Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(C[CH2:5][N:6]([CH3:24])[C:7]([N:9]1[CH2:23][CH2:22][CH2:21][C@H:10]1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])=[O:8])(O)=O.O1CCCC1.C(Cl)(=O)C(Cl)=O.[C:36]1([C:42]2[O:43][C:44](=[O:51])[CH:45]([CH2:47][CH2:48][CH2:49][CH3:50])[N:46]=2)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>CN(C)C=O.C(N(CC)CC)C>[C:42]([NH:46][CH:45]([CH2:47][CH2:48][CH2:49][CH3:50])[C:44](=[O:51])[CH2:5][N:6]([CH3:24])[C:7]([N:9]1[CH2:23][CH2:22][CH2:21][C@H:10]1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])=[O:8])(=[O:43])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CN(CCC(=O)O)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Reactant: CCCCC1N=C(c2ccccc2)OC1=O
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCC(NC(=O)c1ccccc1)C(=O)CN(C)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Reaction time: 1 h
Yield: 15.4 %

Procedure:
1-[[(2-Carboxyethyl)methylamino]carbonyl]-L-proline, phenylmethyl ester (4.8 g., 15 mmole) is taken into 50 ml. of dry tetrahydrofuran with stirring in an ice bath. To this is added dropwise oxalyl chloride (1.58 ml., 18 mmole) followed by 4 drops of dimethylformamide. After 20 minutes the bath is removed and the reaction is run for one hour at room temperature before concentrating to dryness. This material is taken into 30 ml. of tetrahydrofuran, chilled and added dropwise to 2-phenyl-4-butyl-5(4H)-oxazolone (3.42 g., 15.75 mmole) in 24 ml. of tetrahydrofuran while stirring in an ice bath. Triethylamine (2.55 ml.) is added. After 5 minutes the bath is removed and the reaction is run overnight at room temperature. The triethylamine hydrochlorice salt is filtered off, the filtrate is concentrated to dryness, taken into 16 ml. of pyridine, 50 mg. of 4-dimethylamino pyridine is added, and the mixture is stirred for 3 hours. Acetic acid (16 ml.) is added and the mixture is heated at 100° for 45 minutes. The mixture is concentrated to dryness, taken into ethyl acetate and washed neutral with saturated sodium bicarbonate and dilute hydrochloric acid to give 4.7 g. of product. Purification on silica gel in benzene:ethyl acetate (1:2) yields 1.14 g of (±)-1-[[[3-(benzoylamino)-2-oxoheptyl]methylamino]carbonyl]-L-proline, phenylmethyl ester.
Reaction SMILES: [C:1](#[N:10])[C:2]1[CH:9]=[CH:8][CH:7]=[C:4]([C:5]#[N:6])[CH:3]=1.N.[H][H].CC1C=C(C=CC=1)CN>[Ru]>[C:2]1([CH2:1][NH2:10])[CH:9]=[CH:8][CH:7]=[C:4]([CH2:5][NH2:6])[CH:3]=1
Reactant: [H][H]
Reactant: N#Cc1cccc(C#N)c1
Agent: [Ru]
Agent: Cc1cccc(CN)c1
Agent: N
Product: NCc1cccc(CN)c1

Procedure:
5 g of alumina powder containing 5% by weight of ruthenium, 26.8 g of isopthalonitrile and 30 g of liquid ammonia were charged into an autoclave having a net capacity of 200 cc, provided with an electromagnetic stirrer, and subjected to reaction at a reaction temperature of 140° C. and a reaction pressure of 150 kg/cm2 for 60 minutes by continuously supplying hydrogen to the autoclave. As a result of analysis of the reaction product liquid, it was found that the yield of 1,3-BAC was 87.8% and 3-methylbenzylamine and metaxylylenediamine were obtained as by-products in yields of 4.8% and 3%, respectively, while the yield of other lower boiling and higher boiling products than the boiling point of the BAC was 4.4%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH:8]([CH3:13])[C:9]2=[O:12])=[CH:5][CH:4]=1.[CH2:14](OC(OCC)OCC)[CH3:15].[OH-].[Na+]>C(O)C.CCOCC>[CH3:13][C:8]1[CH2:7][C:6]2[C:10]([C:9]=1[O:12][CH2:14][CH3:15])=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2
Reactant: COc1ccc2c(c1)C(=O)C(C)C2
Reactant: CCOC(OCC)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CCO
Product: CCOC1=C(C)Cc2ccc(OC)cc21
Reaction time: 72 h

Procedure:
6-Methoxy-2-methylindanone [1.76 g (0.01 mole)] is dissolved in 6.5 ml of absolute ethanol (containing 20% anhydrous ether). This solution is stirred with 2.4 g (0.016 mole) of triethylorthoformate and a drop of redistilled BF3C2H5O C2H5 for about 72 hours. The reaction mixture is diluted with ether, poured slowly into 8.1 ml of 5.0% sodium hydroxide solution with crushed ice with stirring. Two layers separate and the organic layer is washed with cold water until neutral followed by saturated sodium chloride solution and dried over sodium sulfate. This is then filtered and the solvent removed and the residue distilled with 1 ml of benzene solution which contains about 47.5 mg of anhydrous p-toluene sulfonic acid to obtain 2-methyl-3-ethoxy-5-methoxyindene.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH:13]([CH3:15])[CH3:14])=[C:11]([NH2:16])[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:17][C:18]1[N:22]([CH:23]([CH3:27])[C:24](O)=[O:25])[N:21]=[C:20]([C:28]([F:31])([F:30])[F:29])[N:19]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([CH:13]([CH3:14])[CH3:15])=[C:11]([NH:16][C:24](=[O:25])[CH:23]([N:22]3[C:18]([CH3:17])=[N:19][C:20]([C:28]([F:29])([F:30])[F:31])=[N:21]3)[CH3:27])[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: Cc1nc(C(F)(F)F)nn1C(C)C(=O)O
Reactant: CC(C)c1c(N)cnn1-c1ccc(F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(C(F)(F)F)nn1C(C)C(=O)Nc1cnn(-c2ccc(F)cc2)c1C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 30.7 %

Procedure:
To a solution of 1-(4-fluorophenyl)-5-isopropylpyrazol-4-amine (0.050 g, 0.23 mmol) in DMF (1.0 mL) was added 2-[5-methyl-3-(trifluoromethyl)-1,2,4-triazol-1-yl]propanoic acid (0.051 g, 0.23 mmol), followed by diisopropylethylamine (0.059 g, 0.46 mmol) and HATU (0.105 g, 0.28 mmol). After stirring at room temperature for 1 h, the reaction was diluted with water and the aqueous layer was extracted with ethyl acetate (2×5 mL). The combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The resulting crude product was purified by reverse phase HPLC (C18 column, acetonitrile-H2O with 0.1% TFA as eluent) to give the title compound as a white solid (0.03 g, 0.0706 mmol, 31%). 1H NMR (400 MHz, CDCl3) δ 8.24 (s, 1H), 8.04-7.99 (m, 1H), 7.35-7.25 (m, 2H), 7.22-7.11 (m, 2H), 5.13 (q, J=7.2 Hz, 1H), 3.05-2.93 (m, 1H), 2.62 (s, 3H), 1.93 (d, J=7.2 Hz, 3H), 1.27 (dd, J=7.2, 2.9 Hz, 3H), 1.10 (d, J=7.1 Hz, 3H); MS: (ES) m/z calculated for C19H20F4N6O [M+H]+ 425.2, found 425.0.
Reaction SMILES: FC(F)(F)C(O)=[O:4].O.C(O)(=O)/C=C\C(O)=O.[F:17][C:18]1[CH:19]=[CH:20][C:21]2=[C:22]([CH:52]=1)[O:23][CH2:24][C:25]1[CH:51]=[CH:50][CH:49]=[CH:48][C:26]=1/[C:27]/2=[CH:28]\[C:29]1[CH:47]=[CH:46][C:32]2[N:33]([C@@H:39]3[C@@H:43]([OH:44])[CH2:42][N:41]([CH3:45])[CH2:40]3)/[C:34](=[N:36]/[C:37]#[N:38])/[NH:35][C:31]=2[CH:30]=1.[OH-].[Na+]>C(OCC)(=O)C>[F:17][C:18]1[CH:19]=[CH:20][C:21]2=[C:22]([CH:52]=1)[O:23][CH2:24][C:25]1[CH:51]=[CH:50][CH:49]=[CH:48][C:26]=1/[C:27]/2=[CH:28]\[C:29]1[CH:47]=[CH:46][C:32]2[N:33]([C@@H:39]3[C@@H:43]([OH:44])[CH2:42][N:41]([CH3:45])[CH2:40]3)/[C:34](=[N:36]/[C:37]([NH2:38])=[O:4])/[NH:35][C:31]=2[CH:30]=1
Reactant: CN1C[C@H](O)[C@@H](n2/c(=N/C#N)[nH]c3cc(/C=C4\c5ccccc5COc5cc(F)ccc54)ccc32)C1
Reactant: O=C(O)C(F)(F)F
Agent: O=C(O)/C=C\C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: CN1C[C@H](O)[C@@H](n2/c(=N/C(N)=O)[nH]c3cc(/C=C4\c5ccccc5COc5cc(F)ccc54)ccc32)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
To a mixture of trifluoroacetic acid (30 mL) and water (6.0 eq, 100 mmol, 1.81 mL) in an ice bath add (E)-N-(5-((E)-(3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene)methyl)-1-((3S,4S)-4-hydroxy-1-methylpyrrolidin-3-yl)-1H-benzo[d]imidazol-2(3H)-ylidene)cyanamide maleate (16.73 mmol, 10.00 g). Allow the resulting suspension to warm up to room temperature and stir for 2 h. Dilute the solution with ethyl acetate (250 mL), cool the mixture in an ice bath for 30 min, and treat with 5 N sodium hydroxide to pH=11. Wash the organic layer with brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. Purify the residue by column chromatography eluting with 2.5 to 5% methanol in ethyl acetate to obtain a white solid. Dry in a vacuum oven at 40° C. overnight to obtain the title compound (6.74 g, 81%). LC-MS m/z 500.2 [M+H]+.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C:2]1=[O:11].C([Sn](CCCC)(CCCC)[C:17]([O:19]CC)=[CH2:18])CCC.N1C2C(=CC=CC=2)C=CC=1>>[C:17]([C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[NH:1][C:2](=[O:11])[CH2:3][CH2:4]2)(=[O:19])[CH3:18]
Reactant: O=C1CCc2ccccc2N1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Solvent: c1ccc2ncccc2c1
Product: CC(=O)c1ccc2c(c1)CCC(=O)N2

Procedure:
The 3,4-dihydro-1H-quinolin-2-one derivative of Formula 5 is reacted with tributyl(1-ethoxyvinyl)tin to introduce an acetyl group into the 6 position of the quinoline nucleus and to provide a 6-acetyl-3,4-dihydro-1H-quinolin-2-one derivative of Formula 6. The R3 group (R3 is as defined in connection with Formula 1) is introduced into the molecule by treatment of the compound of Formula 6 with a reagent of the formula R3—I and a strong base, such as sodium hydride in a polar aprotic solvent, such as dimnethylformamide (DMF). Instead of the iodo derivative R3—I, other alkylating agents of the formula R3—X1 (where X1 is a leaving group) could also be used in this reaction to provide a 6-acetyl-1-alkyl (or 1-phenylalkyl) 3,4-dihydro-1H-quinolin-2-one derivative of Formula 7. The 6-acetyl-1-alkyl (or 1-phenylalkyl) 3,4-dihydro-1H-quinolin-2-one derivative of Formula 7 is reacted with a bromophenyl or bromo heteroaryl aldehyde of Formula 8 to give the 1-alkyl-6-[3-(bromo phenyl or bromo-heteroaryl)-acryloyl]-3,4-dihydro-1H-quinolin-2-one of Formula 9. The bromo compound of Formula 9 is reacted with carbon monoxide in the presence of 1,3-bis(diphenylphosphino)propane (DPPP), palladium acetate (Pd(OAc)2), triethylamine (TEA) in dimethylformamide and ethanol and thereafter with base (such as NaOH or KOH) to provide [3-(1-alkyl-2-oxo-1,2,3,4-tetrahydro-quinolin-6-yl)-3-oxo-propenyl]-benzoic or heteroaryl carboxylic acids of Formula 10.
Reaction SMILES: [NH2:1][C:2]([CH3:13])([CH3:12])[CH2:3][O:4][C:5]1[N:6]=[N:7][C:8]([Cl:11])=[CH:9][CH:10]=1.[Cl:14][C:15]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][C:16]=1[O:17][CH2:18][CH:19]1[O:21][CH2:20]1>C(O)C>[Cl:14][C:15]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][C:16]=1[O:17][CH2:18][CH:19]([OH:21])[CH2:20][NH:1][C:2]([CH3:13])([CH3:12])[CH2:3][O:4][C:5]1[N:6]=[N:7][C:8]([Cl:11])=[CH:9][CH:10]=1
Reactant: CC(C)(N)COc1ccc(Cl)nn1
Reactant: Cc1ccc(Cl)c(OCC2CO2)c1
Solvent: CCO
Product: Cc1ccc(Cl)c(OCC(O)CNC(C)(C)COc2ccc(Cl)nn2)c1
Yield: 62.4 %

Procedure:
A solution of 4.6 g of 3-(2-amino-2-methylpropoxy)-6-chloropyridazine obtained in Example 1 (a) and 5.0 g of 1-(2-chloro-5-methylphenoxy)-2,3-epoxypropane in 50 ml of ethanol was refluxed for 4 hours. The solvent was evaporated under reduced pressure a solution of the residue in 100 ml of benzene was extracted with 30 ml of 10% hydrochloric acid. The aqueous layer was made alkaline with 10% sodium hydroxide and extracted with chloroform, and the organic layer was dried over magnesium sulfate. The solvent was evaporated and the residue was chromatographed on a column of Florisil (50 g) using chloroform as an eluent. From the eluate was obtained 5.7 g of 1-(2-chloro-5-methylphenoxy)-3-[1,1-dimethyl-2-(3-chloro-6-pyridazinyloxy)ethylamino)-2-propanol as a colorless oil.
Reaction SMILES: [CH2:1]([C:3]([CH3:5])=[O:4])[CH3:2].[OH:6][CH2:7][CH:8]([CH2:10]O)[OH:9].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>CCCCCC>[CH3:5][C:3]1([CH2:1][CH3:2])[O:9][CH:8]([CH2:7][OH:6])[CH2:10][O:4]1
Reactant: OCC(O)CO
Reactant: CCC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCCCCC
Product: CCC1(C)OCC(CO)O1
Temperature: 60 °C
Reaction time: 30 h

Procedure:
In a reaction vessel having a capacity of 3 L and equipped with a thermometer, a reflux condenser, a Dean-Stark trap, a calcium chloride tube and a stirrer, methyl ethyl ketone (400 g, 5,547 mol), glycerin (561.91 g, 6.102 mol), paratoluene-sulfonic acid monohydrate (21.10 g, 0.1109 mol) and hexane (400 mL) were charged. The contents were heated under stirring and a reaction was conducted at 67 to 74° C. for 30 hours to distill off a calculated amount of water. After completion of the reaction, the reaction mixture was cooled to 60° C., followed by the addition of sodium carbonate (23.51 g, 0.2218 mol) for neutralization. After the resulting mixture was stirred at 60° C. for 30 minutes, the temperature was gradually raised up to 120° C. to recover hexane (400 mL). Filtration was then conducted to obtain the titled product in a crude form (894.74 g). Using a Biglew tube (20 cm×1.5 cm in diameter), distillation was conducted under reduced pressure to obtain the titled compound (725.14 g, yield: 89.4%). By a gas chromatographic analysis, the purity of the compound was found to be 99.1 wt. %. b.p. 101 to 104° C./17 mmHg.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[CH2:8]([NH2:30])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]/[CH:20]=[CH:21]\[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>C(Cl)(Cl)(Cl)Cl>[CH2:8]([NH:30][C:1](=[O:7])/[CH:2]=[CH:3]\[C:4]([OH:6])=[O:5])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]/[CH:20]=[CH:21]\[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCCCC/C=C\CCCCCCCCCCCCN
Reactant: O=C1C=CC(=O)O1
Solvent: ClC(Cl)(Cl)Cl
Product: CCCCCCCC/C=C\CCCCCCCCCCCCNC(=O)/C=C\C(=O)O
Temperature: 75 °C
Reaction time: 4 h
Yield: 96.2 %

Procedure:
A 250 ml, 3-neck flask equipped with a stirrer, thermometer, Dean-Stark receiver and condenser was charged with 18 g of maleic anhydride (0.18 mole) and 60 ml carbon tetrachloride. Erucyl amine (59.0 g, 0.18 mole) was added dropwise at 70° C. under a nitrogen atmosphere. The mixture was stirred at 75° C. for 4 hours. The temperature was raised to 90° C. to distill out carbon tetrachloride and the mixture was then stripped at 100° C. 10 mmHg vacuum for 15 minutes to afford 73 g of N-Erucyl-maleic acid monoamide. An IR spectrum indicated the presence of amide and carboxyl groups. This product had an acid number of 135; no total amine value; a saponification value of 137.6; a melting point of 55° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:12])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[N+:13]([O-])([OH:15])=[O:14].O>C(Cl)Cl>[CH3:1][C:2]1[C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:6][C:5]([N+:13]([O-:15])=[O:14])=[C:4]([OH:12])[CH:3]=1
Reactant: O=[N+]([O-])O
Reactant: Cc1cc(O)ccc1S(C)(=O)=O
Solvent: ClCCl
Solvent: O
Product: Cc1cc(O)c([N+](=O)[O-])cc1S(C)(=O)=O
Yield: 19.5 %

Procedure:
3-Methyl-4-(methylsulfonyl)phenol (D85, 503 mg, 2.29 mmol) was dissolved in DCM (5 mL) and 70% nitric acid (0.16 mL, 3.58 mmol) was added dropwise to the reaction. The mixture was stirred o/n. A further 2 mL of 70% nitric acid was then added. The reaction was stirred for 4 h, then H2O (20 mL) was added and the 2 phases were separated. The aqueous layer was extracted with DCM and the combined organics were dried (Na2SO4) and concentrated by rotary evaporation to give a yellow solid, which was purified via flash column chromatography (silica, iso-hexane to 50% EtOAc/50% iso-hexane) to give a yellow solid. This solid was triturated with Et2O (2×) to give 5-methyl-4-(methylsulfonyl)-2-nitrophenol (D86, 103 mg, 19%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:9]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]([O:18]CC)=O)[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[NH2:27][NH2:28]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:9]2[CH2:10][CH2:11][N:12]([CH2:15][C:16]([NH:27][NH2:28])=[O:18])[CH2:13][CH2:14]2)=[CH:6][CH:7]=1
Reactant: NN
Reactant: CCOC(=O)CN1CCN(C(c2ccccc2)c2ccc(Cl)cc2)CC1
Solvent: CCO
Product: NNC(=O)CN1CCN(C(c2ccccc2)c2ccc(Cl)cc2)CC1

Procedure:
Synthesized according to General Procedure C: 6{26} (7.25 g, 19.4 mmol, 1 equiv.), anhydrous hydrazine (1.8 mL, 58.3 mmol, 3 equiv.), ethanol (39.2 mL). Purification by silica gel column chromatography (4:1 EtOAc:MeOH) afforded 1{26} (6.54 g, 94%) as a yellow oil. 1H-NMR (500 MHz, CDCl3): δ 8.15 (br s, 1H), 7.35-7.32 (m, 4H), 7.27-7.22 (m, 4H) 7.19-7.16 (m, 1H), 4.20 (s, 1H), 3.84 (br s, 2H), 3.06 (s, 2H), 2.52 (br s, 4H), 2.38 (br s, 4H). 13C-NMR (125 MHz, CDCl3): δ 170.3, 141.7, 140.9, 132.5, 129.0, 128.5, 128.5, 127.6, 127.1, 75.1, 60.4, 53.7, 51.6.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6](C(O)=O)=[CH:5][N:4]=1)#[N:2].CCN(CC)CC.Cl[C:20](OCC)=[O:21].[BH4-].[Na+]>C1COCC1>[OH:21][CH2:20][C:5]1[N:4]=[C:3]([C:1]#[N:2])[CH:11]=[CH:10][CH:6]=1
Reactant: CCOC(=O)Cl
Reactant: N#Cc1ccc(C(=O)O)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: N#Cc1cccc(CO)n1
Reaction time: 0.25 h
Yield: 36.8 %

Procedure:
To a solution of 6-cyanonicotinic acid (12 g, 0.081 mol; see step (i) above) in THF at 0° C., Et3N (12.4 mL, 0.0892 mol) was added followed by ethyl chloroformate (8.53 mL, 0.0892 mol). The reaction mixture was stirred for 15 min and NaBH4 (6.14 g, 0.162 mol) was added. Then the mixture was stirred at RT overnight, quenched with water and extracted with methylene chloride. The organic layer was concentrated and purified by column chromatography to yield 4 g (20%) of the alcohol.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[C:12]1([OH:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:8][C:6]1[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=[C:2]([O:18][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=1
Reactant: Oc1ccccc1
Reactant: Cc1cc(Cl)ncc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(Oc2ccccc2)ncc1[N+](=O)[O-]
Temperature: 110 °C
Reaction time: 4 h

Procedure:
A solution of 2-chloro-4-methyl-5-nitropyridine (10 g, 0.058 mol), in DMF (100 mL) was treated with phenol (6.6 g, 0.07 mol) and potassium carbonate (9.6 g, 0.07 mol) and the reaction mixture was stirred at 110° C. for 4 hr and then cooled. To the reaction mixture was then added water. The reaction mixture was extracted into EtOAc, dried and concentrated to a syrup, which was purified via column chromatography (4:2:0.5; CHCl3:hexanes:EtOAc, v/v) to yield 4-methyl-5-nitro-2-phenoxy-pyridine as a light yellow solid.
Reaction SMILES: C(OC([N:11]([CH2:21][C@H:22]1[N:26]([C:27]2[N:32]=[CH:31][C:30]([CH2:33][CH2:34][CH3:35])=[CH:29][N:28]=2)[CH2:25][C@H:24]([S:36][C:37](=[O:39])[CH3:38])[CH2:23]1)[CH2:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[F:20])=O)C1C=CC=CC=1.Br>C(O)(=O)C>[F:20][C:14]1[CH:15]=[CH:16][C:17]([F:19])=[CH:18][C:13]=1[CH2:12][NH:11][CH2:21][C@H:22]1[N:26]([C:27]2[N:32]=[CH:31][C:30]([CH2:33][CH2:34][CH3:35])=[CH:29][N:28]=2)[CH2:25][C@H:24]([S:36][C:37](=[O:39])[CH3:38])[CH2:23]1
Reactant: CCCc1cnc(N2C[C@H](SC(C)=O)C[C@H]2CN(Cc2cc(F)ccc2F)C(=O)OCc2ccccc2)nc1
Agent: Br
Solvent: CC(=O)O
Product: CCCc1cnc(N2C[C@H](SC(C)=O)C[C@H]2CNCc2cc(F)ccc2F)nc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 6.2 %

Procedure:
To 137 mg (2.5 mmol) (3R,5S)-Thioacetic acid S-[5-[[benzyloxycarbonyl-(2,5-difluoro-benzyl)-amino]-methyl]-1-(5-propyl-pyrimidin-2-yl)-pyrrolidin-3-yl]ester in 5 ml EE were added 320 μl 33% HBr in acetic acid at 0° C. The solution was stirred at RT for 12 h, poured on NaHCO3 and the inorganic phase was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4 and were evaporated. Purification with column chromatography with EtOAc as eluent yielded 65 mg (63%) (3R,5S)-Thioacetic acid S-[5-[(2,5-difluoro-benzylamino)-methyl]-1-(5-propyl-pyrimidin-2-yl)-pyrrolidin-3-yl]ester as colorless oil, MS: 421(MH+). (Nicht in Liste).
Reaction SMILES: [N:1]1[C:10]2[NH:9][C:8]3[CH:11]=[C:12]([CH2:15][N:16]4[CH2:21][CH2:20][CH:19]([NH:22][C:23]([C:25]5[CH:26]=[N:27][O:28][C:29]=5[CH3:30])=[O:24])[CH2:18][CH2:17]4)[CH:13]=[CH:14][C:7]=3[S:6][C:5]=2[N:4]=[CH:3][CH:2]=1.COC(OC)N(C)C.O.C(OCC)(=O)C>O1CCCC1>[N:1]1[C:10]2[NH:9][C:8]3[CH:11]=[C:12]([CH2:15][N:16]4[CH2:21][CH2:20][CH:19]([NH:22][C:23](=[O:24])[CH:25]([C:26]#[N:27])[C:29](=[O:28])[CH3:30])[CH2:18][CH2:17]4)[CH:13]=[CH:14][C:7]=3[S:6][C:5]=2[N:4]=[CH:3][CH:2]=1
Reactant: Cc1oncc1C(=O)NC1CCN(Cc2ccc3c(c2)Nc2nccnc2S3)CC1
Agent: COC(OC)N(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)C(C#N)C(=O)NC1CCN(Cc2ccc3c(c2)Nc2nccnc2S3)CC1
Yield: 22 %

Procedure:
To 10 ml of a solution of 500 mg of N-[1-(10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)-piperidin-4-yl]-5-methyl-1,2-oxazole-4-carboxamide in tetrahydrofuran was added 400 μl of N,N-dimethylformamide dimethyl acetal and the resulting mixture was heated under reflux for 4 hours. After distributing into water and ethyl acetate, the aqueous layer was extracted and washed with diethyl ether. After distilling off the organic solvent contained therein under reduced pressure, the residue was acidified with dilute hydrochloric acid and purified by high-porous gel chromatography (CHP20P, 75-150μ; manufactured by Mitsubishi Chemical Industries) (eluted with methanol/water) to thereby give 110 mg of the title compound as pale yellow crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]([OH:11])=O)=[CH:7][C:6]([C:12]([NH2:14])=[O:13])=[CH:5][CH:4]=1.[Cl:15][C:16]1[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:17]=1[NH2:18]>>[Cl:15][C:16]1[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:17]=1[NH:18][C:9](=[O:11])[C:8]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[O:2][CH3:1])[C:12]([NH2:14])=[O:13]
Reactant: Nc1cccc(Cl)c1Cl
Reactant: COc1ccc(C(N)=O)cc1C(=O)O
Product: COc1ccc(C(N)=O)cc1C(=O)Nc1cccc(Cl)c1Cl

Procedure:
The captioned compound was synthesized from 6-methoxyisophthalamic acid and 2,3-dichloroaniline by the same procedure as in the manufacturing method described in step C of Example 1-3-1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([CH:20]([OH:26])[CH2:21][O:22][CH2:23][O:24][CH3:25])=[CH:11][C:12]3[N:16]([CH3:17])[CH:15]=[N:14][C:13]=3[C:18]=2[F:19])=[C:4]([Cl:27])[CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C([O-])(O)=O.[Na+].O.O.O.O.O.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl.CCOCC.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([C:20](=[O:26])[CH2:21][O:22][CH2:23][O:24][CH3:25])=[CH:11][C:12]3[N:16]([CH3:17])[CH:15]=[N:14][C:13]=3[C:18]=2[F:19])=[C:4]([Cl:27])[CH:3]=1
Reactant: COCOCC(O)c1cc2c(ncn2C)c(F)c1Nc1ccc(Br)cc1Cl
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O
Product: COCOCC(=O)c1cc2c(ncn2C)c(F)c1Nc1ccc(Br)cc1Cl
Reaction time: 0.17 h
Yield: 70.7 %

Procedure:
A solution of 1-[6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazol-5-yl]-2-methoxymethoxy-ethanol 10i (44 mg, 0.096 mmol) and the Dess-Martin periodinane (49 mg, 0.12 mmol) in CH2Cl2 (1.5 mL) is stirred for 1.5 hours at room temperature. The reaction mixture is diluted with ether (3 mL). Saturated aqueous NaHCO3 (1 mL) containing sodium thiosulfate pentahydrate (74 mg) is added. The resulting mixture is stirred for 10 minutes and diluted with EtOAc. The organic layer is washed with saturated aqueous NaHCO3 and brine, dried over MgSO4, filtered, and concentrated in vacuo to give a crude material which is purified by flash chromatography (1.5% MeOH in CH2Cl2) to afford the desired product (31 mg, 71%): MS APCI (+) m/z 456, 458 (M+, Br pattern) detected.