaporated to dryness to give the title compound (0.13 g; 100%), as greyish solid. 1H-NMR (CDCl3) 9.91 (s, 1H); 8.59 (s, 1H); 8.33 (dd, 1H, J=2, 9 Hz); 7.63-7.82 (m, 4H); 6.99 (d, 1H, J=9 Hz); 4.14-4.26 (m, 4H); 1.4-1.57 (m, 6H+H2O).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:35])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]([C:15]2([CH2:31][CH2:32]OC)[CH2:20][CH2:19][N:18]([S:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:30])(=[O:23])=[O:22])[CH2:17][CH2:16]2)=[O:14])=[CH:8][CH:7]=1)[CH3:2].[Cl-].C[Al+]C>C1(C)C=CC=CC=1.CCCCCCC>[CH2:1]([O:3][C:4](=[O:35])[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([N:12]2[CH2:32][CH2:31][C:15]3([CH2:20][CH2:19][N:18]([S:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[Cl:30])(=[O:22])=[O:23])[CH2:17][CH2:16]3)[C:13]2=[O:14])=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(NC(=O)C2(CCOC)CCN(S(=O)(=O)c3ccccc3Cl)CC2)cc1
Agent: C[Al+]C
Agent: [Cl-]
Solvent: CCCCCCC
Solvent: Cc1ccccc1
Product: CCOC(=O)Cc1ccc(N2CCC3(CCN(S(=O)(=O)c4ccccc4Cl)CC3)C2=O)cc1
Temperature: 25 °C

Procedure:
(4-{[1-(2-Chloro-benzenesulfonyl)-4-(2-methoxy-ethyl)-piperidine-4-carbonyl]-amino}-phenyl)-acetic acid ethyl ester (2.47 g) in toluene (50 ml) was treated with dimethylaluminium chloride in heptane (1 molar, 5 ml) under an argon atmosphere at RT, and then refluxed for 3 hours. The reaction was then cooled to RT partitioned between AcOEt and 1N aqueous HCl/water. The layers were separated, the organic layer dried over sodium sulphate and the solvent was removed in vacuo to give the desired {4-[8-(2-chloro-benzenesulfonyl)-1-oxo-2,8-diaza-spiro[4.5]dec-2-yl]-phenyl}-acetic acid ethyl ester as a light brown solid. MS (EI): 491.2 (M+).
Reaction SMILES: [CH3:1][CH:2]([CH3:26])[CH2:3][C:4]([C:6]1[C:7]([C:22](OC)=[O:23])=[CH:8][N:9]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=2)[CH:10]=1)=O.[CH3:27][NH:28][NH2:29].Cl>C(O)C>[CH3:27][N:28]1[C:22](=[O:23])[C:7]2=[CH:8][N:9]([CH2:11][C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:15]=[CH:14][CH:13]=3)[CH:10]=[C:6]2[C:4]([CH2:3][CH:2]([CH3:26])[CH3:1])=[N:29]1
Reactant: COC(=O)c1cn(Cc2cccc3ccccc23)cc1C(=O)CC(C)C
Reactant: CNN
Agent: Cl
Solvent: CCO
Product: CC(C)Cc1nn(C)c(=O)c2cn(Cc3cccc4ccccc34)cc12

Procedure:
Methyl 4-(3-methyl-1-oxobutyl)-1-(1-naphthalenylmethyl)-1H-pyrrole-3-carboxylate (0.35 g) prepared as described in c) above and methylhydrazine (0.10 ml) in ethanol (15 ml) were heated to reflux for 16 hours. The mixture was poured into dilute hydrochloric acid and extracted with ethyl acetate, which was washed with brine, dried, and evaporated to a gum. The gum was chromatographed with ethyl acetate-isohexane (1:1) to afford a solid which was recrystallised from cyclohexane to give 2,6-dihydro-2-methyl-4-(2-methylpropyl)-6-(1-naphthalenylmethyl)-1H-pyrrolo[3,4-d]pyridazin-1-one (0.16 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:15][CH3:16])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[NH2:14])[CH:7]=1.[CH3:17][S:18]([C:21]1[CH:22]=[C:23]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[C:24](O)=[O:25])(=[O:20])=[O:19]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:15][CH3:16])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[NH:14][C:24](=[O:25])[C:23]2[CH:27]=[C:28]([C:30]([F:33])([F:31])[F:32])[CH:29]=[C:21]([S:18]([CH3:17])(=[O:20])=[O:19])[CH:22]=2)[CH:7]=1
Reactant: CS(=O)(=O)c1cc(C(=O)O)cc(C(F)(F)F)c1
Reactant: COc1ccc(F)cc1-c1ccncc1N
Product: COc1ccc(F)cc1-c1ccncc1NC(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1

Procedure:
The title compound was prepared in analogy to example 90, from 4-(5-fluoro-2-methoxy-phenyl)-pyridin-3-ylamine and 3-methanesulfonyl-5-trifluoromethyl-benzoic acid (example 114, intermediate a) after a reaction time of 18 hours. The residue was purified by column chromatography eluting with a gradient of n-hexane:EtOAc (40:60 to 20:80. Brown liquid (68%). MS (ESI): m/z=469.2 [M+H]+.
Reaction SMILES: [C:1]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].C([Li])CCC.[C:19]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:24]=[CH:23][C:22]([CH:25](C(O)CC)C(O)=O)=[CH:21][CH:20]=1.Cl>O1CCCC1>[C:8]([O:7][C:1](=[O:6])[CH2:2][C:3](=[O:4])[CH2:5][CH2:25][C:22]1[CH:23]=[CH:24][C:19]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)=[CH:20][CH:21]=1)([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(=O)CC(=O)OC(C)(C)C
Reactant: CCC(O)C(C(=O)O)c1ccc(-c2ccccc2)cc1
Agent: Cl
Agent: [H-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CC(=O)CCc1ccc(-c2ccccc2)cc1
Reaction time: 0.17 h
Yield: 38 %

Procedure:
A solution of t-butyl acetoaceate (1.84 mL, 11.1 mmol) in tetrahydrofuran (20 mL) was added to a stirred suspension of sodium hydride (488 mg, 12.2 mmol) in tetrahydrofuran (10 mL) at 0° C. under nitrogen. After stirring for 10 minutes n-butyl lithium (1.6 M in hexanes; 7.3 mL, 11.6 mmol) was added dropwise over 2 minutes then stirring was continued for a further 10 minutes. A solution of 4-bromomethyl-biphenyl (Intermediate 1, 3.00 g, 12.2 mmol) in tetrahydrofuran (6 mL) was added dropwise over 10 minutes and the resulting solution stirred at 0° C. for 1.5 hours. 6 M Hydrochloric acid (15 mL) was added then the crude reaction mixture was extracted with diethyl ether (3×50 mL). The organic phases were combined, washed with brine (50 mL), dried (MgSO4) then the solvent evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (1:20 diethyl ether:cyclohexane) to give the title compound (1.37 g, 38%) as a yellow solid. LC/MS: 3.78 min; z/e 342, calcd (M+NH4) 342. 1H NMR (400 MHz: CDCl3): 7.55 (2 H), 7.50 (2 H), 7.43 (2 H), 7.32 (1 H), 7.25 (2 H), 3.34 (2 H), 2.95 (4 H), 1.45 (9 H).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][O:7][C:8](=[O:13])[C@H:9]([OH:12])[CH2:10][CH3:11].C(N(CC)CC)C.CC1CCCCC1.C(OCC)(=O)C>ClCCl.O>[CH3:6][O:7][C:8](=[O:13])[C@H:9]([O:12][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:10][CH3:11]
Reactant: CC[C@@H](O)C(=O)OC
Reactant: CS(=O)(=O)Cl
Solvent: CC1CCCCC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC[C@@H](OS(C)(=O)=O)C(=O)OC
Temperature: 25 °C
Yield: 100 %

Procedure:
To a solution of methanesulfonic acid chloride (5.33 g, 46.5 mmol, 1.1 equiv.) in dichloromethane (50 ml, 11 vol.) cooled to 0-5° C. is added over a period of 30 min. a mixture of methyl-(R)-2-hydroxybutyrate (5.1 g, 43.2 mmol, 1 equiv.) and triethylamine (4.7 g, 46.5 mmol, 1.1 equiv.) in dichloromethane (25 ml). When conversion is complete (TLC: methylcyclohexane/ethyl acetate=1/1 (v/v), dying with molybdatophosphoric acid; Rf=0.5), the mixture is allowed to warm to room temperature and 50 ml of water is added. The two resulting layers are separated and the organic layer is washed with 50 ml of water. The organic layer is dried over sodium carbonate and concentrated under reduced pressure to afford methyl-(R)-2-methanesulfonyloxybutyrate (IIg) as yellow oil (8.5 g, 43.2 mmol, 100%)
Reaction SMILES: [CH2:1]([OH:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[C:12](O)(=[O:22])[C:13]1[CH:21]=[CH:20][C:18]([OH:19])=[C:15]([O:16][CH3:17])[CH:14]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[C:12]([O:11][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])(=[O:22])[C:13]1[CH:21]=[CH:20][C:18]([OH:19])=[C:15]([O:16][CH3:17])[CH:14]=1
Reactant: CCCCCCCCCCO
Reactant: COc1cc(C(=O)O)ccc1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CCCCCCCCCCOC(=O)c1ccc(O)c(OC)c1
Yield: 50 %

Procedure:
The n-decyl vanillate was synthesized by refluxing decyl alcohol with vanillic acid in the presence of p-toluenesulfonic acid. After removal of the unreacted alcohol, purification and recrystallization from n-pentane, the n-decyl vanillate had a melting point of 40°-40.5° C. (Yield: about 50%).