Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][N:9]([C:12]([CH3:37])=[C:13](SSC(CCO)=C(NC(CC2C(N)=NC(C)=CC=2)=O)C)[CH2:14][CH2:15][OH:16])[CH:10]=[O:11])=[CH:6][CH:5]=[C:4]([CH3:38])[N:3]=1.[CH2:39]([S:42][S:43]CCC)[CH2:40][CH3:41].[OH-].[Na+].C(OCC)(=O)C>CO.O.C(Cl)(Cl)Cl>[NH2:1][C:2]1[C:7]([CH2:8][N:9]([C:12]([CH3:37])=[CH:13][CH2:14][CH:15]([S:43][S:42][CH2:39][CH2:40][CH3:41])[OH:16])[CH:10]=[O:11])=[CH:6][CH:5]=[C:4]([CH3:38])[N:3]=1
Reactant: CC(NC(=O)Cc1ccc(C)nc1N)=C(CCO)SSC(CCO)=C(C)N(C=O)Cc1ccc(C)nc1N
Reactant: CCCSSCCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCCSSC(O)CC=C(C)N(C=O)Cc1ccc(C)nc1N
Temperature: 40 °C
Reaction time: 18 h
Yield: 81.3 %

Procedure:
To a solution of N-(2-amino-6-methylpyridin-3-ylmethyl)-N-{2-[2-[(2-amino-6-methyl-pyridin-3-ylmethyl)formylamino]-1-(2-hydroxyethyl)-propenyldisulfanyl]-4-hydroxy-1-methylbut-1-enyl}formamide (250 mg, 0.45 mmol) and propyl disulfide (0.21 mL, 1.34 mmol) in methanol (3 ml) was added 1 molar aqueous sodium hydroxide (0.089 mL, 0.089 mmol). The resulting solution was stirred at 35-45° C. for 18 hr. The solution was diluted with water (10 mL) and chloroform (10 mL), but the product remained as a milky insoluble layer. Addition of ethyl acetate (10 mL) and methanol (2 mL) resulted in the formation of two clear layers. The product was contained in the lower layer. This layer was washed with brine (10 mL) dried over sodium sulfate, and evaporated. The residual oil was dissolved in chloroform (1 mL) and chromatographed on silica gel (Waters Sep-Pak 5 g column, using 97.5/2.5 chloroform/methanol as eluent, Fraction size 9 mL). Fractions 4-9 were pooled and evaporated to give 130 mg (41%) of the title compound as nearly colorless oil. MS (LCMS): 356.0 (M+H)+. 1H NMR (CDCl3) δ 0.95 (t, 3H), 1.55 (m, 3H), 1.97 (s, 3H), 2.35 (s, 3H), 2.42 (t, 2H), 2.84 (t, 2H) 3.76 (t, 2H), 5.36 (br. s, 1H), 6.35 (d, 1H), 7.02 (d, 1H), 7.96 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[C:5]([NH2:8])=[CH:6][CH:7]=1.[C:16]([O:20][C:21]([NH:23][C@@H:24]([CH3:28])[C:25](O)=[O:26])=[O:22])([CH3:19])([CH3:18])[CH3:17].C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.C([O-])(O)=O.[Na+]>[C:16]([O:20][C:21](=[O:22])[NH:23][C@H:24]([C:25](=[O:26])[NH:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)[CH3:28])([CH3:17])([CH3:18])[CH3:19]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Nc1ccc(F)cc1Nc1ccccn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc(F)cc1Nc1ccccn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 4-fluoro-N2-pyridin-2-ylbenzene-1,2-diamine (241 mg, 1.19 mmol), (S)-2-tertbutoxycarbonylaminopropionic acid (247 mg, 1.30 mmol), HOAt (178 mg, 1.30 mmol), 4-methylmorpholine (0.287 mL, 2.61 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (250 mg, 1.30 mmol) in DCM (10 mL) was stirred at RT for 2 h. The reaction mixture was diluted with a saturated aqueous solution of NaHCO3 and extracted with DCM (×3). The combined organic fractions were passed through a phase separator and concentrated in vacuo to afford {(S)-1-[4-fluoro-2-(pyridin-2-ylamino)phenylcarbamoyl]ethyl}carbamic acid tert-butyl ester as a pale red solid (505 mg, quantitative). LCMS (Method B): RT 2.30 min [M+H]+ 375.0.
Reaction SMILES: C(O)(=O)C.[N:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=2)[CH:6]=1.[N+:20]([CH3:23])([O-:22])=[O:21].C([O-])(=O)C.[NH4+]>C(OCC)(=O)C.O>[N+:20](/[CH:23]=[CH:16]/[C:15]1[CH:18]=[CH:19][C:12]([O:11][C:7]2[CH:6]=[N:5][CH:10]=[CH:9][CH:8]=2)=[CH:13][CH:14]=1)([O-:22])=[O:21]
Reactant: O=Cc1ccc(Oc2cccnc2)cc1
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])/C=C/c1ccc(Oc2cccnc2)cc1
Temperature: 110 °C
Reaction time: 3 h
Yield: 96.8 %

Procedure:
To an acetic acid (17.0 mL) solution of 4-(pyridine-3-yloxy)-benzaldehyde (1.70 g, 8.53 mmol) described in Manufacturing Example 76-1-1 were added nitromethane (2.60 g, 42.7 mmol) and ammonium acetate (1.32 g, 17.1 mmol) under nitrogen atmosphere, which was stirred for 3 hours at 110° C. Water and ethyl acetate were added to the reaction solution, and the organic layer was then extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure to obtain the title compound (2.00 g) as a crude product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([Cl:11])[CH:10]=1)[C:7](=[O:12])[C:6](=[N:13]O)[CH2:5]2.Cl>CCO.[Pd]>[NH2:13][CH:6]1[CH2:5][C:4]2[C:8](=[C:9]([Cl:11])[CH:10]=[C:2]([Cl:1])[CH:3]=2)[C:7]1=[O:12]
Reactant: O=C1C(=NO)Cc2cc(Cl)cc(Cl)c21
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: NC1Cc2cc(Cl)cc(Cl)c2C1=O
Reaction time: 8 h

Procedure:
To a solution of 5,7-dichloro-2-(hydroxyimino)-2,3-dihydro-1H-inden-1-one (0.56 mmol) in 4 mL EtOH were added Pd on carbon (5 mg) and 0.1 mL 25% HCl solution. The mixture was stirred overnight under a hydrogen atmosphere. It was then filtered over a 2 cm pad of celite and washed with EtOH (20 mL) and EtOAc (20 mL). The filtrate was concentrated in vacuo to give the desired product as brown oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:13]([OH:15])=O)=[CH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2.[Cl:16][C:17]1[CH:18]=[C:19]([C:24]2[CH:29]=[CH:28][C:27]([CH2:30][C@@H:31]([NH2:38])[C:32]3[O:36][N:35]=[C:34]([CH3:37])[N:33]=3)=[CH:26][CH:25]=2)[CH:20]=[CH:21][C:22]=1[F:23]>>[Cl:16][C:17]1[CH:18]=[C:19]([C:24]2[CH:29]=[CH:28][C:27]([CH2:30][C@@H:31]([NH:38][C:13]([C:4]3[C:3]([O:2][CH3:1])=[CH:12][C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[CH:5]=3)=[O:15])[C:32]3[O:36][N:35]=[C:34]([CH3:37])[N:33]=3)=[CH:26][CH:25]=2)[CH:20]=[CH:21][C:22]=1[F:23]
Reactant: COc1cc2ccccc2cc1C(=O)O
Reactant: Cc1noc([C@H](N)Cc2ccc(-c3ccc(F)c(Cl)c3)cc2)n1
Product: COc1cc2ccccc2cc1C(=O)N[C@H](Cc1ccc(-c2ccc(F)c(Cl)c2)cc1)c1nc(C)no1
Yield: 33.2 %

Procedure:
3-Methoxy-2-naphthoic acid 86 mg (0.43 mmol) and the 2-(3′-Chloro-4′-fluoro-biphenyl-4-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethylamine 100 mg (0.35 mmol) were coupled using the general procedure A. to afford the 3-Methoxy-naphthalene-2-carboxylic acid [2-(3′-chloro-4′-fluoro-biphenyl-4-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethyl]-amide 60 mg.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:6][C@@H:5]([CH2:7][CH2:8]O)[CH2:4][O:3]1.C(N(CC)CC)C.CS(Cl)(=O)=O.[NH4+].[Cl-].[Na+].[I-:26]>C(Cl)Cl.CN(C1C=CN=CC=1)C.CC(C)=O.O>[I:26][CH2:8][CH2:7][C@H:5]1[CH2:4][O:3][C:2]([CH3:10])([CH3:1])[O:6]1
Reactant: [I-]
Reactant: CC1(C)OC[C@H](CCO)O1
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Agent: [Cl-]
Solvent: O
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CC1(C)OC[C@H](CCI)O1
Temperature: 0 °C
Yield: 32 %

Procedure:
To a solution of (S)-2-(2,2-dimethyl-1,3-dioxolan-4-yl)ethanol (1.58 mL, 10.0 mmol) in CH2Cl2 (25 mL) was added DMAP (120 mg, 1.0 mmol) and triethylamine (2.08 mL, 15.0 mmol). The reaction mixture was cooled to 0° C. and methanesulfonyl chloride (12.0 mmol, 0.928 mL) was added slowly dropwise under N2 atmosphere. The reaction mixture was stirred for 2 h (monitored by TLC, 1:2 EtOAc—Hexanes). Saturated NH4Cl solution (20 mL) was added and the mixture was extracted with CH2Cl2. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to provide a yellow oil, which was dissolved in dry acetone (25 ml), followed by addition of NaI (7.5 g, 50 mmol). The reaction mixture was refluxed for 2 h (monitored by TLC, 1:4 EtOAc—Hexanes), cooled to room temperature and water (50 mL) was added. Extraction with ethyl acetate, washing of the combined organic layers with brine, drying over anhydrous Na2SO4, filtration and concentration provided a yellow oil, which was purified by flash chromatography (25% EtOAC-Hexane) to afford the title compound, (S)-4-(2-iodoethyl)-2,2-dimethyl-1,3-dioxolane (0.82 g, 32% over two steps) as a clear oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.36 (s, 3H), 1.41 (s, 3H), 1.99-1.16 (m, 2H), 3.25 (dd, J=18.19, 8.84 Hz, 2H), 3.58 (t, J=7.20 Hz, 1H), 4.03-4.13 (m, 1H), 4.13-4.24 (m, 1H). MS (ES) [M+H] calculated for C2H14IO2, 257.00; found 257.08.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:12]=[C:11]([CH3:13])[C:10]([C:14]([OH:16])=O)=[CH:9][N:8]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:50][N:51]1[C:59]2[C:54](=[C:55]([F:60])[CH:56]=[CH:57][CH:58]=2)[CH:53]=[CH:52]1>CN(C=O)C>[F:60][C:55]1[CH:56]=[CH:57][CH:58]=[C:59]2[C:54]=1[CH:53]=[CH:52][N:51]2[NH:50][C:14]([C:10]1[C:11]([CH3:13])=[N:12][C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[N:8][CH:9]=1)=[O:16]
Reactant: Nn1ccc2c(F)cccc21
Reactant: Cc1nc(-c2ccccn2)ncc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(-c2ccccn2)ncc1C(=O)Nn1ccc2c(F)cccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47.9 %

Procedure:
A solution of 2-(pyridine-2-yl)-4-methylpyrimidine-5-carboxylic acid (0.11 g) and HATU (0.19 g) in dry DMF (7 mL) is treated with DIPEA (0.09 mL) and stirred at rt under N2 for 30 min. 1-Amino-4-fluoroindole (0.112 g) is added and the mixture is stirred at rt for 24 h. The mixture is concentrated in vacuo. The residue is dissolved in EtOAc, washed with water and brine and dried (MgSO4), filtered, and concentration in vacuo. The residue is purified by silica gel chromatography eluting with 75% EtOAc to afford 2-(pyridin-2-yl)-4-methylpyrimidine-5-carboxylic acid-(4-fluoroindol-1-yl)amide (0.085 gms, 50%). MS: 348 (M+H); 1H NMR (300 MHz, DMSO-d6): δ 2.82 (s, 3H), 6.65 (d, 1H), 6.93-6.97 (q, 1H), 7.19-7.26 (m, 1H), 7.35-7.38 (d, 1H), 7.62 (d, 1H), 7.74-7.78 (m, 1H), 8.20-8.25 (t, 1H), 8.58-8.61 (d, 1H), 8.85-8.86 (d, 1H), 9.33 (s, 1H), 12.15 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([C:9]([C:11]([F:14])([F:13])[F:12])=[CH2:10])[C:3]=1[F:15].CO[CH2:18][N:19]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:20][Si](C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH2:25]([N:19]1[CH2:20][CH2:10][C:9]([C:4]2[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[C:3]=2[F:15])([C:11]([F:14])([F:13])[F:12])[CH2:18]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: C=C(c1cc(Cl)cc(Cl)c1F)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Fc1c(Cl)cc(Cl)cc1C1(C(F)(F)F)CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.7 %

Procedure:
1,5-dichloro-2-fluoro-3-(3,3,3-trifluoroprop-1-en-2-yl)benzene (6.2 g) and N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine (4.7 g) were dissolved in dichloromethane (100 ml) and slowly added dropwise with a dichloromethane solution (8 ml) of anhydrous trifluoroacetic acid (0.15 ml) under ice cooling. Upon the completion of the dropwise addition, the reaction temperature was raised to the room temperature and stirred overnight. The reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography to obtain 1-benzyl-3-(3,5-dichloro-2-fluorophenyl)-3-(trifluoromethyl)pyrrolidine (3.7 g).
Reaction SMILES: [CH2:1]1[O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:14]1[C:15]2[C:28]([Cl:29])=[C:27]([CH3:30])[S:26][C:16]=2[N:17]=[C:18]([C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[N:19]=1>>[N:23]1[CH:22]=[CH:21][C:20]([C:18]2[N:19]=[C:14]([NH:8][CH2:7][CH2:6][C:5]3[CH:9]=[CH:10][C:11]4[O:12][CH2:1][O:2][C:3]=4[CH:4]=3)[C:15]3[C:28]([Cl:29])=[C:27]([CH3:30])[S:26][C:16]=3[N:17]=2)=[CH:25][CH:24]=1
Reactant: Cc1sc2nc(-c3ccncc3)nc(Cl)c2c1Cl
Reactant: NCCc1ccc2c(c1)OCO2
Product: Cc1sc2nc(-c3ccncc3)nc(NCCc3ccc4c(c3)OCO4)c2c1Cl

Procedure:
With the procedure of Example 1, the reaction of 3,4-methylenedioxyphenethylamine with 4-chloro-2-(pyridin-4-yl)-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-4-yl)-4-(3,4-methylenedioxyphenethylamino)-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]2([C:23]3[C:14](=[CH:15][C:16]4[O:21][CH2:20][CH2:19][O:18][C:17]=4[CH:22]=3)[O:13][CH2:12]2)[C:4]1=[O:24].Cl[C:26]([O:28][CH2:29][CH3:30])=[O:27]>CN(C)C=O>[O:24]=[C:4]1[C:5]2([C:23]3[C:14](=[CH:15][C:16]4[O:21][CH2:20][CH2:19][O:18][C:17]=4[CH:22]=3)[O:13][CH2:12]2)[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[N:3]1[C:26]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: CCOC(=O)Cl
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)N1C(=O)C2(COc3cc4c(cc32)OCCO4)c2ccccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 54.6 %

Procedure:
To a cooled (0° C.) suspension of sodium hydride (60% w/w in mineral oil, 0.16 g, 3.7 mmol) in anhydrous N,N-dimethylformamide (30 mL) was added 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one (0.99 g, 3.39 mmol), followed by ethyl chloroformate (0.35 mL, 3.7 mmol). The reaction mixture was stirred at ambient temperature for 18 h and was concentrated in vacuo. The residue was purified by column chromatography and eluted with a 5% to 66% gradient of ethyl acetate in hexanes to afford ethyl 2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indole]-1′(2′H)-carboxylate (0.68 g, 55%) as a colourless solid: mp 198-200° C. (hexanes/ethyl acetate); 1H NMR (300 MHz, CDCl3) δ7.96 (d, J=7.7 Hz, 1H), 7.39-7.34 (m, 1H), 7.19-7.18 (m, 2H), 6.50 (s, 1H), 6.27 (s, 1H), 4.93 (d, J=9.1 Hz, 1H), 4.63 (d, J=9.1 Hz, 1H), 4.49 (q, J=7.1 Hz, 2H), 4.21-4.18 (m, 2H), 4.13-4.10 (m, 2H) 1.45 (t, J=7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ175.7, 155.1, 150.8, 144.9, 138.7, 138.4, 130.7, 129.2, 125.5, 123.8, 121.0, 115.2, 111.7, 99.4, 80.8, 64.5, 63.9, 63.7, 58.6, 14.2; MS (ES+) m/z 367.7 (M+1).
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:35])[C@H:6]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23](OC2C=CC([N+]([O-])=O)=CC=2)=[O:24])=[CH:18][CH:17]=1)[NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:2]=[CH2:3].[C:36]([O:40][C:41]([NH:43][CH2:44][C@@H:45]([C:47]([OH:49])=[O:48])[NH2:46])=[O:42])([CH3:39])([CH3:38])[CH3:37]>ClC(Cl)C>[CH2:1]([O:4][C:5](=[O:35])[C@@H:6]([NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]([NH:46][C@H:45]([C:47]([OH:49])=[O:48])[CH2:44][NH:43][C:41]([O:40][C:36]([CH3:39])([CH3:37])[CH3:38])=[O:42])=[O:24])=[CH:18][CH:17]=1)[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)[C@H](Cc1ccc(OC(=O)Oc2ccc([N+](=O)[O-])cc2)cc1)NC(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)NC[C@H](N)C(=O)O
Solvent: CC(Cl)Cl
Product: C=CCOC(=O)[C@H](Cc1ccc(OC(=O)N[C@@H](CNC(=O)OC(C)(C)C)C(=O)O)cc1)NC(=O)OC(C)(C)C
Temperature: 85 °C

Procedure:
2.45 g (5.0 mmol) of the compound from example 1A was dissolved in 40 ml dichloroethane. 1.03 g, (5.0 mmol) 3-[(tert-Butoxycarbonyl)amino]-L-alanine was added. The reaction mixture was heated to 85° C. for 2 h. The solvent was removed under reduced pressure. The raw product was dissolved in dichloromethane and chromatographed over approx. 150 ml silica gel. Solvents used were dicloromethane/methanol 20/1 to dichloromethane/methanol 1/1. The product-containing fractions were combined and concentrated to dryness under reduced pressure. This gave 1.23 g (2.2 mmol, 44% of theory) of the desired product.
Reaction SMILES: [CH2:1]([C:8]1[O:9][C:10]([CH3:29])=[C:11]([CH3:28])[C:12]=1[C:13]([C:15]1[CH:20]=[CH:19][C:18]([O:21]C)=[C:17]([CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[CH:16]=1)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(Cl)Cl>[CH3:29][C:10]1[O:9][C:8]2[CH:1]=[C:2]3[C:3](=[C:13]([C:15]4[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([CH:23]5[CH2:27][CH2:26][CH2:25][CH2:24]5)[CH:16]=4)[C:12]=2[C:11]=1[CH3:28])[CH:4]=[CH:5][CH:6]=[CH:7]3
Reactant: COc1ccc(C(=O)c2c(Cc3ccccc3)oc(C)c2C)cc1C1CCCC1
Solvent: ClCCl
Product: Cc1oc2cc3ccccc3c(-c3ccc(O)c(C4CCCC4)c3)c2c1C
Yield: 9 %

Procedure:
The title compound was prepared according to the procedure in Example 1, step 5 using (2-benzyl-4,5-dimethyl-furan-3-yl)-(3-cyclopentyl-4-methoxy-phenyl)-methanone (18.8 g, 48.4 mmol) boron tribromide (34.8 mL, 0.367 mol) in CH2Cl2. Purification on silica gel eluting with a 2, 5, 10 and 20% EtOAc/hexane step gradient gave 1.55 g (10%) of the title compound. 1H NMR (DMSO-d6)δ 1.56-1.69 (m, 9 H), 1.96-1.97 (m, 5 H), 2.37 (s, 3 H), 3.33 (q, 1 H, masked by H2O), 6.91-7.00 (m, 2 H), 7.06 (d, 1 H), 7.30 (t, 1 H), 7.41 (t, 1 H), 7.56 (d, 1 H), 7.91 (s, 1 H), 7.98 (d, 1 H), 9.48 (s, 1 H).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]([N:9]([CH:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[C@H:10]([C:23](OC)=[O:24])[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]([F:22])([F:21])[F:20])[CH:13]=2)=[O:8])[N:4]=[CH:3]1.[BH4-].[Na+].Cl.O>C(O)C>[OH:24][CH2:23][CH:10]([N:9]([CH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1)[C:7]([C:5]1[N:4]=[CH:3][N:2]([CH3:1])[CH:6]=1)=[O:8])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]([F:22])([F:21])[F:20])[CH:13]=1
Reactant: COC(=O)[C@H](Cc1cccc(OC(F)(F)F)c1)N(C(=O)c1cn(C)cn1)C1CCOCC1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cn1cnc(C(=O)N(C2CCOCC2)C(CO)Cc2cccc(OC(F)(F)F)c2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 9.5 %

Procedure:
To a solution of methyl N-[(1-methyl-1H-imidazol-4-yl)carbonyl]-N-(tetrahydro-2H-pyran-4-yl)-3-(trifluoromethoxy)phenylalaninate (55 mg) in ethanol (2.2 mL), sodium borohydride (23 mg) was added and the resulting mixture was heated under reflux for 3 hours. To the ice-cooled reaction mixture, 1 M HCl was added dropwise and the resulting mixture was stirred for 30 minutes at room temperature. After adding water, the mixture was subjected to extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate. After filtering off the desiccant, the filtrate was concentrated under reduced pressure and the resulting residue was purified by TLC (silica gel plate; chloroform/methanol=10:1) and column chromatography (NH silica gel cartridge; chloroform) to give the titled compound (4.9 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH:14]=[C:15]3[S:19][C:18](SCC)=[N:17][C:16]3=[O:23])[CH:12]=2)[N:7]=[CH:6][C:5]=1[S:24]([CH3:27])(=[O:26])=[O:25])[CH3:2].[CH:28]1([NH2:31])[CH2:30][CH2:29]1.C(N(C(C)C)CC)(C)C>>[CH:28]1([NH:31][C:18]2[S:19]/[C:15](=[CH:14]\[C:11]3[CH:12]=[C:13]4[C:8](=[CH:9][CH:10]=3)[N:7]=[CH:6][C:5]([S:24]([CH3:27])(=[O:26])=[O:25])=[C:4]4[O:3][CH2:1][CH3:2])/[C:16](=[O:23])[N:17]=2)[CH2:30][CH2:29]1
Reactant: NC1CC1
Reactant: CCOc1c(S(C)(=O)=O)cnc2ccc(C=C3SC(SCC)=NC3=O)cc12
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1c(S(C)(=O)=O)cnc2ccc(/C=C3\SC(NC4CC4)=NC3=O)cc12

Procedure:
Similar procedure as described in example 41c was used, starting from 5-(4-ethoxy-3-methanesulfonyl-quinolin-6-ylmethylene)-2-ethylsulfanyl-thiazol-4-one (example 74e), cyclopropylamine, and DIEA (diisopropylethylamine) to give 2-cyclopropylamino-5-[1-(4-ethoxy-3-methanesulfonyl-quinolin-6-yl)-meth-(Z)-ylidene]-thiazol-4-one. LC-MS m/e 418 (MH+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]1[C:14](=[O:15])[C:13]([C:16]([NH:18][CH2:19][C:20]([OH:22])=[O:21])=[O:17])=[C:12]([OH:23])[C:11]([CH:24]([CH3:26])[CH3:25])=[N:10]1.[C:27]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)([OH:29])=[O:28].C(=O)([O-])[O-].[K+].[K+].Cl>O1CCOCC1.O.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:20]([CH2:19][NH:18][C:16]([C:13]1[C:14](=[O:15])[N:9]([CH2:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[C:33]2[CH:34]=[CH:35][C:30]([C:27]([OH:29])=[O:28])=[CH:31][CH:32]=2)[N:10]=[C:11]([CH:24]([CH3:26])[CH3:25])[C:12]=1[OH:23])=[O:17])([OH:22])=[O:21]
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: CC(C)c1nn(Cc2ccccc2Br)c(=O)c(C(=O)NCC(=O)O)c1O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)c1nn(Cc2ccccc2-c2ccc(C(=O)O)cc2)c(=O)c(C(=O)NCC(=O)O)c1O
Yield: 36.2 %

Procedure:
To a 5 ml microwave tube was added N-{[2-[(2-bromophenyl)methyl]-5-hydroxy-6-(1-methylethyl)-3-oxo-2,3-dihydro-4-pyridazinyl]carbonyl}glycine (example 78(b), 75 mg, 0.177 mmol), 4-carboxybenzeneboronic acid (29.3 mg, 0.177 mmol), potassium carbonate (73.3 mg, 0.530 mmol), and tetrakis(triphenylphosphine)palladium (0) (6.13 mg, 5.30 μmol) in 1,4-Dioxane (1.5 ml) and Water (0.500 ml). The mixture was irradiated at 100° C. for 20 minutes. The reaction mixture was diluted with water (5 ml), acidified with 1N HCl (2 ml), and extracted with ethyl acetate (20 ml). The organic phase was dried over MgSO4, filtered, and solvents removed under reduced pressure. The crude residue was purified by HPLC chromatography (ODS silica, gradient 10-75% acetonitrile/water (0.1% TFA)) to afford the title compound 2′-{[5-{[(carboxymethyl)amino]carbonyl}-4-hydroxy-3-(1-methylethyl)-6-oxo-1(6H)-pyridazinyl]methyl}-4-biphenylcarboxylic acid (non-preferred name) (30 mg, 0.064 mmol, 36.1% yield) as a white powder. 1H NMR (400 MHz, DMSO-d6) d ppm 15.82 (s, 1H), 12.99 (br. s., 2 H), 10.06 (t, J=5.68 Hz, 1H), 7.99 (d, J=8.34 Hz, 2H), 7.52 (d, J=8.34 Hz, 2 H), 7.38 (dt, J=4.36, 2.24 Hz, 2H), 7.25-7.32 (m, 1H), 7.17-7.24 (m, 1H), 5.26 (s, 2H), 4.06 (d, J=5.56 Hz, 2H), 3.11 (sept, J=6.82 Hz, 1H), 1.10 (d, J=6.82 Hz, 6H). MS (ES+) m/e 466 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[O:7][CH2:6][N:5]([C:8]([CH3:13])([CH3:12])[C:9]([OH:11])=O)[C:4](=[O:14])[C:3]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:40][C:41]1[CH:42]=[C:43]([CH:45]=[CH:46][CH:47]=1)[NH2:44].C(N(CC)CC)C>ClC(Cl)(Cl)Cl.ClCCl>[Cl:40][C:41]1[CH:42]=[C:43]([NH:44][C:9](=[O:11])[C:8]([N:5]2[C:4](=[O:14])[C:3]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:2]([CH3:1])[O:7][CH2:6]2)([CH3:13])[CH3:12])[CH:45]=[CH:46][CH:47]=1
Reactant: CC1=C(c2ccccc2)C(=O)N(C(C)(C)C(=O)O)CO1
Reactant: Nc1cccc(Cl)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1=C(c2ccccc2)C(=O)N(C(C)(C)C(=O)Nc2cccc(Cl)c2)CO1
Yield: 74.9 %

Procedure:
A mixture of 2-(2,3-dihydro-6-methyl-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methylpropanoic acid (27.5 g) and triphenylphosphine (34.5 g) in tetrachloromethane (173 ml) and dichloromethane was heated at reflux for 45 minutes. The reaction mixture was cooled in an ice bath and 3-chloroaniline (12.8 g) and then triethylamine (14.0 ml) were added dropwise with stirring. The mixture was stirred at ambient temperature for 2 hours and evaporated under reduced pressure. The residue was suspended in ethyl acetate and the insoluble material removed by filtration. The filtrate was evaporated under reduced pressure and the residue purified by chromatography on silica gel, eluting with ethyl acetate/hexane to give N-(3-chlorophenyl)-2-(2,3-dihydro-6-methyl-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methylpropanamide (28.8 g) as a white solid, m.p. 146.5-149.9° C.