Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:3]=[C:4]([NH:34][CH3:35])[NH:5][CH2:6][CH2:7][CH2:8][C@:9]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:13]([C:14](=[O:19])[C@@H:15]([O:17][CH3:18])[CH3:16])[N:12]=[C:11]([C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=2[F:27])[S:10]1)#[N:2].[ClH:36].[OH2:37]>CO.O1CCOCC1>[ClH:36].[F:27][C:21]1[CH:22]=[CH:23][C:24]([F:26])=[CH:25][C:20]=1[C:11]1[S:10][C@@:9]([CH2:8][CH2:7][CH2:6][NH:5][C:4]([NH:34][CH3:35])=[N:3][C:1]([NH2:2])=[O:37])([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:13]([C:14](=[O:19])[C@@H:15]([O:17][CH3:18])[CH3:16])[N:12]=1
Reactant: CNC(=NC#N)NCCC[C@@]1(c2ccccc2)SC(c2cc(F)ccc2F)=NN1C(=O)[C@H](C)OC
Reactant: O
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CNC(=NC(N)=O)NCCC[C@@]1(c2ccccc2)SC(c2cc(F)ccc2F)=NN1C(=O)[C@H](C)OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 94 %

Procedure:
To a solution of 2-cyano-1-(3-((S)-5-(2,5-difluorophenyl)-3-((S)-2-methoxypropanoyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propyl)-3-methylguanidine (Example 10; 130 mg, 0.26 mmol) in methanol (3 mL) was added HCl (0.65 mL of a 4 M solution in dioxane) and water (0.05 mL, 2.6 mmol). After stirring at room temperature for 16 hours, the mixture was concentrated under reduced pressure. The residue was triturated with ether to provide the product as a pale pink solid (135 mg, 94% yield). MS ESI (+) m/z 541 (M+Na) detected: 1H NMR (400 MHz, CD3OD) δ 7.66-7.61 (m, 1H), 7.49-7.46 (m, 2H), 7.42-7.37 (m, 2H), 7.34-7.28 (m, 3H), 4.79 (q, 1H, J=6.4 Hz), 3.53-3.43 (m, 2H), 3.36 (s, 3H), 3.30-3.20 (m, 1H), 2.95 (s, 3H), 2.67-2.55 (m, 1H), 2.23-2.11 (m, 1H), 1.75-1.63 (m, 1H), 1.43 (d, 3H, J=6.4 Hz).
Reaction SMILES: [C:1]([O:9][CH:10]([CH3:14])[C:11]([NH2:13])=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:24])=CC=1>COCCOC.C(OCC)(=O)C>[C:1]([O:9][CH:10]([CH3:14])[C:11]([NH2:13])=[S:24])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(OC(=O)c1ccccc1)C(N)=O
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CC(OC(=O)c1ccccc1)C(N)=S
Temperature: 25 °C
Reaction time: 24 h
Yield: 148.4 %

Procedure:
To a solution of 2-amino-1-methyl-2-oxoethyl benzoate (10.0 g, 52.0 mmol) in 1,2-dimethoxyethane (90 mL) was added Lawesson's reagent (11.2 g, 27.7 mmol) at 0° C. and the reaction mixture was allowed to warm up to room temperature. The resulting mixture was stirred at room temperature for 24 hours and the precipitate was removed by filtration. The resulting solution was concentrated under reduced pressure to give a residue. The residue was dissolved in ethyl acetate and the solution was washed with brine. The organic solution was dried, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (hexane-ethyl acetate=2:1) to obtain a crude crystal. The crude crystal was recrystallized from ethyl acetate-hexane to give a title compound (8.60 g, yield 79%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[CH:17]=[C:16]([CH:18]=O)[CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:5][CH:4]=1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[O:29][C:30]3[CH:36]=[C:35]([CH2:37]P(OCC)(OCC)=O)[CH:34]=[CH:33][C:31]=3[N:32]=2)=[CH:24][CH:23]=1.CO>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[CH:17]=[C:16]([CH:18]=[CH:37][C:35]4[CH:34]=[CH:33][C:31]5[N:32]=[C:28]([C:25]6[CH:26]=[CH:27][C:22]([O:21][CH3:20])=[CH:23][CH:24]=6)[O:29][C:30]=5[CH:36]=4)[CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2nc3ccc(C=O)cc3o2)cc1
Reactant: CCOP(=O)(Cc1ccc2nc(-c3ccc(OC)cc3)oc2c1)OCC
Solvent: CO
Solvent: CN(C)C=O
Product: COc1ccc(-c2nc3ccc(C=Cc4ccc5nc(-c6ccc(OC)cc6)oc5c4)cc3o2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.8 %

Procedure:
A solution of 5.06 g (0.02 Mole) of 2-p-methoxyphenyl-6-formylbenzoxazole of the formula ##STR33## (melting point: 161.5°-162.5° C.) and 7.50 g (0.02 mole) of 2-(p-methoxyphenyl)-6-(diethylphosphonomethyl)-benzoxazole of the formula ##STR34## (melting point: 85°-88° C.) in 150 ml of dimethyl formamide is heated to 50° C. and 2.1 g of sodium tert.butylate are added in small amounts to the solution over the course of 15 minutes. The reaction mixture is stirred at room temperature overnight, then poured into 400 ml of methanol with stirring. The product is collected by filtration, washed with water and then with 140 ml of methanol, and subsequently recrystallised from chlorobenzene with the addition of fuller's earth, affording 7.1 g (75% of theory) of 1,2-bis-(2-p-methoxyphenyl-benzoxazol-6-yl)-ethylene of the formula ##STR35## in the form of pale yellow crystals with a melting point of over 300° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:28])=[C:6]([CH:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[F:20])[N:11]=[C:10]([C:21]([F:27])([F:26])[C:22]([F:25])([F:24])[F:23])[CH2:9]2)[CH:7]=1.[CH3:29][S:30][C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1.C(=O)([O-])[O-].[Na+].[Na+].CCCC>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.C(O)C>[F:20][C:14]1[CH:15]=[C:16]([F:19])[CH:17]=[CH:18][C:13]=1[N:12]1[CH:8]([C:6]2[CH:7]=[C:2]([C:35]3[CH:34]=[CH:33][CH:32]=[C:31]([S:30][CH3:29])[CH:36]=3)[CH:3]=[CH:4][C:5]=2[F:28])[CH2:9][C:10]([C:21]([F:27])([F:26])[C:22]([F:25])([F:23])[F:24])=[N:11]1
Reactant: CSc1cccc(B(O)O)c1
Reactant: Fc1ccc(N2N=C(C(F)(F)C(F)(F)F)CC2c2cc(Br)ccc2F)c(F)c1
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: [Na+]
Solvent: CCO
Solvent: CCCC
Product: CSc1cccc(-c2ccc(F)c(C3CC(C(F)(F)C(F)(F)F)=NN3c3ccc(F)cc3F)c2)c1
Temperature: 88 °C
Reaction time: 2 h
Yield: 61.6 %

Procedure:
5-(5-Bromo-2-fluoro-phenyl)-1-(2,4-difluoro-phenyl)-3-pentafluoroethyl-4,5-dihydro-1H-pyrazole (50.0 mg, 0.11 mmol) prepared in Step 5 of Preparation 8, 3-(methylthio)phenylboronic acid (26.7 mg, 0.16 mmol), Pd(PPh3)4 (12.3 mg, cat.) and a 2N sodium carbonate solution (500.0 uL) were added to a mixed solvent of ethanol (500.0 uL) and 1,2-dimethylethane (2.0 mL). The reaction mixture was stirred at 88° C. for 2 hours and then filtered through celite pad. A saturated solution of ammonium chloride was added to the filtrate, which was then extracted with ethyl acetate three times. The combined extract was washed with brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/15) to give 35.0 mg of the titled compound as a white liquid.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([OH:13])=O.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([C:24]2([CH2:29][NH2:30])[CH2:28][CH2:27][CH2:26][CH2:25]2)[CH:19]=[CH:20][C:21]=1[O:22][CH3:23].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C(#N)C>[CH3:14][O:15][C:16]1[CH:17]=[C:18]([C:24]2([CH2:29][NH:30][C:11]([C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[N:1]=3)=[O:13])[CH2:25][CH2:26][CH2:27][CH2:28]2)[CH:19]=[CH:20][C:21]=1[O:22][CH3:23]
Reactant: O=C(O)c1ccc2ccccc2n1
Reactant: COc1ccc(C2(CN)CCCC2)cc1OC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccc(C2(CNC(=O)c3ccc4ccccc4n3)CCCC2)cc1OC
Reaction time: 16 h
Yield: 37.6 %

Procedure:
Quinoline-2-carboxylic acid (0.502 g, 2.90 mmol) and C-[1-(3,4-Dimethoxy-phenyl)-cyclopentyl]-methylamine (0.678 g, 2.90 mmol) were dissolved in acetonitrile (20 mL) containing triethylamine (894 μL, 6.38 mmol). O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1.54 g, 4.06 mmol) was added and the solution was allowed to stir for 16 hours. The reaction mixture was evaporated to dryness and purified by column chromatography on silica gel using a gradient of 0-40% ethyl acetate in hexanes. The pure fractions were combined and evaporated to dryness to yield a white solid (0.426 g, 1.09 mmol, 37.7%). ESI-MS m/z calc. 390.2, found 391.2 (M+1)+. Retention time of 3.94 minutes. 1H NMR (400 MHz, CD3CN) δ 1.69-2.15 (m, 8H), 3.62 (d, J=30.1 Hz, 2H), 3.77 (s, 3H), 3.90 (s, 3H), 6.91-7.03 (m, 3H), 7.69 (t, J=8.1 Hz, 1H), 7.83 (t, J=7.7 Hz, 1H), 7.99 (t, J=8.8 Hz, 2H), 8.08 (s, 1H), 8.18 (d, J=8.5 Hz, 1H), 8.44 (d, J=8.5 Hz, 1H)
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1)CCC.Br[C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[C:26](=[O:30])[N:25]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=1)[CH2:24]2>C1(C)C=CC=CC=1.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>[CH3:38][C:35]1[CH:34]=[CH:33][C:32]([CH2:31][N:25]2[CH2:24][C:23]3[C:27](=[CH:28][CH:29]=[C:21]([C:8]4[CH:7]=[CH:6][CH:11]=[CH:10][N:9]=4)[CH:22]=3)[C:26]2=[O:30])=[CH:37][CH:36]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccncc1
Reactant: Cc1ccc(CN2Cc3cc(Br)ccc3C2=O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(CN2Cc3cc(-c4ccccn4)ccc3C2=O)cc1
Yield: 169 %

Procedure:
4-Tributylstannanylpyridine (37 mg, 0.032 mmol), 5-bromo-2-(4-methyl-benzyl)-2,3-dihydro-isoindol-1-one (50.0 mg, 0.16 mmol) and Pd(PPh3)4 (37 mg, 0.032 mmol) were dissolved in anhydrous toluene (4 mL). The mixture was immersed in a 100° C. oil bath. After eighteen hours, the reaction was cooled and the solvent was removed under reduced pressure. The compound was purified by column chromatography (50% EtOAc/Hexanes) to provide the title compound as a brown solid (17.0 mg, 35%). 1H NMR (300 MHz, CDCl3): δ 8.72 (br s, 2H), 8.01 (d, 1H), 7.75 (dd, 1H), 7.62 (s, 1H), 7.53 (br s, 2H), 7.20 (q, 4H), 4.81 (s, 2H), 4.35 (s, 2H), 2.35 (s, 3H)
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][CH:8]1[CH2:13][N:12]([C:14]2[N:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH2:11][CH:10]([CH3:20])[N:9]1[CH2:21][CH2:22][CH2:23][NH-:24]>C(OCC)C.C1COCC1>[CH3:7][CH:8]1[CH2:13][N:12]([C:14]2[N:15]=[CH:16][CH:17]=[CH:18][N:19]=2)[CH2:11][CH:10]([CH3:20])[N:9]1[CH2:21][CH2:22][CH2:23][NH2:24]
Reactant: CC1CN(c2ncccn2)CC(C)N1CCC[NH-]
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC1CN(c2ncccn2)CC(C)N1CCCN
Temperature: 25 °C
Reaction time: 1 h
Yield: 19.3 %

Procedure:
50 mg (1.54 mmol) of LiAlH4 were added to a solution of 0.2 g (0.77 mmol) of 3-[2,6-dimethyl-4-(2-pyrimidinyl)piperazin-1-yl]propylamide in 5 ml of diethylether and 5 ml of THF. The mixture was stirred one hour at room temperature and one additional hour at reflux, then the reaction was quenched by successive addition of 50 ul of water, 50 ul of 15% aqueous NaOH and 3×50 ul water. The mixture was diluted with diethyl ether, filtered, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by column chromatography on silicagel (CH2Cl2, EtOH, NH4OH: 45, 5, 1) to afford 0.037 g of the title compound.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[CH:16][NH:15][N:14]=2)[N:3]=1.C([O:20][C:21]([C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1)=[O:22])C>>[NH:15]1[CH:16]=[CH:17][C:13]([NH:12][C:4]2[N:3]=[C:2]([C:26]3[CH:27]=[CH:28][C:23]([C:21]([OH:22])=[O:20])=[CH:24][CH:25]=3)[C:11]3[C:6]([CH:5]=2)=[CH:7][CH:8]=[CH:9][CH:10]=3)=[N:14]1
Reactant: Clc1nc(Nc2cc[nH]n2)cc2ccccc12
Reactant: CCOC(=O)c1ccc(B(O)O)cc1
Product: O=C(O)c1ccc(-c2nc(Nc3cc[nH]n3)cc3ccccc23)cc1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and 4-ethoxycarbonyl-phenylboronic acid to give 4-[3-(1H-pyrazol-3-ylamino)-isoquinolin-1-yl]-benzoic acid. LC-MS m/e 331(MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10](Cl)=[N:11][OH:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[Cl:14][C:15]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:16]=1[CH:17]=[CH2:18].C(N(CC)CC)C>C1COCC1>[Cl:14][C:15]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:16]=1[CH:17]1[O:12][N:11]=[C:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[CH2:18]1
Reactant: C=Cc1c(Cl)cccc1Cl
Reactant: O=[N+]([O-])c1cccc(C(Cl)=NO)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cccc(C2=NOC(c3c(Cl)cccc3Cl)C2)c1

Procedure:
3-Nitro-N-hydroxybenzenecarboximidoyl chloride (1.16 g, 5.78 mmol) and 2,6-dichlorostyrene (1.0 g, 5.78 mmol) were dissolved in anhydrous THF (20 mL) and triethylamine (1.21 mL, 8.67 mmol). Upon addition of triethylamine a while solid formed. After 3 h this solid was collected by filtration under reduced pressure to provide the title compound as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])=[CH:16][CH:15]=2)[C@@H:10]([O:34][CH2:35][C:36]2[CH:45]=[C:44]3[C:39]([CH2:40][CH2:41][CH2:42][NH:43]3)=[CH:38][CH:37]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:47][C:48]#[N:49].P([O-])([O-])(O)=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CN1CCCC1=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])=[CH:18][CH:19]=2)[C@@H:10]([O:34][CH2:35][C:36]2[CH:45]=[C:44]3[C:39]([CH2:40][CH2:41][CH2:42][N:43]3[CH2:47][C:48]#[N:49])=[CH:38][CH:37]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: N#CCBr
Reactant: COc1ccccc1COCCCOc1ccc([C@H]2CCN(C(=O)OC(C)(C)C)C[C@@H]2OCc2ccc3c(c2)NCCC3)cc1
Agent: O=P([O-])([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN1CCCC1=O
Product: COc1ccccc1COCCCOc1ccc([C@H]2CCN(C(=O)OC(C)(C)C)C[C@@H]2OCc2ccc3c(c2)N(CC#N)CCC3)cc1
Temperature: 50 °C
Reaction time: 18 h
Yield: 85.9 %

Procedure:
A solution of 2.50 g (4.05 mmol) of (3R,4R)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-3-(1,2,3,4-tetrahydro-quinolin-7-ylmethoxy)-piperidine-1-carboxylic acid tert-butyl ester [example 1(c)] and 0.968 g (8.10 mmol, 2.0 equiv.) of bromoacetonitrile in 15 ml of toluene and 2 ml of N-methyl pyrrolidone was treated with 2.88 g (20.27 mmol, 5.0 equiv.) of anhydrous disodium hydrogen phosphate. The suspension was stirred for 18 h at 50° C., allowed to cool to room temperature, poured into 100 ml of an ice/water mixture and extracted three times with 200 ml of ethyl acetate. The combined organic phases were washed twice with 50 ml of water, evaporated under reduced pressure and dried in a high vacuum. The thus obtained crude product was purified by chromatography on silica gel using a 10:1 v/v mixture of dichloromethane and ethyl acetate as eluent to yield 2.28 g (3.48 mmol, 85.9% of theory) of (3R,4R)-3-(1-cyanomethyl-1,2,3,4-tetrahydro-quinolin-7-ylmethoxy)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-piperidine-1-carboxylic acid tert-butyl ester as a light yellow oil; MS: 656 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][OH:5].[H-].[Na+].F[C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[C:16](=[O:18])[CH3:17].O>O1CCCC1>[F:15][C:13]1[CH:12]=[CH:11][C:10]([C:16](=[O:18])[CH3:17])=[C:9]([O:5][CH2:4][CH2:3][O:2][CH3:1])[CH:14]=1
Reactant: CC(=O)c1ccc(F)cc1F
Reactant: COCCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COCCOc1cc(F)ccc1C(C)=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 69.6 %

Procedure:
A solution of 1.75 g 2-methoxy ethanol in tetrahydrofuran (23 mL) was added dropwise to a suspension of 0.84 g of 60% sodium hydride in tetrahydrofuran (21 mL), and subsequently a solution of 3.0 g 2′,4′-difluoroacetophenone in tetrahydrofuran (19 mL) was added dropwise thereto. The temperature of the mixture was increased to room temperature, then the mixture was stirred for 24 hours, water was carefully added thereto, and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with brine and then dried over anhydrous sodium sulfate, the solvent was removed, and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give 2.84 g of the title compound (yellow oil).
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([N:8]2[CH2:10][CH2:9]2)=[O:7])=[C:4]([O:13][CH3:14])[CH:3]=1.[NH:15]1[CH2:20][CH2:19][CH:18]([N:21]2[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[NH:23][C:22]2=[O:30])[CH2:17][CH2:16]1.CO>C1C=CC=CC=1>[O:30]=[C:22]1[N:21]([CH:18]2[CH2:17][CH2:16][N:15]([CH2:9][CH2:10][NH:8][C:6](=[O:7])[C:5]3[CH:11]=[CH:12][C:2]([F:1])=[CH:3][C:4]=3[O:13][CH3:14])[CH2:20][CH2:19]2)[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[NH:23]1
Reactant: COc1cc(F)ccc1C(=O)N1CC1
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Solvent: c1ccccc1
Solvent: CO
Product: COc1cc(F)ccc1C(=O)NCCN1CCC(n2c(=O)[nH]c3ccccc32)CC1

Procedure:
A mixture of 8 parts of 1-(4-fluor-2-methoxybenzoyl)-aziridine, 3.8 parts of 1,3-dihydro-1-(4-piperidinyl)-2H-benzimidazol-2-one, 54 parts of benzene and 8 parts of methanol is stirred and refluxed for 1.50 hours. The reaction mixture is cooled and 90 parts of benzene are added. The whole is washed with water and the layers are separated. The organic phase is dried, filtered and evaporated. The residue is crystallized from 2-propanone. The product is filtered off and dried, yielding 4 parts of N{2-[4-(2,3-dihydro-2-oxo-lH-benzimidazol-1-yl)-1-piperidinyl] ethyl}-4-fluoro-2-methoxybenzamide; mp. 197.3° C.
Reaction SMILES: [CH:1]1([N:7]([CH2:17][CH:18]2[CH2:20][CH2:19]2)[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([OH:16])=O)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:21][O:22][C:23](=[O:32])[C:24]1[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][C:25]=1[F:31]>>[CH:1]1([N:7]([CH2:17][CH:18]2[CH2:20][CH2:19]2)[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([NH:30][C:27]3[CH:28]=[CH:29][C:24]([C:23]([O:22][CH3:21])=[O:32])=[C:25]([F:31])[CH:26]=3)=[O:16])[CH:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)c1cc(N(CC2CC2)C2CCCCC2)ncn1
Reactant: COC(=O)c1ccc(N)cc1F
Product: COC(=O)c1ccc(NC(=O)c2cc(N(CC3CC3)C3CCCCC3)ncn2)cc1F

Procedure:
Following the general method as outlined in Example 1, starting from 6-(cyclohexyl-cyclopropylmethyl-amino)-pyrimidine-4-carboxylic acid (Intermediate 13) and 4-amino-2-fluoro-benzoic acid methyl ester (Bepharm), the title compound was obtained as a white solid after purification by column chromatography (silica) eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [CH3:1][S:2][C:3]1[C:4]2[S:11][CH:10]=[C:9]([CH:12]=[O:13])[C:5]=2[N:6]=[CH:7][N:8]=1.CS(C)=[O:16].[O-]Cl=O.[Na+]>O.CC(C)=O>[CH3:1][S:2][C:3]1[C:4]2[S:11][CH:10]=[C:9]([C:12]([OH:16])=[O:13])[C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: CS(C)=O
Reactant: CSc1ncnc2c(C=O)csc12
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC(C)=O
Solvent: O
Product: CSc1ncnc2c(C(=O)O)csc12
Reaction time: 2 h

Procedure:
NaH2PO4.2H2O (513 mg, 3.29 mmol) was dissolved in water (2 mL) and then 4-(methylthio)thieno[3,2-d]pyrimidine-7-carbaldehyde (300 mg, 1.68 mmol) dissolved in acetone (3 mL) and DMSO (3 mL) was added thereto at 0° C. NaClO2 (194 mg, 2.15 mmol) dissolved in water (2 mL) was added at the same temperature to the reaction mixture, which was stirred for 2 hours. After the reaction was completed water (10 mL) was further added to the reaction mixture, which was stirred for 2 hours and filtered to obtain a solid. The solid was washed with water several times and dried with N2 gas to obtain the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[CH:19]=[CH:18][CH:17]=[N:16][C:5]2=[N:6][C:7]=1[S:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.ClC1C=CC=C(C(OO)=[O:28])C=1.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl>[CH3:1][C:2]1[N:3]=[C:4]2[CH:19]=[CH:18][CH:17]=[N:16][C:5]2=[N:6][C:7]=1[S:8]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)=[O:28]
Reactant: Cc1nc2cccnc2nc1SCc1ccccn1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cc1nc2cccnc2nc1S(=O)Cc1ccccn1
Yield: 28.3 %

Procedure:
In 14 ml of chloroform was dissolved 1.4 g of 2-methyl-3-(2-pyridylmethylthio)pyrido[2,3-b]pyrazine. To the solution under chilling with ice was added portionwise 1.1 g of m-chloroperbenzoic acid (purity: 80%). The reaction mixture was then left to have room temperature, and poured into saturated aqueous NaHCO3 solution. The aqueous mixture was extracted with chloroform. T he chloroform layer was washed with water and saturated aqueous sodium chloride solution, and dried over sodium sulfate. The sodium sulfate was then removed by filtration, and the solvent was evaporated under reduced pressure from the filtrate. The residue was purified by silica gel column chromatography (chloroform/methanol), to give 420 mg of 2-methyl-3-(2-pyridylmethylsulfinyl)pyrido[2,3-b]pyrazine as a brown crystalline powder, m.p. 120°-125° C. (decompn.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][C:19]=2[N+:20]([O-:22])=[O:21])[C:13]([NH:15][NH2:16])=[O:14])=[CH:5][CH:4]=1.[F:23][C:24]1[CH:25]=[C:26]([CH2:30][CH2:31][C:32](O)=O)[CH:27]=[CH:28][CH:29]=1.P(Cl)(Cl)(Cl)=O.C(=O)([O-])O.[Na+]>>[F:23][C:24]1[CH:25]=[C:26]([CH2:30][CH2:31][C:32]2[O:14][C:13]([C:12]3[CH:17]=[CH:18][C:19]([N+:20]([O-:22])=[O:21])=[C:10]([CH:11]=3)[NH:9][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)=[N:15][N:16]=2)[CH:27]=[CH:28][CH:29]=1
Reactant: COc1ccc(Nc2cc(C(=O)NN)ccc2[N+](=O)[O-])cc1
Reactant: O=C(O)CCc1cccc(F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc(Nc2cc(-c3nnc(CCc4cccc(F)c4)o3)ccc2[N+](=O)[O-])cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 65.7 %

Procedure:
A mixture of 3-[(4-methoxyphenyl)amino]-4-nitrobenzohydrazide (1.60 g, 5.29 mmol), 3-(3-fluorophenyl)propionic acid (0.89 g, 5.29 mmol) and phosphorus oxychloride (5.29 mL) was stirred at 100° C. for 2 hr. The reaction mixture was cooled to 0° C., neutralized with saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=3/1) to give the title compound (1.51 g, yield 69%) as orange crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14](O)=[O:15])[CH:11]=[CH:10][C:9]=2[CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:5]=[CH:6][CH:7]=1.[CH3:22][C:23]([CH3:30])([C:25]1[S:26][CH:27]=[CH:28][N:29]=1)[NH2:24]>>[CH3:22][C:23]([NH:24][C:14]([C:12]1[CH:11]=[CH:10][C:9]([CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[N:13]=1)=[O:15])([C:25]1[S:26][CH:27]=[CH:28][N:29]=1)[CH3:30]
Reactant: CC(C)(N)c1nccs1
Reactant: O=C(O)c1ccc(C2CCCC2)c(-c2cccc(Cl)c2)n1
Product: CC(C)(NC(=O)c1ccc(C2CCCC2)c(-c2cccc(Cl)c2)n1)c1nccs1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-(3-chloro-phenyl)-5-cyclopentyl-pyridine-2-carboxylic acid (Example 106 e) and α,α-dimethyl-2-thiazolemethanamine (CAN 1082393-38-1) as starting materials, MS (EI): m/e=426.1 [M+H]+.