Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C:19]3[N:20]([C:32]4[CH:37]=[CH:36][C:35]([N:38]5[S:42](=[O:44])(=[O:43])[NH:41][C:40](=[O:45])[CH2:39]5)=[CH:34][CH:33]=4)[CH:21]=[C:22]([C:24]4[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=4[Cl:31])[N:23]=3)=[CH:14][CH:13]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][CH:9]([CH3:11])[CH3:10].[CH:46](=O)[CH2:47][CH2:48][CH3:49]>>[CH2:46]([NH:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:13]=[CH:14][C:15]([CH2:18][C:19]3[N:20]([C:32]4[CH:37]=[CH:36][C:35]([N:38]5[S:42](=[O:44])(=[O:43])[NH:41][C:40](=[O:45])[CH2:39]5)=[CH:34][CH:33]=4)[CH:21]=[C:22]([C:24]4[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=4[Cl:31])[N:23]=3)=[CH:16][CH:17]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][CH:9]([CH3:10])[CH3:11])[CH2:47][CH2:48][CH3:49]
Reactant: CCCC=O
Reactant: CC(C)Cc1ccc(-c2ccc(Cc3nc(-c4ccc(Cl)cc4Cl)cn3-c3ccc(N4CC(=O)NS4(=O)=O)cc3)cc2)cc1N
Product: CCCCNc1cc(-c2ccc(Cc3nc(-c4ccc(Cl)cc4Cl)cn3-c3ccc(N4CC(=O)NS4(=O)=O)cc3)cc2)ccc1CC(C)C

Procedure:
5-{4-[2-(3′-Amino-4′-isobutyl-biphenyl-4-ylmethyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-[1,2,5]thiadiazolidin-3-one-1,1-dioxide (22 mg, 0.03 mmol) was reacted with butyraldehyde (2.2 mg, 0.03 mmol) according to general procedure X to give 5-{4-[2-(3′-butylamino-4′-isobutyl-biphenyl-4-ylmethyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]3[C:14](=[O:24])[N:15]([CH2:18][CH2:19][O:20]C(=O)C)[CH2:16][CH2:17][C:12]=3[C:11]([C:25]([F:28])([F:27])[F:26])=[N:10]2)=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+]>CO.O>[OH:20][CH2:19][CH2:18][N:15]1[CH2:16][CH2:17][C:12]2[C:11]([C:25]([F:28])([F:26])[F:27])=[N:10][N:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)[C:13]=2[C:14]1=[O:24]
Reactant: COc1ccc(-n2nc(C(F)(F)F)c3c2C(=O)N(CCOC(C)=O)CC3)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: COc1ccc(-n2nc(C(F)(F)F)c3c2C(=O)N(CCO)CC3)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.7 %

Procedure:
Part B: Acetic acid 2-[1-(4-methoxy-phenyl)-7-oxo-3-trifluoromethyl-1,4,5,7-tetrahydro-pyrazolo[3,4-c]pyridin-6-yl]-ethyl ester (1.26 g, 3.17 mmol) was dissolved in methanol (100 mL) and water (5 mL). Potassium carbonate (1.31 g, 9.52 mmol) was added, and the reaction was stirred overnight at rt. The reaction was concentrated, quenched with water (250 mL), extracted with ethyl acetate (3×250 mL), washed with brine (1×100 mL), dried over MgSO4, concentrated, and purified by flash chromatography with 0–100% ethyl acetate/hexanes gradient as eluent to afford the title compound (1.01 g, 90%): 1HNMR(CDCl3) δ 7.45 (d, j=9.2 Hz, 2H), 6.96 (d, j=8.7 Hz, 2H), 3.84 (s, 3H), 3.82–3.77 (m, 4H), 3.66 (t, j=5.1 Hz, 2H), 3.03 (t, j=6.8 Hz, 2H) ppm; Mass Spec 356.3(M+H)+.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[C:4]([OH:6])=O.CCN(CC)CC.Cl.[CH3:15][O:16][NH:17][CH3:18].CCN=C=NCCCN(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:15][O:16][N:17]([CH3:18])[C:4]([C@@H:2]1[CH2:3][O:1]1)=[O:6]
Reactant: CNOC
Reactant: O=C(O)[C@@H]1CO1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)[C@@H]1CO1
Temperature: 0 °C
Reaction time: 4 h
Yield: 0.1 %

Procedure:
To a solution of the crude acid 2 (˜72.0 g, ˜0.810 mol, 1.0 equiv.) in CH2Cl2 (1600 mL) was added NEt3 (120 mL, 0.859 mol, 1.06 equiv.), DMAP (92 mg, 0.00082 mol, 0.001 equiv.) and O,N-Dimethyl-hydroxylamine hydrochloride (95.74 g, 0.982 mol, 1.21 equiv.) at 0° C. The resultant mixture was stirred for 10 minutes at −5° C. and EDCI (198.5 g, 1.035 mol, 1.27 equiv.) was added. The reaction mixture was stirred for 4 hours at 0° C. and diluted with hexanes (800 mL). The mixture was filtered through a pad of silica gel (2 cm thick of silica gel in a 3 L filtration funnel) and washed with Et2O (10×300 mL). The solvent was removed under reduced pressure to afford the crude amide 3 (92.2 g, 0.709 mmol, 87.5% for two steps) as slight-yellow oil. This crude product was dissolved in 1,2-dichloroethane (200 mL) and dried over molecular sieves at −20° C. for 2 hours before used in the next step).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][C:7](=[CH2:24])[CH:8](O)[CH:9]([NH:20][CH:21]=[O:22])[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])(=[O:3])[CH3:2].C(Cl)Cl.S(Br)([Br:30])=O>O>[C:1]([O:4][CH2:5][CH2:6][C:7]([CH2:24][Br:30])=[CH:8][CH:9]([NH:20][CH:21]=[O:22])[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])(=[O:3])[CH3:2]
Reactant: O=S(Br)Br
Reactant: C=C(CCOC(C)=O)C(O)C(NC=O)C(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: O
Product: CC(=O)OCCC(=CC(NC=O)C(=O)OCc1ccccc1)CBr
Reaction time: 2 h

Procedure:
10.5 g (31.3 mmol) of benzyl 6-acetoxy-2-formylamino-3-hydroxy-4-methylenehexanoate are dissolved in 100 ml of abs. CH2Cl2. Then 2.91 ml (37.6 mmol) of thionyl bromide are added to this solution at room temperature. After 2 hours, 80 ml of water are added and the mixture is stirred vigorously for 10 minutes. The organic phase is separated and washed once with water, once with a 1N solution of KHCO3 and twice with water. The aqueous phases are extracted twice with CH2Cl2. The combined organic phases are dried over MgSO4, filtered and concentrated by evaporation, giving benzyl 6-acetoxy-4-bromomethyl-2-formylamino-hex-3-enoate as a yellowish-brown oil which is further reacted without purification.
Reaction SMILES: [NH2:1][C:2](=[N:14][OH:15])[C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([F:13])[CH:4]=1.[Br:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](O)=O)=[CH:19][C:18]=1[CH2:26][O:27][CH3:28]>C(#N)C>[Br:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]2[O:15][N:14]=[C:2]([C:3]3[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([F:13])[CH:4]=3)[N:1]=2)=[CH:19][C:18]=1[CH2:26][O:27][CH3:28]
Reactant: COCc1cc(C(=O)O)ccc1Br
Reactant: COC(=O)c1ccc(C(N)=NO)cc1F
Solvent: CC#N
Product: COCc1cc(-c2nc(-c3ccc(C(=O)OC)c(F)c3)no2)ccc1Br

Procedure:
The title compound was obtained following procedure described for example 4, step 1, but starting from Intermediate 1 (0.50 g; 2.36 mmol) and Intermediate 37 (0.64 g; 2.59 mmol). Title compound was isolated after trituration with ACN as a white powder. 1H NMR (DMSO-d6, 300 MHz) δ 8.23 (d, J=2 Hz, 1H), 8.14-8.09 (m, 1H), 8.06-8.02 (m, 1H), 8-7.92 (m, 3H), 4.57 (s, 2H), 3.90 (s, 3H), 3.46 (s, 3H). LC/MS (Method B): 423.1 (M+H)+. HPLC (Method A) Rt 5.91 min (purity: 98.5%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[C:19]([N:20]([CH3:24])[CH:21]([CH3:23])[CH3:22])=[N:18][C:17]4[C:12](=[CH:13][CH:14]=[C:15]([C:25]([OH:27])=O)[CH:16]=4)[N:11]=3)=[CH:7][C:6]=2[CH:28]=1.C(N(CC)CC)C.[CH3:36][C:37]([NH2:40])([CH3:39])[CH3:38].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>ClCCl>[C:37]([NH:40][C:25]([C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[N:11]=[C:10]([C:8]1[O:9][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:28][C:6]=3[CH:7]=1)[C:19]([N:20]([CH3:24])[CH:21]([CH3:23])[CH3:22])=[N:18]2)=[O:27])([CH3:39])([CH3:38])[CH3:36]
Reactant: CC(C)(C)N
Reactant: CC(C)N(C)c1nc2cc(C(=O)O)ccc2nc1-c1cc2cc(F)ccc2o1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)N(C)c1nc2cc(C(=O)NC(C)(C)C)ccc2nc1-c1cc2cc(F)ccc2o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-(5-fluorobenzofuran-2-yl)-3-[methyl(propan-2-yl)amino]quinoxaline-6-carboxylic acid (486 mg, 1.28 mmol) in dichloromethane (30 ml) was added triethylamine (366 mg, 3.62 mmol), 2-methylpropan-2-amine (212 mg, 2.90 mmol) and T3P (610 mg, 1.92 mmol), and the resulting mixture was stirred for 1 h at room temperature. The reaction mixture was then quenched with water (120 ml), extracted with dichloromethane (4×60 ml), and the organic layers combined and concentrated in vacuo to afford N-tert-butyl-2-(5-fluorobenzofuran-2-yl)-3-[methyl(propan-2-yl)amino]quinoxaline-6-carboxamide as a yellow solid (600 mg, crude), which was used to the next step without further purification.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:15][CH:14]=[N:13][C:12]=1[CH3:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].CN(C)[CH:29]=[O:30]>O1CCCC1>[CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([CH:29]=[O:30])=[N:13][C:12]=1[CH3:16])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C=O
Reactant: Cc1ncsc1C(=O)NCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1nc(C=O)sc1C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 98 %

Procedure:
To a solution of N-benzyl-4-methylthiazole-5-carboxamide (1.00 g, 4.31 mmol) in tetrahydrofuran (20 mL) was added lithium bis(trimethylsilyl)amide (9.5 mL of 1.0 M solution in tetrahydrofuran, 9.5 mmol) at −78° C. The reaction mixture was stirred for 5 minutes, and N,N-dimethylformamide (0.35 mL, 4.54 mmol) was added. The reaction mixture was slowly warmed to ambient temperature over 4 hours, quenched with 5% hydrochloric acid (10 mL), extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography to afford the title compound in 98% yield (1.1 g): MS (ES+) m/z 261.1 (M+1).
Reaction SMILES: FC(F)(F)S(O[C:7]1[N:12]=[C:11]2[N:13]([CH2:16][CH3:17])[N:14]=[CH:15][C:10]2=[C:9]([C:18]2[CH:19]=[N:20][CH:21]=[C:22]([CH3:24])[CH:23]=2)[C:8]=1[C:25]#[N:26])(=O)=O.[F:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1.P(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.CCOC(C)=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>[CH2:16]([N:13]1[C:11]2=[N:12][C:7]([C:33]3[CH:34]=[CH:35][C:30]([F:29])=[CH:31][CH:32]=3)=[C:8]([C:25]#[N:26])[C:9]([C:18]3[CH:19]=[N:20][CH:21]=[C:22]([CH3:24])[CH:23]=3)=[C:10]2[CH:15]=[N:14]1)[CH3:17]
Reactant: CCn1ncc2c(-c3cncc(C)c3)c(C#N)c(OS(=O)(=O)C(F)(F)F)nc21
Reactant: OB(O)c1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=[PH]([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCn1ncc2c(-c3cncc(C)c3)c(C#N)c(-c3ccc(F)cc3)nc21
Yield: 79.6 %

Procedure:
To a mixture of 5-cyano-1-ethyl-4-(5-methyl-3-pyridyl)-1H-pyrazolo[3,4-b]pyridin-6-yl trifluoromethanesulfonate (253 mg), 4-fluorobenzeneboronic acid (129 mg), powdered potassium phosphonate (195 mg) in 1,4-dioxane (4 ml) was added tetrakis(triphenylphosphine)palladium(0) (18 mg) at room temperature. The mixture was refluxed for 7 hours. Resulting mixture was diluted with EtOAc (10 ml), washed with water (×2) and brine and dried over MgSO4. The solvent was evaporated and the residue was purified with silica gel column chromatography to give 1-ethyl-6-(4-fluorophenyl)-4-(5-methyl-3-pyridyl)-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile (175 mg) as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[N:24]=[N:23][C:22]([NH:25][NH:26]C(=O)CC2CCOCC2)=[CH:21][C:20]=1[C:36]1[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([NH:26][NH:25][C:22]2[N:23]=[N:24][C:19]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[Cl:12])=[C:20]([C:36]3[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=3)[CH:21]=2)=[O:11])=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(Cl)cc1
Reactant: O=C(CC1CCOCC1)NNc1cc(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)nn1
Product: O=C(Cc1ccc(Cl)cc1)NNc1cc(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)nn1
Yield: 62 %

Procedure:
The title compound (90 mg, 62%) as a white solid was prepared from 2-(4-chlorophenyl)acetic acid (62 mg, 0.36 mmol) and 1-(6-(2-chlorophenyl)-5-(4-chlorophenyl)pyridazin-3)hydrazine (99 mg, 0.3 mmol) according to the procedures described for N′-(6-(2-chlorophenyl)-5-(4-chlorophenyl)pyridazin-3-yl)-2-(tetrahydro-2H-pyran-4-yl)acetohydrazide (Example 9A). HPLC/MS (method A): retention time 3.57 min, (M+H)+ 483.2.
Reaction SMILES: [CH:1](=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[C:11](OC(=O)C)(=[O:13])[CH3:12].C([O-])(=O)C.[K+]>>[C:11]([O:10][CH:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])(=[O:13])[CH3:12]
Reactant: CCCCCCCCC=O
Reactant: CC(=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: [K+]
Product: CCCCCCCC=COC(C)=O

Procedure:
A mixture of one mole of nonanal, 2.5 moles of acetic anhydride, and 15 g. of anhydrous potassium acetate is refluxed for one hour and cooled. Excess acid is removed by a 2X wash with water, followed by 5% sodium carbonate wash to give 1-nonen-1-yl acetate as a relatively pure oil.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[N:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=2)=[CH:11][CH:10]=1>CN(C)C=O.C(OCC)C>[Br:1][C:18]1[CH:17]=[C:16]([CH2:15][C:12]2[CH:13]=[CH:14][N:9]=[CH:10][CH:11]=2)[CH:22]=[CH:21][C:19]=1[NH2:20]
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1ccc(Cc2ccncc2)cc1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Nc1ccc(Cc2ccncc2)cc1Br
Reaction time: 1 h

Procedure:
A solution of 18.34 g (0.103 mol) of N-bromosuccinimide in 60 ml of dimethylformamide is added dropwise, shielded from light, to a solution of 20 g (0.1084 mol) of 4-(4-pyridylmethyl)aniline in 180 ml of dimethylformamide. After 1 hour, the solvent is evaporated off under reduced pressure and the solid is taken up in 200 ml of dichloromethane. The solution is subsequently washed with 100 ml of water and then with 100 ml of a saturated sodium chloride solution. After customary treatment of the organic phase, an oil is obtained which is taken up in 500 ml of diethyl ether, and the whole is left in a refrigerator for 2 days. After filtration, the expected product is obtained.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][N:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]=O.Br.Br.Br.[CH2:16]([C:18]1[C:19]([C:26]2[CH:34]=[C:33]3[C:29]([C:30]([C:35]4[NH:36][C:37]5[CH2:42][CH2:41][NH:40][CH2:39][C:38]=5[N:43]=4)=[N:31][NH:32]3)=[CH:28][CH:27]=2)=[CH:20][C:21]([F:25])=[C:22]([OH:24])[CH:23]=1)[CH3:17]>>[CH2:16]([C:18]1[C:19]([C:26]2[CH:34]=[C:33]3[C:29]([C:30]([C:35]4[NH:36][C:37]5[CH2:42][CH2:41][N:40]([CH2:11][C:2]6[CH:3]=[CH:4][C:5]7[C:10](=[N:9][CH:8]=[CH:7][CH:6]=7)[N:1]=6)[CH2:39][C:38]=5[N:43]=4)=[N:31][NH:32]3)=[CH:28][CH:27]=2)=[CH:20][C:21]([F:25])=[C:22]([OH:24])[CH:23]=1)[CH3:17]
Reactant: O=Cc1ccc2cccnc2n1
Reactant: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCNC4)n[nH]c2c1
Agent: Br
Product: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCN(Cc3ccc5cccnc5n3)C4)n[nH]c2c1
Yield: 32.8 %

Procedure:
The title compound was prepared from [1,8]naphthyridine-2-carbaldehyde (31 mg, 198 μmol) and 5-ethyl-2-fluoro-4-[3-(4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-6-yl]-phenol trihydrobromide salt (Preparation 25, 50 mg, 132 μmol) using the method of Example 22. The crude material was purified by HPLC Method B to afford 22.5 mg of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8][CH3:9])[CH:5]=[C:4]([F:10])[C:3]=1[C:11]1[N:16]=[C:15]([C:17]([O:19]C)=[O:18])[CH:14]=[CH:13][C:12]=1[F:21].[OH-].[Na+].Cl>C1COCC1.CO>[F:1][C:2]1[CH:7]=[C:6]([S:8][CH3:9])[CH:5]=[C:4]([F:10])[C:3]=1[C:11]1[N:16]=[C:15]([C:17]([OH:19])=[O:18])[CH:14]=[CH:13][C:12]=1[F:21]
Reactant: COC(=O)c1ccc(F)c(-c2c(F)cc(SC)cc2F)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CSc1cc(F)c(-c2nc(C(=O)O)ccc2F)c(F)c1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 55 %

Procedure:
Methyl 6-[2,6-difluoro-4-(methylthio)phenyl]-5-fluoropyridine-2-carboxylate (80.0 mg, 0.255 mmol) was dissolved in THF (0.3 mL) and MeOH (0.3 mL), then 1.0 M aq. NaOH (1.28 mL, 1.28 mmol) was added. The reaction mixture was stirred at room temperature for 50 min., then neutralized with HCl (12 M) to pH=7 and concentrated under reduced pressure to remove all the solvents. The residue was dissolved in THF, dried, filtered and concentrated under vacuum to give the sub-title compound as a white powder (42 mg, 55%). LCMS calc. for C13H9F3NO2S (M+H)+: m/z=300.0. Found: 300.2.
Reaction SMILES: [CH3:1][C:2]1[C:6]([NH2:7])=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[NH:4][N:3]=1.C(N(CC)CC)C.[O:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[C:26](Cl)=[O:27]>C(Cl)Cl>[CH3:1][C:2]1[C:6]([NH:7][C:26]([C:22]2[O:21][CH:25]=[CH:24][CH:23]=2)=[O:27])=[C:5]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:4][N:3]=1
Reactant: Cc1n[nH]c(-c2ccccc2)c1N
Reactant: O=C(Cl)c1ccco1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1n[nH]c(-c2ccccc2)c1NC(=O)c1ccco1
Reaction time: 2 h

Procedure:
To a RT solution of 337.3 mg of 3-methyl-5-phenyl-1H-pyrazol-4-ylamine in 4 mL methylene chloride was added 407 μL of triethylamine and 201 μL of 2-furoyl chloride. After 2 h at RT, the reaction mixture was concentrated under reduced pressure and the residue was dissolved in chloroform and washed with saturated aqueous sodium carbonate and brine. The organic portion was dried with sodium sulfate and concentrated under reduced pressure. The residue contained the title compound as a yellow, amorphous solid and was used without further purification.
Reaction SMILES: [CH3:1][O:2][CH2:3]Cl.[OH:5][C@@H:6]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]#[CH:13])[C:7]1=[O:14].C(N(C(C)C)C(C)C)C>C(Cl)Cl>[CH2:11]([N:8]1[CH2:9][CH2:10][C@@H:6]([O:5][CH2:1][O:2][CH3:3])[C:7]1=[O:14])[C:12]#[CH:13]
Reactant: C#CCN1CC[C@@H](O)C1=O
Reactant: COCCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C#CCN1CC[C@@H](OCOC)C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1.0 g of chloromethyl methyl ether in 15 ml of methylene chloride is added dropwise to a solution of 1.5 g of (R)-3-hydroxy-1-(2-propynyl)-2-pyrrolidinone, prepared by the procedure of Example 1, U.S. Pat. No. 5,089,518, and 1.5 g of ethyldiisopropylamine in 15 ml of methylene chloride which is stirred in an ice bath. The reaction is allowed to warm to room temperature and stirred overnight. The solution was washed with water, aqueous sodium bicarbonate and dried over anhydrous sodium sulfate. The methylene chloride solution is concentrated at reduced pressure and purified by column chromatography (silica gel: mehylene chloride) to give the product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[CH3:9][O:10][C:11](=[O:38])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]([C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=2)[C:20](=[O:29])[C:21]#[C:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:13]=1>>[CH3:9][O:10][C:11](=[O:38])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]2[C:30]3[C:35](=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=3)/[C:21](=[C:22](\[C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)/[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)/[C:20]2=[O:29])[CH:13]=1
Reactant: COC(=O)c1cccc(CN(C(=O)C#Cc2ccccc2)c2ccc(OC)cc2)c1
Reactant: Clc1ccc(I)cc1
Product: COC(=O)c1cccc(CN2C(=O)/C(=C(\c3ccccc3)c3ccc(Cl)cc3)c3cc(OC)ccc32)c1

Procedure:
The title compound was prepared in analogy to Example 5 starting from 1-chloro-4-iodobenzene (commercially available) and 3-{[(4-methoxy-phenyl)-(3-phenyl-propynoyl)-amino]-methyl}-benzoic acid methyl ester. 1H NMR (300 Hz, CDCl3): δppm 3.49 (s, 3H), 3.91 (s, 3H), 4.92 (s, 2H), 6.10 (dd, 1H), 6.51 (d, 1H), 6.62 (dd, 1H), 7.25-7.50 (m, 1H), 7.93 (d, 1H), 7.99 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10](=[O:17])[C:11](=[CH:15][CH:16]=2)[C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[Si](C)(C)C.Cl[C:31]([O:33][CH3:34])=[O:32]>ClCCl>[CH3:34][O:33][C:31]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:9][C:10](=[O:17])[C:11](=[CH:15][CH:16]=2)[C:12]([OH:14])=[O:13])=[CH:6][CH:7]=1)=[O:32]
Reactant: COC(=O)Cl
Reactant: Nc1ccc(-c2ccc(C(=O)O)c(=O)[nH]2)cc1
Agent: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)Nc1ccc(-c2ccc(C(=O)O)c(=O)[nH]2)cc1
Yield: 87.4 %

Procedure:
Using the method for the preparation of the side chain acid in Example 3, 4.62 g (20 mmol) of 6-(4-aminophenyl)-1,2-dihydro-2-oxonicotinic acid, 8.4 ml (60 mmol) of triethylamine, 8.0 ml (63 mmol) of chlorotrimethylsilane, 200 ml of dichloromethane, and 2.5 ml (30 mmol) of methyl chloroformate gives 5.04 g of 6-[4-(methoxycarbonylamino)phenyl]-1,2-dihydro-2-oxonicotinic acid.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[C@H:14]([CH2:15][NH2:16])[CH2:13][C@H:12]3[C@@H:10]2[CH2:11]3)=[O:8])[N:6]=1.[CH3:24][C:25]1[C:29]([C:30](O)=[O:31])=[C:28]([C:33]([F:36])([F:35])[F:34])[O:27][N:26]=1>>[NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[C@H:14]([CH2:15][NH:16][C:30]([C:29]3[C:25]([CH3:24])=[N:26][O:27][C:28]=3[C:33]([F:36])([F:34])[F:35])=[O:31])[CH2:13][C@H:12]3[C@@H:10]2[CH2:11]3)=[O:8])[N:6]=1
Reactant: Cc1noc(C(F)(F)F)c1C(=O)O
Reactant: NC[C@@H]1C[C@@H]2C[C@@H]2N1C(=O)c1nc(N)sc1-c1cccc(F)c1
Product: Cc1noc(C(F)(F)F)c1C(=O)NC[C@@H]1C[C@@H]2C[C@@H]2N1C(=O)c1nc(N)sc1-c1cccc(F)c1

Procedure:
prepared by reaction of [2-amino-5-(3-fluoro-phenyl)-thiazol-4-yl]-((1S,3S,5S)-3-aminomethyl-2-aza-bicyclo[3.1.0]hex-2-yl)-methanone with 3-methyl-5-trifluoromethyl-isoxazole-4-carboxylic acid. LC-MS (basic): tR=0.85 min; [M+H]+=510.2.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][O:7][C:8]2=[C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][C:12]2=[O:20])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[Cl:30][CH2:31][CH2:32][CH2:33][C:34](Cl)=[O:35]>C1COCC1>[Cl:30][CH2:31][CH2:32][CH2:33][C:34]([NH:1][C:2]1[CH:10]=[C:9]2[C:5](=[CH:4][CH:3]=1)[CH2:6][O:7][C:8]2=[C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][C:12]1=[O:20])=[O:35]
Reactant: Nc1ccc2c(c1)C(=C1C(=O)Nc3ccccc31)OC2
Reactant: O=C(Cl)CCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(CCCCl)Nc1ccc2c(c1)C(=C1C(=O)Nc3ccccc31)OC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.4 %

Procedure:
To a solution of 3-(6-Amino-3H-isobenzofuran-1-ylidene)-1,3-dihydro-indol-2-one (50.0 mg, 0.189 mmol) and N,N-diisopropylethylamine (98.8 μL, 0.567 mmol) in 2.0 mL THF was added 4-chlorobutryl chloride (21.2 μL, 0.189 mmol). After stirring at room temperature for 1 h, the slurry was filtered and rinsed with MeOH and EtOAc/hexanes (1:1) to afford the title compound (58.8 mg, 84%) as a yellow solid.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([Cl:19])[CH:18]=[C:13]3[C:12]([CH2:20][C:21]3[CH:22]=[N:23][C:24](S(C)(=O)=O)=[N:25][CH:26]=3)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:31][CH:32]1[CH2:37][CH2:36][CH:35]([NH2:38])[CH2:34][CH2:33]1.O>CN1CCCC1=O>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([Cl:19])[CH:18]=[C:13]3[C:12]([CH2:20][C:21]3[CH:22]=[N:23][C:24]([NH:38][CH:35]4[CH2:36][CH2:37][CH:32]([CH3:31])[CH2:33][CH2:34]4)=[N:25][CH:26]=3)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC1CCC(N)CC1
Reactant: CS(=O)(=O)c1ncc(Cc2cn(S(=O)(=O)c3ccccc3)c3ncc(Cl)cc23)cn1
Solvent: CN1CCCC1=O
Solvent: O
Product: CC1CCC(Nc2ncc(Cc3cn(S(=O)(=O)c4ccccc4)c4ncc(Cl)cc34)cn2)CC1
Temperature: 160 °C
Yield: 80.1 %

Procedure:
In a microwave vial, to 1-benzenesulfonyl-5-chloro-3-(2-methanesulfonyl-pyrimidin-5-ylmethyl)-1H-pyrrolo[2,3-b]pyridine (37, 0.140 g, 0.302 mmol) in 2.0 mL of N-methylpyrrolidinone, 4-methylcyclohexylamine (63, 0.30 g, 2.6 mmol) is added. The reaction is heated at 160° C. for 20 minutes in a microwave, then poured into water and extracted with ethyl acetate. The organic layer is dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material is purified by silica gel column chromatography, eluting with 20-100% ethyl acetate in hexane. Appropriate fractions are combined and concentrated under vacuum to provide the desired compound (64, 0.120 g). MS (ESI) [M+H+]+=496.4.