Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[C:6](=[O:13])[C:5]([N+:14]([O-:16])=[O:15])=[C:4](OS(C(F)(F)F)(=O)=O)[CH:3]=1.[F:25][C:26]([F:36])([F:35])[C:27]1[CH:32]=[CH:31][C:30]([CH2:33]Br)=[CH:29][CH:28]=1>>[CH3:1][C:2]1[N:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[C:6](=[O:13])[C:5]([N+:14]([O-:16])=[O:15])=[C:4]([CH2:33][C:30]2[CH:29]=[CH:28][C:27]([C:26]([F:25])([F:35])[F:36])=[CH:32][CH:31]=2)[CH:3]=1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: COC(=O)Cn1c(C)cc(OS(=O)(=O)C(F)(F)F)c([N+](=O)[O-])c1=O
Product: COC(=O)Cn1c(C)cc(Cc2ccc(C(F)(F)F)cc2)c([N+](=O)[O-])c1=O

Procedure:
This compound is prepared from 5.58 g (14.9 mmol) of methyl 6-methyl-3-nitro-2-oxo-4-[[(trifluoromethyl)sulphonyl]oxy]-1,2-dihydropyridine-1-acetate and 5 g (20.9 mmol) of [4-(trifluoromethyl)-phenyl]methyl bromide according to the method described in Example 1.5.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[C:18]([C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1)([CH3:21])([CH3:20])[CH3:19]>>[C:18]([C:22]1[CH:23]=[CH:24][C:25]([C:26]([NH:1][C:2]2[N:7]=[C:6]3[C:8]([CH:11]4[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]4)=[CH:9][NH:10][C:5]3=[CH:4][CH:3]=2)=[O:27])=[CH:29][CH:30]=1)([CH3:21])([CH3:19])[CH3:20]
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4ccc(C(C)(C)C)cc4)nc23)CC1
Yield: 75.7 %

Procedure:
Beginning with 0.010 gm (0.044 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.011 mL (0.057 mMol) 4-tert-butylbenzoyl chloride, 0.013 gm (76%) of the title compound were prepared essentially by the procedure described in Example 7.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[CH:9][S:10][C:3]=12.[Li]CCCC.Br[C:17]1[CH:18]=[CH:19][C:20]([CH:23]2[O:28][CH2:27][CH2:26][CH2:25][O:24]2)=[N:21][CH:22]=1>C1COCC1.[Cl-].[Cl-].[Zn+2]>[O:24]1[CH2:25][CH2:26][CH2:27][O:28][CH:23]1[C:20]1[N:21]=[CH:22][C:17]([C:9]2[S:10][C:3]3[C:4](=[N:5][CH:6]=[CH:7][C:2]=3[Cl:1])[CH:8]=2)=[CH:18][CH:19]=1
Reactant: Clc1ccnc2ccsc12
Reactant: Brc1ccc(C2OCCCO2)nc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Zn+2]
Solvent: C1CCOC1
Product: Clc1ccnc2cc(-c3ccc(C4OCCCO4)nc3)sc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58.8 %

Procedure:
To a stirred solution of 7-chlorothieno[3,2-b]pyridine (12.08 g, 71.2 mmol) in THF (138 mL) at −15° C. was added n-BuLi (30.7 mL, 77.0 mmol). After 30 min, a solution of ZnCl2 0.5 M in THF (142 mL, 71.2 mmol) was added at −15° C. and the reaction mixture was allowed to warm to RT over 45 min. A solution of palladium tetrakistriphenylphosphine (1.266 g, 1.096 mmol) and bromide 278 (13.37 g, 54.8 mmol) in THF (18.5 mL) was added and the mixture was heated to reflux for 2 h then concentrated. The residue was diluted with water and ammonium hydroxide and extracted with DCM. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was triturated with MTBE to afford the title compound 279 (10.70 g, 32.2 mmol, 59% yield) as light brown solid. MS (m/z): 333.33 (M+H).
Reaction SMILES: Br[CH2:2][C:3]1[C:11]2[O:10][CH:9]=[CH:8][C:7]=2[CH:6]=[C:5]([N+:12]([O-:14])=[O:13])[CH:4]=1.[CH3:15][C@H:16]1[CH2:21][NH:20][C@H:19]([CH3:22])[CH2:18][NH:17]1>>[CH3:15][C@H:16]1[CH2:21][NH:20][C@H:19]([CH3:22])[CH2:18][N:17]1[CH2:2][C:3]1[C:11]2[O:10][CH:9]=[CH:8][C:7]=2[CH:6]=[C:5]([N+:12]([O-:14])=[O:13])[CH:4]=1
Reactant: O=[N+]([O-])c1cc(CBr)c2occc2c1
Reactant: C[C@@H]1CN[C@@H](C)CN1
Product: C[C@@H]1CN(Cc2cc([N+](=O)[O-])cc3ccoc23)[C@@H](C)CN1
Yield: 63.4 %

Procedure:
The title compound was prepared according to the procedure of Example 112, Step 1, starting from 7-(bromomethyl)-5-nitro-1-benzofuran (0.16 g, 0.6 mmol) and trans-2,5-dimethylpiperazine (0.36 g, 3.1 mmol). This afforded the title product (0.11 g, 60%) as a light yellow solid. HPLC 98% RT=1.26 min (System A; 10-97% MeCN over 3 min). 1H NMR (400 MHz, CDCl3) δ ppm 0.93 (d, J=6.3 Hz, 3H) 1.17 (d, J=6.0 Hz, 3H) 1.48 (br s, 1H) 1.79 (dd, J=11.0, 10.3 Hz, 1H) 2.29-2.41 (m, 1H) 2.63-2.75 (m, 2H) 2.80-2.89 (m, 1H) 2.93 (dd, J=12.0, 3.3 Hz, 1H) 3.61 (d, J=14.6 Hz, 1H) 4.28 (d, J=14.3 Hz, 1H) 6.91 (d, J=2.3 Hz, 1H) 7.76 (d, J=2.3 Hz, 1H) 8.29 (d, J=2.3 Hz, 1H) 8.41 (d, J=2.3 Hz, 1H). MS (ESI+) m/z 290.1 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]#[C:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5])[CH3:2].[C:14]([CH2:16][CH2:17][N:18]([CH:23]=O)[CH2:19]C(O)=O)#[N:15]>C(OC(=O)C)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:19][N:18]([CH2:17][CH2:16][C:14]#[N:15])[CH:23]=1)=[O:5])[CH3:2]
Reactant: N#CCCN(C=O)CC(=O)O
Reactant: CCOC(=O)C#Cc1ccccc1
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)c1cn(CCC#N)cc1-c1ccccc1

Procedure:
17.4 g of phenylacetylenecarboxylic acid ethyl ester and 15.6 g of N-(2-cyanoethyl)-N-formylglycine are dissolved in 100 ml of acetic anhydride, and the solution is refluxed for 24 h. The mixture is concentrated by evaporation under reduced pressure; the residue is then taken up in toluene, and purified by chromatography through silica gel. The solvent is evaporated off, and from the eluate is obtained 4-ethoxycarbonyl-1-(2-cyanoethyl)-3-phenylpyrrole in the form of a yellow oil (compound No. 3.3).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([C:6]([NH:8][C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[CH:14][CH:15]=[C:16]3[N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[CH:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1.[CH:27](=O)[CH2:28][CH3:29].C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[CH:14][CH:15]=[C:16]3[N:19]3[CH2:24][CH2:23][N:22]([CH2:27][CH2:28][CH3:29])[CH2:21][CH2:20]3)=[CH:11][CH:10]=2)=[O:7])=[CH:25][CH:26]=1
Reactant: CCC=O
Reactant: O=C(Nc1ccc2cccc(N3CCNCC3)c2c1)c1ccc(Cl)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCCN1CCN(c2cccc3ccc(NC(=O)c4ccc(Cl)cc4)cc23)CC1

Procedure:
A mixture of 7-(4-chlorobenzamido)-1-(1-piperazinyl)-naphthalene (0.20 g, 0.547 mmol, the product of Example 12), propionaldehyde (0.041 mL, 0.563 mmol) and sodium cyanoborohydride (0.103 g, 1.64 mmol)in methanol (12 mL) and acetic acid (1.2 mL) was stirred at ambient temperature for 20 hours. The solvent was removed at reduced pressure and the residue was partitioned between methylene chloride and saturated aqueous sodium bicarbonate. Phases were separated and the organic layer was washed with brine, dried, concentrated onto silica gel and flash chromatographed (1×3 inches). Elution proceeded as follows: ethyl acetate (50 mL) unweighed forrun; ethyl acetate (250 mL) 0.164 g of yellow foam. The foam was triturated with pentane and 0.079 g (28%) of the title compound was collected as a white solid. mp 130°-132° C. Analysis calculated for C24H26ClN3O: C, 70.66; H, 6.42; N, 10.30. Found: C, 70.91; H, 6.66; N, 10.50.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]2[C:14]([OH:17])=[N:15][NH:16][C:10]=2[CH2:9]1)C1C=CC=CC=1>[Pd].CO>[NH:16]1[C:10]2[CH2:9][NH:8][CH2:13][CH2:12][C:11]=2[C:14]([OH:17])=[N:15]1
Reactant: Oc1n[nH]c2c1CCN(Cc1ccccc1)C2
Agent: [Pd]
Solvent: CO
Product: Oc1n[nH]c2c1CCNC2
Reaction time: 48 h

Procedure:
A mixture of 6-benzyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-ol (2.00 g, 8.72 mmol) and palladium on carbon (0.200 g, 1.88 mmol, Aldrich) in MeOH (100 mL) was stirred under H2 atmosphere for 48 h. The mixture was filtered through Celite® and the filter cake was washed with MeOH. The mixture was concentrated in vacuo. The filter cake was washed with water and the filtrate was concentrated in vacuo. Both fractions contained the title compound. MS (ESI, pos. ion) m/z: 140 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:21][CH2:22][CH2:23][O:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)[C:11]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1)[C:5]([O:7][CH3:8])=[O:6].[C:31]([C:35]1[CH:40]=[CH:39][C:38]([S:41](Cl)(=[O:43])=[O:42])=[CH:37][CH:36]=1)([CH3:34])([CH3:33])[CH3:32]>N1C=CC=CC=1.C1(C)C=CC=CC=1>[C:31]([C:35]1[CH:40]=[CH:39][C:38]([S:41]([NH:1][C:2]2[CH:3]=[C:4]([CH:9]=[C:10]([O:21][CH2:22][CH2:23][O:24][CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][O:26]3)[C:11]=2[O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)[C:5]([O:7][CH3:8])=[O:6])(=[O:43])=[O:42])=[CH:37][CH:36]=1)([CH3:34])([CH3:32])[CH3:33]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)c1cc(N)c(Oc2cccc(OC)c2)c(OCCOC2CCCCO2)c1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)c(Oc2cccc(OC)c2)c(OCCOC2CCCCO2)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
0.35 g of methyl 3-amino-4-(3-methoxy-phenoxy)-5-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-benzoate was dissolved in pyridine (10 ml), treated dropwise while cooling with ice with a solution of 0.312 g of 4-tert.butyl-benzenesulphonyl chloride in toluene (3 ml) and subsequently stirred at RT for 24 hours. The reaction mixture was poured on to ice/3M HCl, the product was extracted with ethyl acetate, the organic phase was washed with 2M KHCO3 solution and dried over magnesium sulphate. After removing the solvent there was obtained the desired methyl 3-(4-tert-butyl-benzenesulphonylamino)-4-(3-methoxy-phenoxy)-5-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-benzoate as a solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:33]=[CH:32][C:8]2[CH:9]=[C:10]([C:12]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])=[C:19]([CH3:31])[CH:18]=3)([CH2:15][CH3:16])[CH2:13][CH3:14])[O:11][C:7]=2[CH:6]=1)=[O:4].[BH4-].[Na+]>C1COCC1>[CH2:13]([C:12]([C:10]1[O:11][C:7]2[CH:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:33]=[CH:32][C:8]=2[CH:9]=1)([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH:25]([OH:30])[C:26]([CH3:28])([CH3:29])[CH3:27])=[C:19]([CH3:31])[CH:18]=1)[CH2:15][CH3:16])[CH3:14]
Reactant: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1cc2ccc(C(=O)OC)cc2o1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(CC)(c1ccc(OCC(O)C(C)(C)C)c(C)c1)c1cc2ccc(C(=O)O)cc2o1
Yield: 91.2 %

Procedure:
2-{1-[4-(3,3-Dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-benzofuran-6-carboxylic acid methyl ester (0.88 g, 1.95 mmol) in THF (40 mL) is reacted with NaBH4 (0.148 g, 3.91 mmol) analogous to Example 22 to obtain the title compound (0.78 g, 89%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:10]([CH3:21])=[N:11][CH:12]=[C:13]([C:19]=2[CH3:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:5]=[CH:4][N:3]=1.[Br:22]Br>CC(O)=O>[NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:10]([CH3:21])=[N:11][CH:12]=[C:13]([C:19]=2[CH3:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:5]([Br:22])=[CH:4][N:3]=1
Reactant: BrBr
Reactant: CCOC(=O)c1cnc(C)c(Oc2ccnc(N)c2)c1C
Solvent: CC(=O)O
Product: CCOC(=O)c1cnc(C)c(Oc2cc(N)ncc2Br)c1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59 %

Procedure:
Ethyl 5-(2-aminopyridin-4-yloxy)-4,6-dimethylnicotinate (2.5 g, 8.7 mmol) in AcOH (30 mL) was charged with dropwise addition of bromine (1M in AcOH, 8.7 ml, 8.7 mmol). The solution was stirred at room temperature for 30 minutes. The solution was then concentrated and neutralized with saturated NaHCO3 solution. The material was then extracted with EtOAc and the organic layer was dried, and concentrated. Flash chromatography gave ethyl 5-(2-amino-5-bromopyridin-4-yloxy)-4,6-dimethylnicotinate (1.88 g, 59%) as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:20][C:21]4[NH:26][C:25](=[O:27])[CH2:24][O:23][C:22]=4[N:28]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:39].[NH4+].[Cl-]>CN(C=O)C>[C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:19]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)=[CH:20][C:21]4[N:26]([CH3:39])[C:25](=[O:27])[CH2:24][O:23][C:22]=4[N:28]=3)=[CH:16][CH:17]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)NC(=O)CO4)cc2)CCC1
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CN1C(=O)COc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 60.2 %

Procedure:
To a solution of tert-butyl(1-(4-(2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutyl)carbamate (60 mg, 0.13 mmol) in dry DMF (1 mL) was added sodium hydride (6 mg, 0.14 mmol) at 0° C. under nitrogen. After 1 h at 0° C., iodomethane (9 μL, 0.14 mmol) was added and the resulting mixture was stirred for an additional 10 min at 0° C. A saturated solution of NH4Cl was added and the mixture was extracted with dichloromethane (3×) using a phase separator (Isolute® SPE). The combined organic phases were concentrated to dryness under reduced pressure. The resulting residue was purified by Biotage silica gel chromatography (gradient 0 to 30% EtOAc in cyclohexane) to give the title compound as a white solid (38 mg, 60%). 1H NMR (500 MHz, CDCl3): 7.31-7.24 (8H, m), 721-7.19 (2H,m), 5.01 (1H, br s), 4.90 (2H, s), 3.39 (3H, s),2.55-2.25 (4H, m), 2.09-2.01 (1H, m), 1.84-1.76 (1H, m), 1.44-1.15 (9H, br).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[NH3:12]>[Cu]I>[NH2:12][C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: N
Reactant: O=C(O)c1ccc(Cl)nc1Cl
Agent: [Cu]I
Product: Nc1nc(Cl)ccc1C(=O)O
Temperature: 125 °C
Yield: 72 %

Procedure:
To liquid ammonia (approximately 20 mL) was added 2,6-dichloro-nicotinic acid (0.38 g, 2 mmol) and copper(I) iodide (720 mg, 3.8 mmol) at −78° C. in a sealed tube, and the solution was heated for 25 hours (the temperature of the oil bath was 115° C.). The temperature of the oil bath was raised to 125° C., which was further heated for 14 hours 30 minutes. The reaction mixture was allowed to room temperature, and ammonia was evaporated. Methanol was added, insoluble matter was removed by filtration, and the filtrate was concentrated to obtain the title compound (0.25 g, 1.45 mmol, 72%) as a solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([C:16](=[O:27])[C@@H:17]([NH:19]C(=O)OC(C)(C)C)[CH3:18])[CH2:12][CH2:11]2)=[C:6]([Cl:28])[N:5]=[C:4]([CH3:29])[N:3]=1.O1CCOCC1.Cl>CO>[ClH:28].[NH2:19][C@@H:17]([CH3:18])[C:16]([N:13]1[CH2:14][CH2:15][CH:10]([CH2:9][CH2:8][C:7]2[C:2]([NH2:1])=[N:3][C:4]([CH3:29])=[N:5][C:6]=2[Cl:28])[CH2:11][CH2:12]1)=[O:27]
Reactant: Cc1nc(N)c(CCC2CCN(C(=O)[C@H](C)NC(=O)OC(C)(C)C)CC2)c(Cl)n1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cc1nc(N)c(CCC2CCN(C(=O)[C@H](C)N)CC2)c(Cl)n1
Reaction time: 0.17 h

Procedure:
Add tert-butyl N-[(1S)-2-[4-[2-(4-amino-6-chloro-2-methyl-pyrimidin-5-yl)ethyl]-1-piperidyl]-1-methyl-2-oxo-ethyl]carbamate (28.75 g, 67.49 mmol) to 1,4-dioxane (143.7 mL). Then add 4M hydrogen chloride in 1,4-dioxane (168.7 mL, 674.9 mmol) and stir for 10 min. Add MeOH (20 mL) and stir the mixture for 3 h with vigorous stirring. Concentrate the mixture under reduced pressure, dilute the solids with diethyl ether (200 mL), and stir overnight. Filter the material, rinsing with diethyl ether (2×25 mL). Dry the material via suction for 15 min, then place under vacuum for 1 h at 45° C. to obtain the title compound as a crude white powder (27.7 g). LC-ES/MS m/z (35Cl/37Cl) 326.1/328.2 (M+1).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5](/[CH:9]=[CH:10]/[C:11]2[N:16]=[C:15]([CH3:17])[CH:14]=[C:13]([N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[N:12]=2)[CH:6]=[CH:7][CH:8]=1.ClC1C=C(C)N=C(/C=C/C2C=CC=C(OC)C=2)N=1.B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[C:5](/[CH:9]=[CH:10]/[C:11]2[N:16]=[C:15]([CH3:17])[CH:14]=[C:13]([N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[N:12]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(/C=C/c2nc(C)cc(N3CCCC3)n2)c1
Agent: BrB(Br)Br
Agent: COc1cccc(/C=C/c2nc(C)cc(Cl)n2)c1
Solvent: ClCCl
Product: Cc1cc(N2CCCC2)nc(/C=C/c2cccc(O)c2)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 47 %

Procedure:
To a solution of (E)-2-[2-(3-methoxy-phenyl)-vinyl]-4-methyl-6-pyrrolidin-1-yl-pyrimidine (100 mg, 0.34 mmol), product of example 29, in CH2Cl2 there was added dropwise and under stirring at 0° C. a 1M solution of BBr3 in CH2Cl2 (0.51 ml). The reaction mixture was stirred for 1 h at 0° C. after which time the reaction was complete according to TLC analysis. The mixture was poured on ice and the product extracted into CH2Cl2. The organic layer was dried over Na2SO4 and concentrated in vacuo. The crystalline solid which formed was filted off by suction and dried in a high vacuum to give (E)-2-[2-(3-hydroxy-phenyl)-vinyl]-4-methyl-6-pyrrolidin-1-yl-pyrimidine (45 mg, 47.2%) as a light grey solid. ISP mass spectrum, m/e: 282.2 (M+1 calculated for C17H19N3O: 282).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:35][C:36]([F:39])([F:38])[F:37])=[C:6]([C:8]2[C:13]([C:14]#[N:15])=[CH:12][N:11]([CH:16]([CH3:33])[C:17]([NH:19][C:20]3[CH:32]=[CH:31][C:23]([C:24]([O:26]C(C)(C)C)=[O:25])=[CH:22][CH:21]=3)=[O:18])[C:10](=[O:34])[CH:9]=2)[CH:7]=1.C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:35][C:36]([F:39])([F:37])[F:38])=[C:6]([C:8]2[C:13]([C:14]#[N:15])=[CH:12][N:11]([CH:16]([CH3:33])[C:17]([NH:19][C:20]3[CH:32]=[CH:31][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=3)=[O:18])[C:10](=[O:34])[CH:9]=2)[CH:7]=1
Reactant: CC(C(=O)Nc1ccc(C(=O)OC(C)(C)C)cc1)n1cc(C#N)c(-c2cc(Cl)ccc2OC(F)(F)F)cc1=O
Solvent: O=C(O)C(F)(F)F
Product: CC(C(=O)Nc1ccc(C(=O)O)cc1)n1cc(C#N)c(-c2cc(Cl)ccc2OC(F)(F)F)cc1=O

Procedure:
107 mg (purity 94%, 0.18 mmol) of tert-butyl 4-[(2-{4-[5-chloro-2-(trifluoromethoxy)phenyl]-5-cyano-2-oxopyridin-1(2H)-yl}propanoyl)amino]benzoate (racemate) (Example 18.2A) were hydrolysed with TFA according to General Method 2. Yield: 59 mg (65% of theory)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][C:12]([OH:14])=O)=[CH:5][CH:4]=1.[NH2:15][C:16]1[N:21]=[N:20][C:19]([N:22]2[CH2:27][CH2:26][N:25]([C:28]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[C:36]([F:39])([F:38])[F:37])=[O:29])[CH2:24][CH2:23]2)=[CH:18][CH:17]=1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][CH2:11][C:12]([NH:15][C:16]2[N:21]=[N:20][C:19]([N:22]3[CH2:23][CH2:24][N:25]([C:28](=[O:29])[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[C:36]([F:39])([F:38])[F:37])[CH2:26][CH2:27]3)=[CH:18][CH:17]=2)=[O:14])=[CH:7][CH:8]=1
Reactant: COc1ccc(CCCC(=O)O)cc1
Reactant: Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Product: COc1ccc(CCCC(=O)Nc2ccc(N3CCN(C(=O)c4ccccc4C(F)(F)F)CC3)nn2)cc1

Procedure:
Following the procedure of Example 1, making variations only as required to use 4-(4-methoxyphenyl)butyric acid in place of 4-methylpentanoic acid to react with [4-(6-aminopyridazin-3-yl)piperazin-1-yl](2-trifluoromethylphenyl)-methanone, the title compound was obtained as a white powder (20% yield). 1H NMR (300 MHz, CDCl3) δ 9.14, 8.29, 7.67, 7.55, 7.49, 7.30, 7.01, 6.98, 6.73, 3.95-3.91, 3.86-3.81, 3.70, 3.61-3.55, 3.48-3.45, 3.26-3.24, 2.57, 2.45, 1.96.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.[CH:14]1([C:18](Cl)=[O:19])[CH2:17][CH2:16][CH2:15]1>>[CH:14]1([C:18]([NH:1][C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=2)=[O:19])[CH2:17][CH2:16][CH2:15]1
Reactant: O=C(Cl)C1CCC1
Reactant: Nc1ccc(C(=O)O)c([N+](=O)[O-])c1
Product: O=C(O)c1ccc(NC(=O)C2CCC2)cc1[N+](=O)[O-]

Procedure:
B 4-Cyclobutanecarbonylamino-2-nitro-benzoic acid was prepared as described in Example 3 from 10.9 g (0.06 mol) of 4-amino-2-nitro-benzoic acid and 7.83 g (0.066 mol) of cyclobutanecarboxylic acid chloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][SH:8])=[CH:5][CH:4]=1.[H-].[Na+].Br[C:14]1[C:15]([C:20]([NH2:22])=[O:21])=[N:16][CH:17]=[CH:18][CH:19]=1>CS(C)=O>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][S:8][C:14]2[C:15]([C:20]([NH2:22])=[O:21])=[N:16][CH:17]=[CH:18][CH:19]=2)=[CH:5][CH:4]=1
Reactant: NC(=O)c1ncccc1Br
Reactant: COc1ccc(CS)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1ccc(CSc2cccnc2C(N)=O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
By the procedure of Efxample 1, a solution of p-methoxybenzyl mercaptan in dimethylsulfoxide is added slowly to a stirred suspension of sodium hydride in dry dimethylsulfoxide under nitrogen. After stirring for one hour at room temperature, 3-bromopicolinamide is added and the mixture is kept about 75°C. for three hours, then worked up by cooling, diluting with ice water, filtering off the resulting solid, washing it with water, drying and recrystallizing from aqueous dimethylformamide to give 3-(p-methoxybenzylthio)picolinamide, m.p. 252°C. (dec.).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([N+:9]([O-])=O)=[CH:7][C:6]([CH3:12])=[C:5]([C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][C:14]=2[O:24][CH3:25])[N:4]=1>CO.[Pd]>[CH3:1][O:2][C:3]1[C:8]([NH2:9])=[CH:7][C:6]([CH3:12])=[C:5]([C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]([F:22])([F:23])[F:21])=[CH:15][C:14]=2[O:24][CH3:25])[N:4]=1
Reactant: COc1cc(OC(F)(F)F)ccc1-c1nc(OC)c([N+](=O)[O-])cc1C
Agent: [Pd]
Solvent: CO
Product: COc1cc(OC(F)(F)F)ccc1-c1nc(OC)c(N)cc1C
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Pd/C (10%, 1.6 g) is added to a solution of 2-methoxy-6-(2-methoxy-4-trifluoromethoxy-phenyl)-5-methyl-3-nitro-pyridine (16.35 g, 45.635 mmol) in MeOH (450 ml) at room temperature. The suspension is stirred under hydrogen at room temperature for 5 hours. The catalyst is removed by filtration and the filtrate is concentrated under reduced pressure to give 2-methoxy-6-(2-methoxy-4-trifluoromethoxy-phenyl)-5-methyl-pyridin-3-ylamine as a gum. Rf (hexane/EtOAc=9:1)=0.18.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([CH:9]=O)[N:8]=1)[CH3:2].[S:11]1[CH2:17][C:15](=[O:16])[N:14]([CH2:18][C:19]([OH:21])=[O:20])[C:12]1=[S:13].[Cl-].[NH4+].N>C(O)C>[CH2:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([CH:9]=[C:17]2[S:11][C:12](=[S:13])[N:14]([CH2:18][C:19]([OH:21])=[O:20])[C:15]2=[O:16])[N:8]=1)[CH3:2]
Reactant: CCNc1nc(C=O)cs1
Reactant: O=C(O)CN1C(=O)CSC1=S
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CCNc1nc(C=C2SC(=S)N(CC(=O)O)C2=O)cs1
Yield: 84.8 %

Procedure:
The reaction described in Example 1 was repeated, but using 1.27 g of 2-ethylaminothiazole-4-carbaldehyde, 1.3 g of rhodanine-3-acetic acid, 1 g of ammonium chloride, 1 ml of 28% v/v aqueous ammonia and 30 ml of ethanol, giving 1.9 g of the title compound as yellow needles.
Reaction SMILES: C(Cl)CCl.Cl.[O:6]=[C:7]1[NH:16][C:15]2[N:14]=[CH:13][C:12](/[CH:17]=[CH:18]/[C:19]([OH:21])=O)=[CH:11][C:10]=2[CH:9]=[CH:8]1.C1C=CC2N(O)N=NC=2C=1.[CH3:32][NH:33][CH2:34][C:35]1[O:36][C:37]2[CH:44]=[CH:43][CH:42]=[CH:41][C:38]=2[C:39]=1[CH3:40].C(N(C(C)C)C(C)C)C>CN(C=O)C.O>[CH3:32][N:33]([CH2:34][C:35]1[O:36][C:37]2[CH:44]=[CH:43][CH:42]=[CH:41][C:38]=2[C:39]=1[CH3:40])[C:19](=[O:21])/[CH:18]=[CH:17]/[C:12]1[CH:13]=[N:14][C:15]2[NH:16][C:7](=[O:6])[CH:8]=[CH:9][C:10]=2[CH:11]=1
Reactant: O=C(O)/C=C/c1cnc2[nH]c(=O)ccc2c1
Reactant: CNCc1oc2ccccc2c1C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(CN(C)C(=O)/C=C/c2cnc3[nH]c(=O)ccc3c2)oc2ccccc12
Temperature: 40 °C

Procedure:
EDC (0.18 g, 0.95 mmol) was added to a suspension of (E)-3-(7-oxo-7,8-dihydro-1,8-naphthyridin-3-yl)acrylic acid hydrochloride (0.20 g, 0.79 mmol), HOBt (0.12 g, 0.87 mmol), Methyl-(3-methyl-benzofuran-2-ylmethyl)-amine (0.15 g, 0.87 mmol) and (i-Pr)2EtN (0.8 mL, 4.74 mmol) in DMF (10 mL). The mixture was heated at 40° C. overnight then diluted with H2O (30 mL) with rapid stirring. The resulting precipitate was filtered, washed with H2O (20 mL) and dried under high vacuum for 4 hours. The solid was suspended in 50% Et2O:hexanes (20 mL), sonicated then filtered and dried under vacuum overnight. Yield: 0.13 g (44.1%) as a mixture of amide rotamers; 1H NMR (300 MHz, DMSO-d6) δ 12.33 (s, 1H), 8.90 and 8.87 (2×s, 1H), 8.53 (s, 1H), 7.91 (d, 111, J=9 Hz), 7.65-7.25 (m, 6H), 6.63 (d, 1H, J=9.0 Hz), 5.04 and 4.83 (2×s, 2H), 3.23 and 2.96 (2×s, 3H), 2.29 (s, 3H); ESI MS m/z 374 [C22H19N3O3+H]+