Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21](=[O:30])[NH:22][CH2:23][C:24]4[N:29]=[CH:28][CH:27]=[CH:26][N:25]=4)=[CH:17][C:16]=3[C:31]3[C:32]([C:38]([OH:40])=[O:39])=[CH:33][C:34]([CH3:37])=[CH:35][CH:36]=3)=[CH:8][N:9]2[CH2:12][CH3:13])=[CH:5][CH:4]=1)#[N:2].C(C1C=C2C(C(CC3C=CC(C(=O)NCC4C=NC=CC=4)=CC=3C3C(C(O)=O)=CC(C)=CC=3)=CN2CC)=CC=1)(=N)[NH2:42].C(O)(=O)C(O)=O.NCC1N=CC=CN=1>>[C:1]([C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21](=[O:30])[NH:22][CH2:23][C:24]4[NH:29][CH2:28][CH2:27][CH2:26][N:25]=4)=[CH:17][C:16]=3[C:31]3[C:32]([C:38]([OH:40])=[O:39])=[CH:33][C:34]([CH3:37])=[CH:35][CH:36]=3)=[CH:8][N:9]2[CH2:12][CH3:13])=[CH:5][CH:4]=1)(=[NH:42])[NH2:2]
Reactant: CCn1cc(Cc2ccc(C(=O)NCc3cccnc3)cc2-c2ccc(C)cc2C(=O)O)c2ccc(C(=N)N)cc21
Reactant: CCn1cc(Cc2ccc(C(=O)NCc3ncccn3)cc2-c2ccc(C)cc2C(=O)O)c2ccc(C#N)cc21
Agent: NCc1ncccn1
Agent: O=C(O)C(=O)O
Product: CCn1cc(Cc2ccc(C(=O)NCC3=NCCCN3)cc2-c2ccc(C)cc2C(=O)O)c2ccc(C(=N)N)cc21
Yield: 55 %

Procedure:
Part A. 2′-(6-cyano-1-ethyl-1H-indol-3-ylmethyl)-4-methyl-5′-[(pyrimidin-2-ylmethyl)-carbamoyl]-biphenyl-2-carboxylic acid: The amide was prepared in 55% yield from the acid of Example 37, Part D following the procedure of Example 37, Part E using 2-aminomethylpyrimidine oxalate in place of 3-aminomethylpyridine. 1H NMR (500 MHz, CDCl3) δ ppm 1.38 (t, J=7.42 Hz, 3H) 2.41 (s, 3H) 3.79 (s, 2H) 4.03 (q, J=7.15 Hz, 2H) 4.86 (m, 2H) 4.96 (m, 2H) 6.67 (s, 1H) 7.03 (m, 3H) 7.17 (dd, J=15.40, 8.25 Hz, 2H) 7.24 (m, 5H) 7.41 (t, J=12 Hz, 1H) 7.56 (s, 1H) 7.60 (s, 1H) 7.74 (d, J=9.90 Hz, 1H) 7.84 (s, 1H) 8.71 (d, J=0.40 Hz, 2H). LC/MS m/z 620.4 (M+H)+.
Reaction SMILES: [CH:1]1[C:15](=[O:16])[N:14]=[C:13]2[N:3]([C@@H:4]3[O:8][C@H:7]([CH2:9][OH:10])[C@@H:6]([OH:11])[C@@H:5]3[O:12]2)[CH:2]=1.C[O-].[Mg+2].C[O-].C(O)(=[O:24])C>CO>[C@@H:4]1([N:3]2[CH:2]=[CH:1][C:15](=[O:16])[NH:14][C:13]2=[O:12])[O:8][C@H:7]([CH2:9][OH:10])[C@@H:6]([OH:11])[C@H:5]1[OH:24]
Reactant: CC(=O)O
Reactant: O=c1ccn2c(n1)O[C@H]1[C@H](O)[C@@H](CO)O[C@H]12
Agent: C[O-]
Agent: [Mg+2]
Solvent: CO
Product: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Temperature: 150 °C

Procedure:
2,2'-anhydro uridine (1, 75 g, 331.56 mmol) was added to the freshly prepared solution of 15% magnesium methoxide (1218.75 ml, 1.66 mol) in methanol. The mixture was refluxed at 150° C. for five hours. The mixture was cooled down to room temperature and then to 5° C. on ice bath. The pH was adjusted to 7 by using glacial acetic acid. The solution was roto-evaporated to a foam. This solid was refluxed with ethyl alcohol (1500 ml) for two hours. The solid was filtered and filtrate was roto-evaporated to a solid mass. The isolated yield of the compound was 78.75 g (92%). The product was >95% pure by HPLC. The yield after quantitation against uridine was 89%. The structure of the compound was confirmed by 1H-NMR and elemental analysis. Table 1 shows the PMR results of the compounds.
Reaction SMILES: [CH2:1]([C:7]1[CH:8]=[C:9]([C:13]2[N:17]([CH3:18])[C:16]([C:19]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[CH2:23][CH2:22]3)=[O:20])=[C:15](I)[N:14]=2)[CH:10]=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[N:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1B(O)O>>[CH2:1]([C:7]1[CH:8]=[C:9]([C:13]2[N:17]([CH3:18])[C:16]([C:19]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[CH2:23][CH2:22]3)=[O:20])=[C:15]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][N:33]=3)[N:14]=2)[CH:10]=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCc1cccc(-c2nc(I)c(C(=O)N3CCC(N4CCCC4)CC3)n2C)c1
Reactant: OB(O)c1ccccn1
Product: CCCCCCc1cccc(-c2nc(-c3ccccn3)c(C(=O)N3CCC(N4CCCC4)CC3)n2C)c1

Procedure:
In analogy to the procedure described for example 7, [2-(3-hexyl-phenyl)-5-iodo-3-methyl-3H-imidazol-4-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 2) was reacted with pyridin-2-yl-boronic acid to give the title compound as yellow solid. MS: 500.0 (MH+).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:7]=1[CH:14]1[C:19](=[O:20])[N:18]([CH3:21])[C:17]2[CH:22]=[CH:23][CH:24]=[CH:25][C:16]=2[S:15]1.[C:26](=[O:29])([O-:28])[O-].[Na+].[Na+].[CH3:32][NH:33][CH2:34][CH2:35][O:36][C:37]1[CH:42]=[CH:41][C:40]2[O:43][CH2:44][O:45][C:39]=2[CH:38]=1.Cl>CN(C)C=O.C(Cl)(Cl)Cl>[C:19]([OH:20])(=[O:36])/[CH:14]=[CH:7]/[C:26]([OH:28])=[O:29].[CH3:13][O:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][CH2:2][N:33]([CH3:32])[CH2:34][CH2:35][O:36][C:37]2[CH:42]=[CH:41][C:40]3[O:43][CH2:44][O:45][C:39]=3[CH:38]=2)=[C:7]([CH:14]2[C:19](=[O:20])[N:18]([CH3:21])[C:17]3[CH:22]=[CH:23][CH:24]=[CH:25][C:16]=3[S:15]2)[CH:8]=1
Reactant: O=C([O-])[O-]
Reactant: CNCCOc1ccc2c(c1)OCO2
Reactant: COc1ccc(OCCCBr)c(C2Sc3ccccc3N(C)C2=O)c1
Agent: Cl
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: COc1ccc(OCCCN(C)CCOc2ccc3c(c2)OCO3)c(C2Sc3ccccc3N(C)C2=O)c1
Product: O=C(O)/C=C/C(=O)O
Temperature: 80 °C
Reaction time: 2 h
Yield: 140.2 %

Procedure:
To a stirred solution of 2-[2-(3-bromopropoxy)-5-methoxyphenyl]-3,4-dihydro-4-methyl-3-oxo-2H-1,4-benzothiazine (1.2 g) and sodium carbonate (0.4 g) in dimethylformamide (5 ml), N-methyl-2-[(3,4-methylenedioxy)phenoxy]ethylamine (0.8 g) was added and the mixture was stirred for 2 hours at 80° C. The reaction mixture was poured into a mixture of chloroform (50 ml) and 2N hydrochloric acid (50 ml). The following treatments were carried out by the similar procedure as in Example 1 to give 1.3 g (70%) of the titled compound.
Reaction SMILES: [C:1]1([C:11]([OH:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]=1.[CH2:14]=[CH:15][CH:16]=[CH2:17].OC1C=CC=CC=1C>C1(C)C=CC=CC=1>[CH2:14]1[C@@H:2]2[C@@:1]([C:11]([OH:13])=[O:12])([C:10]3[C:5]([CH2:4][CH2:3]2)=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:17][CH:16]=[CH:15]1
Reactant: C=CC=C
Reactant: O=C(O)C1=CCCc2ccccc21
Agent: Cc1ccccc1O
Solvent: Cc1ccccc1
Product: O=C(O)[C@]12CC=CC[C@H]1CCc1ccccc12
Yield: 27 %

Procedure:
To a solution of 3,4-dihydronaphthalene-1-carboxylic acid (29.7 g) in toluene (75 ml) was added butadiene (16 g) and a trace of butyrated hydroxy toluene (BHT). The solution was heated to 180° for 18 hours in a sealed reactor, then chromatographed twice over silica gel. Recrystallization from ethyl acetate/heptane affords the title compound as a colorless crystalline solid (10.5 g). The recovered starting material was rereacted with butadiene to afford, after workup, additional title product (8.0 g).
Reaction SMILES: [CH3:1][N:2]([CH3:24])[CH2:3][CH2:4][N:5]1[C:21](=[O:22])[C:20]2[C:19]3[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([Cl:23])[CH:17]=4)[NH:12][C:11]=3[CH:10]=[CH:9][C:8]=2[C:6]1=[O:7].[CH3:25][I:26]>CN(C)C=O>[I-:26].[CH3:1][N+:2]([CH3:25])([CH3:24])[CH2:3][CH2:4][N:5]1[C:21](=[O:22])[C:20]2[C:19]3[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([Cl:23])[CH:17]=4)[NH:12][C:11]=3[CH:10]=[CH:9][C:8]=2[C:6]1=[O:7]
Reactant: CI
Reactant: CN(C)CCN1C(=O)c2ccc3[nH]c4ccc(Cl)cc4c3c2C1=O
Solvent: CN(C)C=O
Product: C[N+](C)(C)CCN1C(=O)c2ccc3[nH]c4ccc(Cl)cc4c3c2C1=O
Product: [I-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.7 %

Procedure:
In 10 ml of N,N-dimethylformamide was dissolved 200 mg of N-(2-dimethylaminoethyl)-6-chlorocarbazole-3,4-dicarboximide. Thereto was added 830 mg of methyl iodide. The mixture was stirred at room temperature for 2 hours. The resulting crystals were collected by filtration, washed with ethyl acetate, and dried to obtain 220 mg (yield: 78%) of N-(2-tri methylammonioethyl)-6-chlorocarbazole-3,4-dicarboximide iodide as yellow crystals.
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[N:6][CH:7]=[C:8]3[C:13]=2[CH:12]=[CH:11][CH:10]=[CH:9]3)[CH:4]=[CH:3][CH:2]=1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=1)[C:20](Cl)=[O:21].[NH:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27]1>>[NH:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]([CH:7]2[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:14]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[N:6]2[C:20]([C:19]2[CH:23]=[CH:24][CH:25]=[C:17]([O:16][CH3:15])[CH:18]=2)=[O:21])=[CH:27]1
Reactant: COc1cccc(C(=O)Cl)c1
Reactant: c1ccc2c(c1)cnc1ccccc12
Reactant: c1ccc2[nH]ccc2c1
Product: COc1cccc(C(=O)N2c3ccccc3-c3ccccc3C2c2c[nH]c3ccccc23)c1

Procedure:
[6-(1H-Indol-3-yl)-6H-phenanthridin-5-yl]-(3-methoxy-phenyl)-methanone was prepared from phenanthridine, 3-methoxybenzoyl chloride, and indole according to GP 2. Yield, 84%. 1H-NMR (CD3OD): δ=3.62 (s, 3H), 6.19 (s, 1H), 6.37 (s, br., 1H), 6.71-6.86 (m, 3H), 6.91 (dd, J=8.1 Hz, J=1.9 Hz, 1H), 7.02-7.26 (m, 5H), 7.32 (s, br., 1H), 7.39-7.48 (m, 2H), 7.54 (td, J=7.1 Hz, J=2.5 Hz, 1H), 7.90 (dd, J=7.9 Hz, J=1.2 Hz, 1H), 7.97 (s, br., 1H), 8.06 (d, J=7.8 Hz, 1H); (+)-ESI-MS: m/z=431 [M+H]+, 314 [M-indole+H]+.
Reaction SMILES: COP([CH2:7][C:8](=[O:14])[CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])(=O)OC.[H-].[Na+].[C:17]12([CH:23]3[CH2:24][CH2:25][CH:20]1[C:21](=[O:27])[C:22]3=O)[CH2:19][CH2:18]2>C1COCC1>[CH3:11][C:10]([CH3:13])([CH3:12])[CH2:9][C:8](=[O:14])/[CH:7]=[C:22]1/[C:21](=[O:27])[CH:20]2[C:17]3([CH2:18][CH2:19]3)[CH:23]/1[CH2:24][CH2:25]2.[CH3:11][C:10]([CH3:13])([CH3:12])[CH2:9][C:8](=[O:14])/[CH:7]=[C:22]1\[C:21](=[O:27])[CH:20]2[C:17]3([CH2:18][CH2:19]3)[CH:23]\1[CH2:24][CH2:25]2
Reactant: O=C1C(=O)C2CCC1C21CC1
Reactant: COP(=O)(CC(=O)CC(C)(C)C)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)CC(=O)/C=C1/C(=O)C2CCC1C21CC1
Product: CC(C)(C)CC(=O)/C=C1\C(=O)C2CCC1C21CC1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution (4,4-dimethyl-2-oxo-pentyl)-phosphonic acid dimethyl ester (1.249 g) in THF (40 ml) was cooled to 0° C. under an argon atmosphere and sodium hydride (0.268 g) was added in 4 portions. Spiro[bicyclo[2.2.1]heptane-7,1′-cyclopropane]-2,3-dione (1.023 g) dissolved in THF (30 ml) was then added dropwise to the reaction mixture. The mixture was then stirred for further 15 minutes at 0° C. (until completion of reaction according to TLC analysis). The reaction mixture was partitioned between water/3N HCl and AcOEt, the layers were separated, the organic layer washed with saturated, aqueous NaCl, dried over Na2SO4, filtered and evaporated. The residue was purified by flash chromatography with heptane/AcOEt: 100% to 95% as eluant to give (3E)-3-(4,4-dimethyl-2-oxopentylidene)spiro[bicyclo[2.2.1]heptane-7,1′-cyclopropan]-2-one (0.284 g) and (3Z)-3-(4,4-dimethyl-2-oxopentylidene)spiro[bicyclo[2.2.1]heptane-7,1′-cyclopropan]-2-one (0.287 g) as yellow oils, respectively, that were directly used in the next step. Assignment of the E/Z isomers was done by NMR.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24]3[N:29]=[CH:28][C:27]([NH:30][C:31](=[O:50])[C:32]4[CH:37]=[C:36]([NH:38][C:39](=[O:48])[C:40]5[CH:45]=[CH:44][C:43]([C:46]#[N:47])=[CH:42][CH:41]=5)[CH:35]=[CH:34][C:33]=4[Cl:49])=[CH:26][N:25]=3)=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.[C:51]([OH:57])([C:53]([F:56])([F:55])[F:54])=[O:52]>C(Cl)Cl>[Cl:49][C:33]1[CH:34]=[CH:35][C:36]([NH:38][C:39](=[O:48])[C:40]2[CH:41]=[CH:42][C:43]([C:46]#[N:47])=[CH:44][CH:45]=2)=[CH:37][C:32]=1[C:31]([NH:30][C:27]1[CH:26]=[N:25][C:24]([NH:23][C:20]2[CH:19]=[CH:18][C:17]([S:14]([CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)(=[O:15])=[O:16])=[CH:22][CH:21]=2)=[N:29][CH:28]=1)=[O:50].[C:51]([OH:57])([C:53]([F:56])([F:55])[F:54])=[O:52]
Reactant: CC(C)(C)OC(=O)N1CCC(S(=O)(=O)c2ccc(Nc3ncc(NC(=O)c4cc(NC(=O)c5ccc(C#N)cc5)ccc4Cl)cn3)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1ccc(C(=O)Nc2ccc(Cl)c(C(=O)Nc3cnc(Nc4ccc(S(=O)(=O)C5CCNCC5)cc4)nc3)c2)cc1
Reaction time: 18 h

Procedure:
A stirred suspension of intermediate 27 (Example 39) (0.12 g, 0.143 mmol) in DCM (8 mL) was treated with TFA (0.200 mL) and stirred for 18 h. Solvents were then removed yielding desired product as TFA salt (0.104 g, 99%). 1H NMR (DMSO-d6): δ 1.61-1.70 (m, 2H), 2.01-2.04 (m, 2H), 2.80-2.90 (m, 2H), 7.61 (d, J=8.8 Hz, 1H), 7.74 (d, J=8.9 Hz, 2H), 7.90 (dd, J=8.7 Hz, J=2.5 Hz, 1H), 8.04-8.13 (m, 7H), 8.21-8.25 (m, 1H), 8.64-8.68 (m, 1H), 8.90 (s, 2H), 10.37 (s, 1H), 10.78 (s, 1H), 10.80 (s, 1H).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[N:12]2)=[CH:7][N:6]=1)=[O:4].[Li+].[OH-]>CO.C1COCC1.O>[F:19][C:16]([F:17])([F:18])[C:13]1[CH:14]=[CH:15][N:11]([C:8]2[CH:9]=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[N:6][CH:7]=2)[N:12]=1
Reactant: COC(=O)c1ccc(-n2ccc(C(F)(F)F)n2)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(-n2ccc(C(F)(F)F)n2)cn1
Reaction time: 22 h
Yield: 99.2 %

Procedure:
To a solution of 5-(3-trifluoromethyl-pyrazol-1-yl)-pyridine-2-carboxylic acid methyl ester (67 mg) in MeOH (4 ml) and THF (0.5 ml) was added a solution of LiOH (23 mg) in water (1 ml) and stirring was continued at 22° C. for 22 h. The mixture was evaporated and the residue partitioned between 1 N aqueous HCl and ethyl acetate, the organic layer was washed with water, dried and evaporated to give 5-(3-trifluoromethyl-pyrazol-1-yl)-pyridine-2-carboxylic acid (63 mg) as a white solid. MS (ESI): m/z=255.9 [M−H]−.
Reaction SMILES: [CH:1]([NH:3][C@H:4]([C:9]([OH:11])=O)[CH2:5][CH2:6][S:7][CH3:8])=[O:2].[F:12][C@:13]12[C@@H:33]([OH:34])[CH2:32][C@@:31]3([CH3:35])[C@@H:23]([CH2:24][C@H:25]([CH3:37])[C@:26]3([OH:36])[C:27](=[O:30])[CH2:28][SH:29])[C@@H:22]1[CH2:21][CH2:20][C:19]1[C@:14]2([CH3:39])[CH:15]=[CH:16][C:17](=[O:38])[CH:18]=1.C1(N=C=NC2CCCCC2)CCCCC1>C(OCC)(=O)C>[F:12][C@:13]12[C@@H:33]([OH:34])[CH2:32][C@@:31]3([CH3:35])[C@@H:23]([CH2:24][C@H:25]([CH3:37])[C@:26]3([OH:36])[C:27](=[O:30])[CH2:28][S:29][C:9](=[O:11])[CH:4]([NH:3][CH:1]=[O:2])[CH2:5][CH2:6][S:7][CH3:8])[C@@H:22]1[CH2:21][CH2:20][C:19]1[C@:14]2([CH3:39])[CH:15]=[CH:16][C:17](=[O:38])[CH:18]=1
Reactant: C[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@]2(C)[C@@]1(O)C(=O)CS
Reactant: CSCC[C@H](NC=O)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Product: CSCCC(NC=O)C(=O)SCC(=O)[C@@]1(O)[C@@H](C)C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@@]21C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of of N-formyl-L-methionine (7.8 gm) in dry ethyl acetate (120 ml) were added 9-fluoro-11β,17-dihydroxy-16β-methylpregna-1,4-diene-3,20-dione-21-thiol (6.0 gm) in dry ethyl acetate (100 ml) and dicyclohexylcarbodiimide (18.2 gm) in dry ethyl acetate (100 ml) at room temperature. The reaction mixture was stirred at room temperature for for 4 hours.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:13])=[C:6]([CH:8]=[CH:9][C:10](Cl)=[O:11])[CH:7]=1.Cl.[CH3:15][NH:16][O:17][CH3:18].N1C=CC=CC=1>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:13])=[C:6]([CH:8]=[CH:9][C:10]([N:16]([O:17][CH3:18])[CH3:15])=[O:11])[CH:7]=1
Reactant: O=C(Cl)C=Cc1cc(Br)ccc1F
Reactant: CNOC
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CON(C)C(=O)C=Cc1cc(Br)ccc1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 90.2 %

Procedure:
The unpurified 3-(5-bromo-2-fluoro-phenyl)-acryloyl chloride (1.4 g, 5.0 mmol) prepared in Step 2, N,O-dimethylhydroxylamine hydrochloride (0.52 g, 5.3 mmol), and pyridine (0.9 mL, 11.1 mmol) were added at 0° C. to dichloromethane (10.0 mL). The reaction mixture was stirred at room temperature for 12 hours, quenched with a 1N hydrochloric acid solution, and then extracted with diethyl ether two times. The combined extract was washed with a saturated solution of sodium hydrogen carbonate and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was recrystallized from diethyl ether and n-hexane to give 1.3 g of the titled compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH2:12]Cl)=[C:8]([CH2:10]Cl)[CH:9]=1)=[O:4].[S-2:14].[Na+].[Na+]>CO>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]2[CH2:12][S:14][CH2:10][C:8]=2[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc(CCl)c(CCl)s1
Reactant: [S-2]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc2c(s1)CSC2
Yield: 49.9 %

Procedure:
A solution of 4.8 g (20 mmol) (2) in 240 mL methanol was heated up and kept mild boiling. Sodium sulfide solution (1.7 g, 22 mmol) in 160 mL methanol was added dropwise in 2 h. After cooling of the reaction mixture, the precipitate was filtered off. The solvent was removed by evaporation and the residue was washed by water. Column chromatography on silica gel using dichloromethane yielded the pure title compound as a white solid 2.0 g (50%). 1HNMR (CDCl3): δ 3.87 (3H, s), 4.05-4.06 (2H, t, J=3 Hz), 4.19-4.20 (2H, t, J=3 Hz), 7.48 (1H, s). 13CNMR (CDCl3): δ 33.12, 33.47, 52.19, 127.90, 137.30, 143.90, 146.64, 162.51.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH:7]([OH:13])[CH:8]([NH2:12])[C:9]([OH:11])=[O:10])=[CH:3][CH:2]=1.[C:14]1([CH2:20][C:21](O)=O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:20]([C:21]1[O:13][C:7]([C:4]2[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=2)=[C:8]([C:9]([OH:11])=[O:10])[N:12]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(O)Cc1ccccc1
Reactant: NC(C(=O)O)C(O)c1ccccc1
Product: O=C(O)c1nc(Cc2ccccc2)oc1-c1ccccc1

Procedure:
Prepared starting from DL-3-phenylserine hydrate following sequentially general procedures Y, Z with phenyl-acetic acid, Z1 and Z2. LC-MS-conditions 02: tR=0.95 min; [M+H]+=220.18.
Reaction SMILES: [H-].[Na+].[I:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[Br:11][C:12]1[CH:13]=[N:14][C:15](Cl)=[C:16]([CH:20]=1)[C:17]([OH:19])=[O:18].CC(O)=O>CN(C=O)C.O>[Br:11][C:12]1[CH:13]=[N:14][C:15]([O:10][C:7]2[CH:8]=[CH:9][C:4]([I:3])=[CH:5][CH:6]=2)=[C:16]([CH:20]=1)[C:17]([OH:19])=[O:18]
Reactant: Oc1ccc(I)cc1
Reactant: O=C(O)c1cc(Br)cnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1cc(Br)cnc1Oc1ccc(I)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 86.1 %

Procedure:
A 3-neck 12 L flask equipped with an overhead stirrer, thermometer, condenser and nitrogen inlet was charged with NaH (186.1 g, 4.653 mol) and DMF (1500 mL). The slurry was cooled to 0° C. and a solution of 4-iodophenol (488.6 g, 2.221 mol) in DMF (1500 mL) and added. The temperature of the reaction mixture was maintained below 25-30° C. during this addition. After complete addition, the cooling bath was promptly removed and the mixture continued to stir at RT for 1 h. 5-Bromo-2-chloronicotinic acid (500 g, 2.115 mol) was then added to the slurry portion wise. The reaction mixture was heated to 115° C. overnight. The dark brown reaction mixture was cooled to 20° C. and diluted with water (2 L). The reaction mixture was acidified using HOAc (845 ml). The black homogenous solution (pH=5) was allowed to stir for 1 h at RT and poured slowly onto ice-water (20 L). The slurry was filtered at RT, washed with water (2×2 L) and dried in air to give 765 g of 5-Bromo-2-(4-iodophenoxy)-nicotinic acid as light orange solid.
Reaction SMILES: [C:1]1([O-:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na+].Cl[C:10]([N:12]1[CH2:16][CH2:15][NH:14][C:13]1=[O:17])=[O:11].C(N(CC)CC)C.[OH-].[Na+]>O1CCCC1.O>[O:7]([C:10]([N:12]1[CH2:16][CH2:15][NH:14][C:13]1=[O:17])=[O:11])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)N1CCNC1=O
Reactant: [O-]c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: O=C1NCCN1C(=O)Oc1ccccc1

Procedure:
12.7 parts by weight of sodium phenolate were dissolved in 120 parts by volume of 80% strength tetrahydrofurane and the solution was adjusted to pH = 8. 14.9 parts by weight of N-chlorocarbonyl-imidazolid-2-one were now introduced while stirring and keeping the pH value constant at 8 by simultaneous addition of triethylamine. The mixture was further stirred until the pH remained constant even without addition of triethylamine. 100 parts by volume of water were now added, the tetrahydrofurane was stripped off in vacuo, the residue was adjusted to pH = 10 with sodium hydroxide solution, and the solution was extracted with ethyl acetate. The organic solution was washed with water, dried over MgSO4 and evaporated and the residue was dried under an oil pump at 60°C for 1 hour and recrystallized from acetone.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[F:9][C:10]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:11]=1[C:12](Cl)=[O:13]>[Cl-].[Zn+2].[Cl-].Cl>[NH2:6][C:5]1[CH:7]=[CH:8][C:2]([Br:1])=[CH:3][C:4]=1[C:12]([C:11]1[C:10]([F:9])=[CH:18][CH:17]=[CH:16][C:15]=1[F:19])=[O:13]
Reactant: Nc1ccc(Br)cc1
Reactant: O=C(Cl)c1c(F)cccc1F
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Product: Nc1ccc(Br)cc1C(=O)c1c(F)cccc1F
Temperature: 180 °C
Reaction time: 3 h
Yield: 28.9 %

Procedure:
4-Bromoaniline (14.9 g, 86.5 mmol) was heated to 120° C. and 2,6-difluorobenzoyl chloride (36.7 g, 208 mmol) was added. The temperature of the mixture was raised to 180° C. and zinc chloride (14.2 g, 104 mmol) was added. The temperature of the mixture was raised to 205° C. and the mixture was stirred for 3 hrs. The reaction mixture was cooled to 150° C., and 4N hydrochloric acid (100 ml) was added, and the mixture was heated under reflux for 15 min. The supernatant was removed, 4N hydrochloric acid (100 ml) was added to the residue, and the mixture was heated under reflux for 15 min. The supernatant was removed and the residue was dissolved in acetic acid (85 ml). Conc. hydrochloric acid (85 ml) was added at 120° C. and the mixture was heated under reflux for 12 hrs. The reaction mixture was concentrated under reduced pressure and 1N aqueous sodium hydroxide solution (200 ml) was added to the residue. The mixture was extracted with ethyl acetate, and the extract was washed with 1N hydrochloric acid and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give a crude product of (2-amino-5-bromophenyl)(2,6-difluorophenyl)methanone (7.8 g). To a solution of the crude product (5.2 g) and 5-methyl-3-oxohexanenitrile (2.1 g, 17 mmol) in toluene (100 ml) was added methanesulfonic acid (1.6 g, 17 mmol) and the mixture was heated under reflux for 17 hrs. The reaction mixture was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give 6-bromo-4-(2,6-difluorophenyl)-2-isobutylquinoline-3-carbonitrile (1.6 g, yield 4.6%) as a yellow solid.