Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].[CH:6]([C:8]1[CH:16]=[C:12]([C:13]([OH:15])=[O:14])[C:11]([OH:17])=[CH:10][CH:9]=1)=O.C(N)C1C=CC=CC=1>C(O)C>[C:3]([C:2]([C:1]#[N:5])=[CH:6][C:8]1[CH:9]=[CH:10][C:11]([OH:17])=[C:12]([CH:16]=1)[C:13]([OH:15])=[O:14])#[N:4]
Reactant: O=Cc1ccc(O)c(C(=O)O)c1
Reactant: N#CCC#N
Solvent: NCc1ccccc1
Solvent: CCO
Product: N#CC(C#N)=Cc1ccc(O)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 32.7 %

Procedure:
Malononitrile (132 mg, 2 mmol) was dissolved in ethanol (6 mL), and 5-formylsalicylic acid (332 mg, 2 mmol) was added. After cooling with ice bath, benzylamine (0.1 mL) was added and the mixture was stirred at room temperature for 2 hours. The separated yellow crystal was filtered and recrystallized (ethanol) to give the title compound (139.9 mg, 32.7%) as a light yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:17]([F:18])=[CH:16][C:15]([Br:19])=[C:14]2[C:10]=1[C:11]([CH2:21][C:22]([OH:24])=[O:23])=[CH:12][N:13]2C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1C(F)=CC(Br)=C2C=1C=CN2)C1C=CC=CC=1>ClCCl.CO>[CH2:1]([O:8][C:9]1[C:17]([F:18])=[CH:16][C:15]([Br:19])=[C:14]2[C:10]=1[C:11]([CH2:21][C:22]([OH:24])=[O:23])=[CH:12][NH:13]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cn1cc(CC(=O)O)c2c(OCc3ccccc3)c(F)cc(Br)c21
Agent: Fc1cc(Br)c2[nH]ccc2c1OCc1ccccc1
Solvent: ClCCl
Solvent: CO
Product: O=C(O)Cc1c[nH]c2c(Br)cc(F)c(OCc3ccccc3)c12
Yield: 58 %

Procedure:
Following the procedure (step 3, scheme 33) used to prepare compound 33-4, compound 17-1 gave compound 34-2 in 58% yield as a yellow solid after column chromatography on silica gel eluting with dichloromethane/methanol (5:1). LRMS: calc 377.0 and found: 378.0 [M+1].
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH3:8][O:9][C:10](=[O:28])[C:11]1[CH:16]=[CH:15][C:14]([NH:17][CH:18]2[CH2:24][CH:23]3[N:25]([CH3:26])[CH:20]([CH2:21][CH2:22]3)[CH2:19]2)=[C:13]([OH:27])[CH:12]=1.F[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[N+]([O-])=O.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:8][O:9][C:10]([C:11]1[CH:16]=[CH:15][C:14]2[N:17]([CH:18]3[CH2:19][CH:20]4[N:25]([CH3:26])[CH:23]([CH2:22][CH2:21]4)[CH2:24]3)[C:30]3[C:35]([O:27][C:13]=2[CH:12]=1)=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:28]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: COC(=O)c1ccc(NC2CC3CCC(C2)N3C)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc2c(c1)Oc1ccccc1N2C1CC2CCC(C1)N2C
Temperature: 25 °C
Yield: 88 %

Procedure:
A mixture of the TFA salt of 3-hydroxy-4-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-ylamino)-benzoic acid methyl ester, 1a (0.424 g, 0.734 mmol), 2-fluoronitrobenzene (95 μL, 0.9 mmol) and potassium carbonate (564 mg, 4 mmol) in DMF was heated to reflux for 70 min. The mixture was allowed to cool to rt, filtered, and purified via reverse phase HPLC to yield 440 mg (88%) of 10-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazine-3-carboxylic acid methyl ester, 2a, as TFA salt. MS m/z (MH+) 365.1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[CH2:11]([O:13][CH:14]([O:17][CH2:18][CH3:19])[CH2:15]Br)[CH3:12]>CN(C)C=O.C(OCC)C>[CH2:11]([O:13][CH:14]([O:17][CH2:18][CH3:19])[CH2:15][O:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1)[CH3:12]
Reactant: CCOC(CBr)OCC
Reactant: Oc1cccc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOC(COc1cccc(Br)c1)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.7 %

Procedure:
A solution of 10 gm (57.8 mMol) 3-bromophenol in 25 mL dimethylformamide was added dropwise to a mixture of 2.8 gm (70 mMol) sodium hydride (60% suspension in mineral oil) in 30 mL dimethylformamide. The reaction mixture was stirred for one hour after the addition was complete. To the reaction mixture was then added 9.7 mL (64.5 mMol) bromoacetaldehyde diethyl acetal and the resulting mixture was stirred at 153° C. for 2 hours. The reaction mixture was then allowed to cool to room temperature and was diluted with 300 mL diethyl ether. This mixture was then washed with two 150 ml portions of water, washed with 50 mL saturated aqueous sodium chloride, dried over magesium sulfate and concentrated under reduced pressure to provide about 17 gm of the desired compound.
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11]([CH2:13]Cl)[CH:10]=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:15]([CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)C(C)C)(C)C>C(Cl)(Cl)Cl>[C:1]1([C:7]2[N:12]=[C:11]([CH2:13][N:25]3[CH2:26][CH2:27][CH:22]([CH2:15][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH2:23][CH2:24]3)[CH:10]=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClCc1ccnc(-c2ccccc2)n1
Reactant: c1ccc(CC2CCNCC2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: c1ccc(CC2CCN(Cc3ccnc(-c4ccccc4)n3)CC2)cc1
Temperature: 25 °C

Procedure:
To a solution of 50 mg of 2-phenyl-4-chloromethylpyrimidine in 5 mL chloroform was added 80 mg 4-benzylpiperidine and 1 mL of N,N-diisopropylethylamine. The reaction mixture was heated at reflux temperature for 4 hr, cooled to room temperature, washed with 5 mL 1N sodium hydroxide solution and the solvent removed by evaporation under reduced pressure to yield 2-phenyl-4-[(4-benzyl-piperidin-1-yl)methyl]-pyrimidine. This material was purified by chromatography on silica gel using 5% methanol in dichloromethane as eluent. Evaporation of the solvent yielded a solid which was treated with ethereal-HCl to give 15 mg of 2-phenyl-4-[(4-benzyl-piperidin-1-yl)methyl]-pyrimidine dihydrochloride (Compound 11), mp 211-213° C.
Reaction SMILES: Cl.[CH2:2]([NH2:4])[CH3:3].C[Al](C)C.[OH:9][CH:10]([CH3:18])[CH2:11][CH2:12][CH2:13][CH2:14][C:15](O)=[O:16].Cl>C1(C)C=CC=CC=1.CCCCCC>[CH2:2]([NH:4][C:15](=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]([OH:9])[CH3:18])[CH3:3]
Reactant: CC(O)CCCCC(=O)O
Reactant: CCN
Agent: C[Al](C)C
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CCNC(=O)CCCCC(C)O
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 81.9 %

Procedure:
A stirred suspension of dry ethylamine hydrochloride (3.26 g, 0.04 mol) in toluene, under nitrogen, was cooled in an ice bath and treated during 40 minutes with 20 ml of a 2.0M solution of trimethylaluminum in hexane. The mixture was kept at 0° for 10 minutes and at ambient temperature for 2.5 hours. A portion of the resulting solution (46.8 ml) was added, under nitrogen, during 15 minutes to a solution of the product from Step I (2.0 g, 0.016 mol) in toluene (100 ml). This mixture was warmed at 80° C. for 3 hours, cooled and added continuously to dilute HCl. The product was extracted with ethyl acetate. The extracts were dried (MgSO4) and concentrated to give 2.27 g of N-ethyl-6-hydroxyheptanamide.
Reaction SMILES: FC(F)(F)C([O-])=O.[Na+].[CH3:9][NH:10][C@H:11]([C:15]([NH:17][C@H:18]([C:22]([N:24]([C@@H:26]([C@@H:67]([CH3:70])[CH2:68][CH3:69])[C@H:27]([O:65][CH3:66])[CH2:28][C:29]([N:31]1[CH2:35][CH2:34][CH2:33][C@H:32]1[C@H:36]([O:63][CH3:64])[C@@H:37]([CH3:62])[C:38]([NH:40][C@@H:41]([CH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)[CH2:42][O:43][CH2:44][C:45]1[CH:50]=[CH:49][C:48]([C:51]([O:53][CH3:54])=[O:52])=[CH:47][CH:46]=1)=[O:39])=[O:30])[CH3:25])=[O:23])[CH:19]([CH3:21])[CH3:20])=[O:16])[CH:12]([CH3:14])[CH3:13].O=[CH:72][CH2:73][CH2:74][C:75]([OH:77])=[O:76].C([BH3-])#N.[Na+].O1CCOCC1>O1CCOCC1.O>[C:75]([CH2:74][CH2:73][CH2:72][N:10]([CH3:9])[C@H:11]([C:15]([NH:17][C@H:18]([C:22]([N:24]([C@@H:26]([C@@H:67]([CH3:70])[CH2:68][CH3:69])[C@H:27]([O:65][CH3:66])[CH2:28][C:29]([N:31]1[CH2:35][CH2:34][CH2:33][C@H:32]1[C@H:36]([O:63][CH3:64])[C@@H:37]([CH3:62])[C:38]([NH:40][C@@H:41]([CH2:55][C:56]1[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=1)[CH2:42][O:43][CH2:44][C:45]1[CH:46]=[CH:47][C:48]([C:51]([O:53][CH3:54])=[O:52])=[CH:49][CH:50]=1)=[O:39])=[O:30])[CH3:25])=[O:23])[CH:19]([CH3:20])[CH3:21])=[O:16])[CH:12]([CH3:14])[CH3:13])([OH:77])=[O:76]
Reactant: O=CCCC(=O)O
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](COCc1ccc(C(=O)OC)cc1)Cc1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@@H](NC)C(C)C)C(C)C
Agent: O=C([O-])C(F)(F)F
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](COCc1ccc(C(=O)OC)cc1)Cc1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)O)C(C)C

Procedure:
11.5 mg (12 μmol) of N-methyl-L-valyl-N-[(3R,4S,5S)-3-methoxy-1-{(2S)-2-[(1R,2R)-1-methoxy-3-{[(2S)-1-{[4-(methoxycarbonyl)benzyl]oxy}-3-phenylpropane-2-yl]amino}-2-methyl-3-oxopropyl]pyrrolidin-1-yl}-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide sodium trifluoroacetate (intermediate 46) were dissolved in 0.7 ml of dioxane/water (1:1) and treated in analogy to example 1 with 15 aqueous solution of 4-ketobutyric acid in the presence of sodium cyanoborohydride. Following lyophilization from dioxane, the yield was 8.3 mg (74% o. th.) of the title compound in the form of a white solid substance.
Reaction SMILES: N/[C:2](/[CH3:6])=[CH:3]\[C:4]#[N:5].Cl.[CH:8]1([NH:12][NH2:13])[CH2:11][CH2:10][CH2:9]1>C(O)C>[CH:8]1([N:12]2[C:4]([NH2:5])=[CH:3][C:2]([CH3:6])=[N:13]2)[CH2:11][CH2:10][CH2:9]1
Reactant: NNC1CCC1
Reactant: C/C(N)=C/C#N
Agent: Cl
Solvent: CCO
Product: Cc1cc(N)n(C2CCC2)n1
Temperature: 75 °C
Reaction time: 0.17 h

Procedure:
(2Z)-3-Amino-2-butenenitrile (1.339 g, 16.31 mmol) and cyclobutylhydrazine HCl (2 g, 16.31 mmol) were added to ethanol (20 mL) and heated at 75° C. for 16 h. After cooling to room temperature, the solvent was removed under reduced pressure. The crude residue was suspended in saturated NaHCO3 (30 mL) and EtOAc (50 mL), and stirred for 10 min. The phases were separated and the aq. phase extracted with EtOAc (3×50 mL). The combined EtOAc extracts were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was purified via silica gel chromatography (eluent: 0 to 5% EtOAc:DCM, then gradient to 100% EtOAc). The final product was collected as 0.4 g (16%). LCMS E-S (M+H)=:152.0. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.67-2.00 (m, 2 H) 2.21 (s, 3 H) 2.32-2.43 (m, 2 H) 2.69 (ddd, J=10.55, 9.41, 2.53 Hz, 2 H) 3.26-3.55 (br s, 2 H) 4.48-4.59 (m, 1 H) 5.36 (s, 1 H)
Reaction SMILES: [CH2:1]([N:3](CC)CC)[CH3:2].[Cl:8][C:9]1[C:18]([C:19](Cl)=[O:20])=[C:17]([S:22]([CH3:25])(=[O:24])=[O:23])[CH:16]=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12].Br.NCCBr>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Cl:8][C:9]1[C:18]([C:19]2[O:20][CH2:2][CH2:1][N:3]=2)=[C:17]([S:22]([CH3:25])(=[O:24])=[O:23])[CH:16]=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: CCN(CC)CC
Reactant: COC(=O)c1ccc(S(C)(=O)=O)c(C(=O)Cl)c1Cl
Agent: Br
Agent: NCCBr
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(S(C)(=O)=O)c(C2=NCCO2)c1Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 45.6 %

Procedure:
At room temperature, 41.8 g (0.41 mol) of triethylamine and then 31.1 g (0.10 mol) of methyl 2-chloro-3-chlorocarbonyl-4-methylsulfonylbenzoate in 150 ml of toluene were added dropwise to 26.6 g (0.13 mol) of 1-amino-2-bromoethane hydrobromide in 5.00 ml of toluene. The mixture was heated under reflux for 5 hours and then stirred at room temperature for 12 hours, another 5.0 g (0.02 mol) of 1-amino-2-bromoethane hydrobromide were added and the mixture was heated under reflux for 7.5 hours. The reaction mixture was allowed to cool, diluted with ethyl acetate, washed with water, dried and concentrated. The residue was then recrystallized from methyl tert-butyl ether/ethyl acetate. 14.5 g (46% of theory) of methyl 2-chloro-4-methylsulfonyl-3-(4,5-dihydrooxazol-2-yl)benzoate were obtained.
Reaction SMILES: [CH:1]([S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH:13][C:14]1[N:19]=[C:18](S(C)(=O)=O)[N:17]=[C:16]2[NH:24][N:25]=[CH:26][C:15]=12)(=[O:6])=[O:5])([CH3:3])[CH3:2].[CH:27]([O:30][C:31]1[CH:37]=[C:36]([CH:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)[C:35]([CH3:44])=[CH:34][C:32]=1[NH2:33])([CH3:29])[CH3:28].CC1C=CC(S(O)(=O)=O)=CC=1>C(O)(C)C>[CH:27]([O:30][C:31]1[CH:37]=[C:36]([CH:38]2[CH2:39][CH2:40][NH:41][CH2:42][CH2:43]2)[C:35]([CH3:44])=[CH:34][C:32]=1[NH:33][C:18]1[N:17]=[C:16]2[NH:24][N:25]=[CH:26][C:15]2=[C:14]([NH:13][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[S:4]([CH:1]([CH3:3])[CH3:2])(=[O:6])=[O:5])[N:19]=1)([CH3:29])[CH3:28]
Reactant: Cc1cc(N)c(OC(C)C)cc1C1CCNCC1
Reactant: CC(C)S(=O)(=O)c1ccccc1Nc1nc(S(C)(=O)=O)nc2[nH]ncc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Product: Cc1cc(Nc2nc(Nc3ccccc3S(=O)(=O)C(C)C)c3cn[nH]c3n2)c(OC(C)C)cc1C1CCNCC1
Temperature: 150 °C
Reaction time: 3 h

Procedure:
To a suspension of N-(2-(isopropylsulfonyl)phenyl)-6-(methylsulfonyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.5 mmol) in 1 mL of isopropanol, was added 2-isopropoxy-5-methyl-4-(piperidin-4-yl)aniline (0.5 mmol) and 4-methylbenzenesulfonic acid (0.5 mmol). The suspension was stirred at 150° C. for 3 hours. After prep-HPLC, the final product was obtained. 1H NMR (CDCl3, 400 MHz) δ 8.74-8.77 (d, 1H), 8.24 (s, 1H), 7.92-7.96 (m, 2H), 7.65-7.70 (m, 1H), 7.27-7.33(m, 1H), 6.85(s, 1H), 4.60-4.67 (m. 1H), 3.71-3.74 (m, 2H), 3.25-3.32 (m, 1H), 2.78-2.97(m, 6H), 2.28-2.33 (m, 5H), 1.95-1.98 (m, 2H), 1.39-1.41(d, 6H), 1.33-1.35 (d, 6H); MS (ES+): 578.28 (M+1)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH:8]=O)=[C:6]([CH3:10])[N:5]=[CH:4][N:3]=1.[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:13]=1[CH2:19][C:20]#[N:21]>>[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:13]=1[C:19]1[C:20]([NH2:21])=[N:1][C:2]2[N:3]=[CH:4][N:5]=[C:6]([CH3:10])[C:7]=2[CH:8]=1
Reactant: Cc1ncnc(N)c1C=O
Reactant: N#CCc1c(Cl)cccc1Cl
Product: Cc1ncnc2nc(N)c(-c3c(Cl)cccc3Cl)cc12

Procedure:
4-Amino-6-methylpyrimidine-5-carboxaldehyde is then condensed with 2,6-dichlorophenylacetonitrile. The crude product is isolated by concentrating the reaction mixture to dryness and partitioning the residue between chloroform and water. Drying and concentration of the organic layer gives a residue which is chromatographed on silica gel. The product is eluted with 1/99 mixture of methanol/chloroform and recrystallized from ethanol to give pure 6-(2,6-dichlorophenyl)-4-methylpyrido[2,3-d]pyrimidin-7-amine, mp 280°-282° C.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:11].[Cl:12]N1C(=O)CCC1=O.FC(F)(F)S(O)(=O)=O>C(#N)C.C(OCC)C>[Cl:12][C:6]1[CH:5]=[CH:4][C:3]([OH:11])=[C:2]([CH3:1])[C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: Cc1c(O)cccc1[N+](=O)[O-]
Reactant: O=C1CCC(=O)N1Cl
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CCOCC
Solvent: CC#N
Product: Cc1c(O)ccc(Cl)c1[N+](=O)[O-]
Temperature: 75 °C
Reaction time: 1.5 h

Procedure:
2-Methyl-3-nitrophenol (25.5 g), N-chlorosuccinimide (44.5 g), and trifluormethanesulfonic acid (50.0 g) were combined in dry acetonitrile (500 mL) and allowed to stir under an atmosphere of nitrogen at 75° C. for 1.5 hr. The reaction mixture was cooled to room temperature, diluted with ethyl ether (650 mL), washed with water, 10% sodium bisulfite solution, water, and finally saturated sodium chloride solution. Evaporation of the solvent afforded a crude material which was flash chromatographed on silica and eluted with acetone:hexane (1:9) to afford 16.8 g as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:21]=[CH:20][C:12]3[N:13]=[C:14]([NH:16][C:17](=[O:19])[CH3:18])[S:15][C:11]=3[CH:10]=2)[CH:5]=[N:6][C:7]=1[Cl:8].[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1>N1C=CC=CC=1.C(Cl)Cl.C(=O)(O)[O-].[Na+]>[Cl:8][C:7]1[N:6]=[CH:5][C:4]([C:9]2[CH:21]=[CH:20][C:12]3[N:13]=[C:14]([NH:16][C:17](=[O:19])[CH3:18])[S:15][C:11]=3[CH:10]=2)=[CH:3][C:2]=1[NH:1][S:29]([C:26]1[CH:27]=[CH:28][C:23]([Cl:22])=[CH:24][CH:25]=1)(=[O:31])=[O:30]
Reactant: CC(=O)Nc1nc2ccc(-c3cnc(Cl)c(N)c3)cc2s1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Nc1nc2ccc(-c3cnc(Cl)c(NS(=O)(=O)c4ccc(Cl)cc4)c3)cc2s1
Yield: 23.4 %

Procedure:
N-(6-(5-amino-6-chloropyridin-3-yl)benzo[d]thiazol-2-yl)acetamide (0.040 g, 0.13 mmol) was dissolved in pyridine (1 ml), then 4-chlorobenzene-1-sulfonyl chloride (0.026 g, 0.13 mmol) was added to the mixture while stirring. The mixture was allowed to stir under inert atmosphere for 3 days. The progress of the reaction was monitored by LC/MS, which showed product. The mixture was diluted with DCM and saturated sodium bicarbonate solution. The organic layer was extracted with DCM (3×20 ml). Combined organics, dried over sodium sulfate, filtered and concentrated in vacuo. The crude was purified by ISCO silica-gel chromatography in a gradient of 0-10% Methanol/DCM. The fractions with desired material were combined and concentrated in vacuo. The residue was diluted with ethyl acetate and allowed to stir 10 minutes. The precipitate was collected by filtration and washed with 1:1 ethyl acetate/hexanes to give N-(6-(6-chloro-5-(4-chlorophenylsulfonamido)pyridin-3-yl)benzo[d]thiazol-2-yl)acetamide (0.015 g, 24% yield) as a white crystalline solid. MS (ESI pos. ion) m/z: 494 (MH+). Calc'd exact mass for C20H14Cl2N4O3S2: 493. 1H NMR (400 MHz, DMSO-d6): 2.23 (s, 3H), 5.73 (s, 1H), 7.48-8.17 (m, 7H), 8.84 (s, 1H), 8.62 (s, 1H), 12.45 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][N:11]([CH2:13][CH2:14][CH2:15][CH2:16][N:17]3C(=O)C4C(=CC=CC=4)C3=O)[CH:12]=2)=[CH:4][CH:3]=1.O.NN>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[CH:10][N:11]([CH2:13][CH2:14][CH2:15][CH2:16][NH2:17])[CH:12]=2)=[CH:6][CH:7]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCCn1cnc(-c2ccc(Cl)cc2)c1
Agent: NN
Solvent: CCO
Solvent: O
Product: NCCCCn1cnc(-c2ccc(Cl)cc2)c1

Procedure:
Using the procedure of Stage B of Example 1, 14.2 g of product of Stage B and 3.6 ml of hydrazine hydrate in 200 ml of ethanol were reacted to obtain 12 g of crude product which was chromatographed on silica (eluant CH2Cl2 --MeOH--NH4OH 8-2-0.04) to obtain the expected product, which is used as is for the synthesis.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:15][C:16]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][C:17]=1F>CC(C)=O.CCOC(C)=O>[Cl:15][C:16]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][C:17]=1[O:8][C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[N:7][CH:6]=1
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Reactant: Cc1ccc(O)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: Cc1ccc(Oc2ccc([N+](=O)[O-])cc2Cl)cn1
Temperature: 25 °C

Procedure:
6-methyl-pyridin-3-ol Compound 80b (3.10 g, 28.4 mmol) and potassium carbonate (7.80 g, 56.8 mmol) were added to a solution of 2-chloro-1-fluoro-4-nitro-benzene Compound 80a (5.0 g, 28.4 mmol) in acetone (50 mL). The suspension was refluxed for 20 hrs and then cooled to 25° C. The reaction mixture was diluted with EtOAc and washed with water and brine. The organic solution was dried over Na2SO4, then filtered and concentrated to yield 5-(2-chloro-4-nitro-phenoxy)-2-methyl-pyridine Compound 80c (5.6 g, 80%). MS 350 (M−).
Reaction SMILES: C([O:3][C:4](=O)[CH:5]=[C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[CH:10][CH:9]=1)[CH3:7])C.O.[NH2:23][NH2:24]>C(O)C>[F:20][C:17]1[CH:18]=[CH:19][C:14]([C:11]2[CH:12]=[CH:13][C:8]([C:6]3([CH3:7])[CH2:5][C:4](=[O:3])[NH:24][NH:23]3)=[CH:9][CH:10]=2)=[CH:15][CH:16]=1
Reactant: CCOC(=O)C=C(C)c1ccc(-c2ccc(F)cc2)cc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: CC1(c2ccc(-c3ccc(F)cc3)cc2)CC(=O)NN1

Procedure:
A solution of 28.4 g of 3-(4'-fluoro-4-biphenylyl)-2-butenoic acid ethyl ester [obtainable by dehydrating 3-(4'-fluoro-4-biphenylyl)-3-hydroxybutyric acid ethyl ester employing p-toluenesulfonic acid] and 25 g of hydrazine hydrate (100% strength) in 400 ml of ethanol is boiled for 18 hours. The mixture is cooled, poured onto ice water and worked up in the usual manner to give 3-(4'-fluoro-4-biphenylyl)-3-methyl-pyrazolidin-5-one, m.p. 194°-196°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH:18]([N:22]3[CH:26]=[N:25][CH:24]=[N:23]3)[CH:19]([CH3:21])[CH3:20])=[CH:14][C:13]=2[N+:27]([O-])=O)=[O:10])=[CH:4][CH:3]=1.N1C=CC=CC=1.[K].Cl>CC(O)(C)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:10])[NH:11][C:12]3[C:13]([N:27]=2)=[CH:14][C:15]([CH:18]([N:22]2[CH:26]=[N:25][CH:24]=[N:23]2)[CH:19]([CH3:21])[CH3:20])=[CH:16][CH:17]=3)=[CH:4][CH:3]=1
Reactant: CC(C)C(c1ccc(NC(=O)Cc2ccc(Cl)cc2)c([N+](=O)[O-])c1)n1cncn1
Agent: Cl
Agent: [K]
Solvent: c1ccncc1
Solvent: CC(C)(C)O
Product: CC(C)C(c1ccc2[nH]c(=O)c(-c3ccc(Cl)cc3)nc2c1)n1cncn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.8 %

Procedure:
To a stirred mixture of 11 parts of 4-chloro-N-[4-[2-methyl-1-(1H-1,2,4-triazol-1-yl)propyl]-2-nitrophenyl]benzeneacetamide and 49 parts of pyridine were added 3.6 parts of 2-methyl-2-propanol, potassium salt under a nitrogen atmosphere. After stirring for 1 hour at room temperature, the reaction mixture was poured into ice-water. The whole was neutralized with HCl 3N and the product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography (silica gel; CH2Cl2 /CH3OH 98:2). The eluent of the desired fraction was evaporated, yielding 6.6 parts (61.8%) of 3-(4-chlorophenyl)-6-[2-methyl-1-(1H-1,2,4-triazol-1-yl)propyl]-2(1H)-quinoxalinone, N4 -oxide (comp. 221).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH2:10])[C:5]=1[F:11].[Br:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH:17]=O>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N:10]=[CH:17][C:16]2[CH:19]=[CH:20][CH:21]=[C:14]([Br:13])[CH:15]=2)[C:5]=1[F:11]
Reactant: COC(=O)c1cccc(N)c1F
Reactant: O=Cc1cccc(Br)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc(N=Cc2cccc(Br)c2)c1F
Temperature: 25 °C
Yield: 100 %

Procedure:
To a stirred solution of 3-amino-2-fluoro-benzoic acid (25 g, 161 mmol) in methanol (300 mL) was added thionyl chloride (30 mL, 403 mmol) dropwise at 0° C. Then the mixture solution was refluxed for 12 hours before cooling to room temperature. Then the reaction mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate (500 mL), washed with saturated aqueous sodium bicarbonate solution (3×100 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to afford 3-amino-2-fluoro-benzoic acid methyl ester (27.5 g, quant.) as a pale-white solid: LC/MS m/e calcd for C8H8FNO2 (M+H)+: 170.16, observed: 169.9. A mixture solution of 3-amino-2-fluoro-benzoic acid methyl ester (26 g, 153.8 mmol), 3-bromo-benzaldehyde (28.5 g, 153.8 mmol) and p-toluenesulfonic acid (590 mg, 3.2 mmol) in toluene (200 mL) was heated to reflux for 12 hours. Then the reaction mixture was cooled to room temperature. The solvent was removed in vacuo and the residue was washed with ether to afford 3-[(3-bromo-benzylidene)-amino]-2-fluoro-benzoic acid methyl ester (51.7 g, quant.) as a pale-white solid: MS calcd. for C15H11BrFlNO2 337.16, obsd. (ESI+) [(M+H)+]336.0 & 338.0.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]([C:15]2[CH:20]=[C:19](O)[CH:18]=[C:17]([O:22][CH2:23][CH3:24])[CH:16]=2)[C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1)#[N:2].C([C:27]1[CH:32]=[CH:31][C:30]([NH:33]C(C2C=C(OS(C(F)(F)F)(=O)=O)C=C(OCC)C=2)C(OC)=O)=[CH:29][CH:28]=1)#N.NC1C=C(B(O)O)C=CC=1>>[NH2:33][C:30]1[CH:29]=[C:28]([C:19]2[CH:18]=[C:17]([O:22][CH2:23][CH3:24])[CH:16]=[C:15]([CH:10]([NH:9][C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=3)[C:11]([O:13][CH3:14])=[O:12])[CH:20]=2)[CH:27]=[CH:32][CH:31]=1
Reactant: CCOc1cc(OS(=O)(=O)C(F)(F)F)cc(C(Nc2ccc(C#N)cc2)C(=O)OC)c1
Reactant: CCOc1cc(O)cc(C(Nc2ccc(C#N)cc2)C(=O)OC)c1
Agent: Nc1cccc(B(O)O)c1
Product: CCOc1cc(-c2cccc(N)c2)cc(C(Nc2ccc(C#N)cc2)C(=O)OC)c1

Procedure:
Analogously to Example 155, from methyl (RS)-(4-cyano-phenylamino)-(3-ethoxy-5-hydroxy-phenyl)-acetate via methyl (RS)-(4-cyano-phenylamino)-(3-ethoxy-5-trifluoromethanesulphonyloxy-phenyl)-acetate by reaction with 3-aminophenylboronic acid there was obtained the compound methyl (RS)-(3′-amino-5-ethoxy-biphenyl-3-yl)-(4-cyano-phenylamino)-acetate, which was converted into methyl (RS)-(3′-amino-5-ethoxy-biphenyl-3-yl)-(4-carbamimidoyl-phenylamino)-acetate hydrochloride; MS: 419 ([M+H]+).