Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:34]=[CH:33][C:6]2[NH:7][C:8]([C:10]([C:21]3[C:29]([O:30][CH3:31])=[CH:28][C:27]([CH3:32])=[C:26]4[C:22]=3[CH:23]=[CH:24][NH:25]4)([O:15][CH2:16][C:17]([O:19]C)=[O:18])[C:11]([F:14])([F:13])[F:12])=[N:9][C:5]=2[CH:4]=1)#[N:2].[OH-].[Na+]>C1COCC1.CO>[C:1]([C:3]1[CH:34]=[CH:33][C:6]2[NH:7][C:8]([C:10]([C:21]3[C:29]([O:30][CH3:31])=[CH:28][C:27]([CH3:32])=[C:26]4[C:22]=3[CH:23]=[CH:24][NH:25]4)([O:15][CH2:16][C:17]([OH:19])=[O:18])[C:11]([F:13])([F:14])[F:12])=[N:9][C:5]=2[CH:4]=1)#[N:2]
Reactant: COC(=O)COC(c1nc2cc(C#N)ccc2[nH]1)(c1c(OC)cc(C)c2[nH]ccc12)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(C)c2[nH]ccc2c1C(OCC(=O)O)(c1nc2cc(C#N)ccc2[nH]1)C(F)(F)F
Temperature: 40 °C
Reaction time: 1 h

Procedure:
(−) or (+)-methyl 2-(1-(5-cyano-1H-benzo[d]imidazol-2-yl)-2,2,2-trifluoro-1-(5-methoxy-7-methyl-1H-indol-4-yl)ethoxy)acetate (tr=3.5 min—from Example 35-B) (110 mg, 0.233 mmol) was dissolved in THF (1.2 mL) and MeOH (1.2 mL). A 3N aq. NaOH solution (0.45 mL, 1.35 mmol) was added. The reaction was stirred at 40° C. for 1 hour. At this point the reaction mixture was concentrated. The residue was dissolved in MeOH, and purified with RP-HPLC(HC-A) to provide (+)-2-(1-(5-cyano-1H-benzo[d]imidazol-2-yl)-2,2,2-trifluoro-1-(5-methoxy-7-methyl-1H-indol-4-yl)ethoxy)acetic acid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])[N:5]=[C:4]([CH2:19][OH:20])[N:3]=1.[C:21]([C:24]([C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1)([CH3:26])[CH3:25])([OH:23])=[O:22].C([O-])([O-])=O.[Cs+].[Cs+].Cl>COCCOC.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>[Cl:18][C:12]1[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:11]=1[CH2:10][CH2:9][NH:8][C:6]1[N:5]=[C:4]([CH2:19][OH:20])[N:3]=[C:2]([C:29]2[CH:28]=[C:27]([C:24]([CH3:26])([CH3:25])[C:21]([OH:23])=[O:22])[CH:32]=[CH:31][CH:30]=2)[CH:7]=1
Reactant: OCc1nc(Cl)cc(NCCc2ccc(Cl)cc2Cl)n1
Reactant: CC(C)(C(=O)O)c1cccc(B(O)O)c1
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: COCCOC
Solvent: O
Product: CC(C)(C(=O)O)c1cccc(-c2cc(NCCc3ccc(Cl)cc3Cl)nc(CO)n2)c1
Temperature: 90 °C
Reaction time: 16 h
Yield: 17.9 %

Procedure:
Argon is bubbled through a mixture of {4-chloro-6-[2-(2,4-dichloro-phenyl)-ethylamino]-pyrimidin-2-yl}-methanol (67 mg, 0.2 mmol), 3-(1-Carboxy-1-methyl-ethyl)-phenyl boronic acid [92 mg, 0.44 mmol, see Example 49(b) step 2], Cs2CO3 (197 mg, 0.6 mmol), and tetrakis(triphenylphosphine)palladium (0) (16.3 mg, 0.014 mmol) in ethylene glycol dimethyl ether (1.6 mL) and water (0.4 mL), for a period of 10 minutes. The reaction vessel is sealed and heated to 90° C. After stirring for 16 hours the mixture is diluted with water (25 mL, brought to pH 4 with HCl and extracted thrice with EtOAc (25 mL). The organic extracts are combined and dried over magnesium sulfate, filtered and concentrated to afford 2-(3-{6-[2-(2,4-dichloro-phenyl)-ethylamino]-2-hydroxymethyl-pyrimidin-4-yl}-phenyl)-2-methyl-propionic acid [16.5 mg, 18%, Example 86] as a solid. LCMS RT=2.47 minutes, MS: 460 (M+H). IC50=71 nM
Reaction SMILES: C([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:17]3[CH2:18][O:19][CH2:20][CH:21]=3)[CH:14]=2)[CH2:9]1)C1C=CC=CC=1.[H][H]>>[O:19]1[CH2:20][CH2:21][CH:17]([C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[CH2:9][NH:8][CH2:16]3)[CH2:18]1
Reactant: [H][H]
Reactant: C1=C(c2ccc3c(c2)CN(Cc2ccccc2)C3)COC1
Product: c1cc2c(cc1C1CCOC1)CNC2

Procedure:
Prepared in analogy to Example A62(c) from 2-benzyl-5-(2,5-dihydro-furan-3-yl)-2,3-dihydro-1H-isoindole and hydrogen. Brown oil. MS (m/e): 190.4 ([M+H]+, 100%).
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[CH:16][C:17]([NH:19][C:20]3[N:39]=[C:23]4[C:24]([C:28]5[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[CH:30][C:29]=5[Cl:38])=[CH:25][CH:26]=[CH:27][N:22]4[N:21]=3)=[CH:18][C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:38][C:29]1[CH:30]=[CH:31][C:32]([C:34]([F:37])([F:35])[F:36])=[CH:33][C:28]=1[C:24]1[C:23]2[N:22]([N:21]=[C:20]([NH:19][C:17]3[CH:16]=[CH:15][C:12]4[CH2:13][CH2:14][NH:8][CH2:9][CH2:10][C:11]=4[CH:18]=3)[N:39]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Nc3nc4c(-c5cc(C(F)(F)F)ccc5Cl)cccn4n3)cc2CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: FC(F)(F)c1ccc(Cl)c(-c2cccn3nc(Nc4ccc5c(c4)CCNCC5)nc23)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71 %

Procedure:
7-[8-(2-Chloro-5-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino]-1,2,4,5-tetrahydro-3-benzazepine-3-carboxylic acid tert-butyl ester (0.089 mg, 0.16 mmol) in dichloromethane (2.0 mL) was added trifluoroacetic acid (0.10 mL, 1.6 mmoL) dropwise at room temperature, and the reaction was stirred at room temperature for 30 min. The solvent was evaporated, and the residue was diluted with dichloromethane, washed with 5% sodium carbonate solution, brine, dried over sodium sulfate, and concentrated to give the product [8-(2-chloro-5-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl]-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-amine (0.052 g, 83%). MS=558 (MH)+.
Reaction SMILES: CC1(C)OC([C@H]2[N:11]([O:12][CH3:13])[C@:10]3([CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[C:14]4[C:19]([C:20](=[O:22])[CH:21]=[C:9]3[O:8]2)=[CH:18][CH:17]=[CH:16][CH:15]=4)CO1.[ClH:29]>O1CCCC1>[ClH:29].[OH:8][C:9]1[C@@:10]([NH:11][O:12][CH3:13])([CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:20](=[O:22])[CH:21]=1
Reactant: CON1[C@H](C2COC(C)(C)O2)OC2=CC(=O)c3ccccc3[C@]21CCC(C)C
Agent: Cl
Solvent: C1CCOC1
Product: CON[C@@]1(CCC(C)C)C(O)=CC(=O)c2ccccc21
Yield: 87 %

Procedure:
The product from Example 22C (60 mg, 0.15 mmol) in a 2:1 mixture of tetrahydrofuran:2N aq. HCl (0.9 mL) was stirred at rt for 3 h and concentrated in vacuo. The crude product was purified by column chromatography on silica gel using 2:1 ethyl acetate:hexanes to give the hydrochloride salt of the title compound as a colorless amorphous solid (42 mg, 87%): [α]D=+152° (c 1.4, methanol).
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[CH3:22][N:23]([CH3:35])[C:24]([C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[NH:31][CH:30]=[CH:29]2)=[O:25]>>[CH3:22][N:23]([CH3:35])[C:24]([C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[N:31]([C:2]1[N:7]=[CH:6][C:5]([NH:8][CH:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]3)=[CH:4][CH:3]=1)[CH:30]=[CH:29]2)=[O:25]
Reactant: CN(C)C(=O)c1ccc2[nH]ccc2c1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccc(Br)nc2)CC1
Product: CN(C)C(=O)c1ccc2c(ccn2-c2ccc(NC3CCN(C(=O)OC(C)(C)C)CC3)cn2)c1

Procedure:
The title compound was prepared by following the similar procedure as described in Example-1 by using tert-butyl 4-((6-bromopyridin-3-yl)amino)piperidine-1-carboxylate (intermediate-5) and N,N-dimethyl-1H-indole-5-carboxamide (intermediate-12).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].[Br:21][CH2:22][CH2:23][C:24](Cl)=[O:25]>ClCCl>[Br:21][CH2:22][CH2:23][C:24]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1)=[O:25]
Reactant: CC1CC(=O)NN=C1c1ccc(N)cc1
Reactant: O=C(Cl)CCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC1CC(=O)NN=C1c1ccc(NC(=O)CCBr)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 86 %

Procedure:
(-)-6-(4-Aminophenyl)-5-methyl-4,5-dihydro-3(2H)-pyridazinone (0.195 g) suspended in dichloromethane (15 ml) was cooled to 0° C. Aqueous saturated sodium bicarbonate (15 ml) was added to form a two phase system. To the organic phase was added with stirring 3-bromopropionyl chloride (0.248 g) in dichloromethane (5 ml). The mixture was allowed to warm to room temperature and vigorously stirred for 3 hours to give a fine suspension. This was filtered to give the title compound (0.279 g); [α]D25 =-333° [concentration 0.91% in dimethylformamide]: nuclear magnetic resonance spectrum consistent with racemic material. Material from another run gave C, 49.41%; H, 4.73%; H, 12.22%; Br, 23.14%: theory C, 49.72%, H, 4.77%; N, 12.43%; Br, 23.63%.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][O:7][C:8]([C@@H:10]1[CH2:14][C@@H:13]([OH:15])[CH2:12][N:11]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:9]>N1C=CC=CC=1.ClCCl>[CH3:6][O:7][C:8]([C@@H:10]1[CH2:14][C@@H:13]([O:15][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:12][N:11]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:9]
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
Add methanesulfonyl chloride (1.56 mol, 179 g) drop wise to a solution of (2S,4R)-4-hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (0.65 mol, 160 g) in pyridine (600 mL) at 0° C. under a nitrogen atmosphere. Upon complete addition, warm the reaction mixture to room temperature and stir for 2 h. Dilute the reaction mixture with dichloromethane, wash with 0.1 N hydrochloric acid solution and saturated sodium bicarbonate solution. Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate under vacuum to obtain the title compound (185 g, 91%) as a thick oil. ES-MS m/z 324.1 [M+1]+, 224.0 [M−Boc]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[C:5]#[N:6].C1C(=O)N([Br:18])C(=O)C1>C(#N)C>[NH2:1][C:2]1[C:9]([F:10])=[CH:8][C:7]([Br:18])=[C:4]([CH:3]=1)[C:5]#[N:6]
Reactant: N#Cc1ccc(F)c(N)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: N#Cc1cc(N)c(F)cc1Br
Yield: 62.1 %

Procedure:
3-amino-4-fluorobenzonitrile (9.82 g, 72.1 mmol) was dissolved in acetonitrile to give a pale yellow solution. NBS (13.5 g, 75.7 mmol) was added in portions; the reaction mixture turned brown-blackish but remained a solution. After the completion of the reaction was confirmed by TLC and HPLC, silica gel was added to the reaction mixture and the solvent was evaporated under reduced pressure. The crude product was leaded on a CombiFlash column (330 g) and the product was eluted with hexanes/ethyl acetate (0→15% gradient). The clean fractions were combined to give 9.63 g (62%) of a yellowish off-white solid. More product was found in mixed fractions which were discarded. 1H NMR (300 MHz, dmso) δ 7.57 (d, J=10.9 Hz, 1H), 7.17 (d, J=8.7 Hz, 1H), 5.85 (s br, 2H); MS (ES) 213/215 (M−H).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH:9][C:10](=[O:27])[C@H:11]([CH2:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[NH:12]C(OC(C)(C)C)=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.C(OCC)(=O)C>C(OCC)(=O)C>[N:1]1([CH2:7][CH2:8][NH:9][C:10](=[O:27])[C@H:11]([CH2:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[NH2:12])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)C(=O)NCCN1CCCCC1
Agent: Cl
Solvent: CCOC(C)=O
Product: N[C@@H](CC1CCCCC1)C(=O)NCCN1CCCCC1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 97.5 %

Procedure:
To a solution (0.5 mL) of 233.3 mg of N-t-butoxycarbonyl-β-cyclohexyl-L-alanine 2-(1-piperidinyl)ethyl amide (0.611 mmol) in ethyl acetate, 1.5 mL of 4 M hydrogen chloride/ethyl acetate solution (6 mmol) was added and the reaction mixture was stirred for 4.5 hours at room temperature. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on alumina [alumina 2.5 g, methanol-chloroform (1:5)], whereby 167.7 mg of the title compound (97%) was obtained as a colorless oil (yield 97%).
Reaction SMILES: [OH:1][CH:2]=[C:3]([CH2:8][C:9]1[N:10]([CH3:18])[C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:4](OC)=O.[NH2:19][C:20]([NH2:22])=[S:21]>CO>[CH3:18][N:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:17]=[C:9]1[CH2:8][C:3]1[C:2](=[O:1])[NH:19][C:20](=[S:21])[NH:22][CH:4]=1
Reactant: COC(=O)C(=CO)Cc1cc2ccccc2n1C
Reactant: NC(N)=S
Solvent: CO
Product: Cn1c(Cc2c[nH]c(=S)[nH]c2=O)cc2ccccc21
Temperature: 50 °C
Yield: 56.7 %

Procedure:
To a solution of methyl 3-hydroxy-2-[(1-methyl-1H-indol-2-yl)methyl]-2-propenoate (0.363 g, 1.482 mmol) in MeOH (5 mL) was added thiourea (0.30 g, 3.94 mmol). The mixture was heated at 50° C. for 6 h. Purification via MDAP then afforded the title compound (240 mg, 0.840 mmol, 56.7% yield). LCMS: rt=2.40 min, [M+H+]=272
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15](C3C(=O)C4C(=CC=C(F)C=4)OC=3C3C=CC=CC=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)(C)(C)C.I[C:38]1[C:39](=[O:59])[C:40]2[CH:45]=[CH:44][N:43]([CH2:46][CH2:47][O:48][CH3:49])[C:42](=[O:50])[C:41]=2[O:51][C:52]=1[C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1>>[NH2:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:38]3[C:39](=[O:59])[C:40]4[CH:45]=[CH:44][N:43]([CH2:46][CH2:47][O:48][CH3:49])[C:42](=[O:50])[C:41]=4[O:51][C:52]=3[C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)=[CH:14][CH:13]=2)[CH2:9][CH2:10][CH2:11]1
Reactant: COCCn1ccc2c(=O)c(I)c(-c3ccccc3)oc2c1=O
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Product: COCCn1ccc2c(=O)c(-c3ccc(C4(N)CCC4)cc3)c(-c3ccccc3)oc2c1=O
Yield: 100 %

Procedure:
(1-{4-[7-(2-Methoxy-ethyl)-4,8-dioxo-2-phenyl-7,8-dihydro-4H-pyrano[2,3-c]pyridin-3-yl]-phenyl}-carbamic acid tert-butyl ester: Following the procedure used to prepare {1-[4-(6-fluoro-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester, 3-iodo-7-(2-methoxy-ethyl)-2-phenyl-7H-pyrano[2,3-c]pyridine-4,8-dione was reacted to give the title compound as a colourless oil (82 mg, 100%). LCMS (Method B): RT=4.63 min, [M+H]+=543.
Reaction SMILES: C([O:3][C:4](=[O:34])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][C:23]=3Br)[CH:15]=2)=[CH:9][C:8]=1[CH3:33])C.[C:35]1([OH:41])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[F:20][C:18]1[CH:19]=[C:14]([CH:15]=[C:16]([O:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:24][C:23]=2[O:41][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:17]=1)[O:13][C:10]1[CH:11]=[CH:12][C:7]([CH2:6][CH2:5][C:4]([OH:3])=[O:34])=[C:8]([CH3:33])[CH:9]=1
Reactant: Oc1ccccc1
Reactant: CCOC(=O)CCc1ccc(Oc2cc(F)cc(Oc3ccc(C(F)(F)F)cc3Br)c2)cc1C
Product: Cc1cc(Oc2cc(F)cc(Oc3ccc(C(F)(F)F)cc3Oc3ccccc3)c2)ccc1CCC(=O)O

Procedure:
The title compound is prepare by reacting the compound of 3-{4-[3-(2-bromo-4-trifluoromethyl-phenoxy)-5-fluoro-phenoxy]-2-methyl-phenyl}-propionic acid ethyl ester with phenol as in Example 45 to afford 0.080 g (28%). 1H NMR (400 MHz, CDCl3); MS (ES+) m/z mass calculated for C29H22O5F4 526, found 527 (M+1, 100%).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:13]=[N:12][CH:11]=[N:10]2)=[CH:5][CH:4]=1)=[CH2:2].[Li]CCCC.[CH3:19][S:20]SC>C1COCC1>[CH3:19][S:20][C:13]1[N:9]([C:6]2[CH:5]=[CH:4][C:3]([CH:1]=[CH2:2])=[CH:8][CH:7]=2)[N:10]=[CH:11][N:12]=1
Reactant: C=Cc1ccc(-n2cncn2)cc1
Reactant: CSSC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=Cc1ccc(-n2ncnc2SC)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 1-(4-vinyl-phenyl)-1H-[1,2,4]triazole (1 g, 5.8 mmol) in 50 mL of THF, was added n-BuLi (0.41 g, 6.4 mmol) at −78° C. and stirred for 30 min To this dimethyldisulfide in THF (0.6 g, 6.43 mmol) was added and the resultant reaction mixture was stirred at ambient temperature for 16 h. The reaction mixture was quenched with a saturated aqueous NH4Cl solution and extracted with EtOAc (3×25 mL). The combined EtOAc layer was washed with brine and dried over sodium sulphate and concentrated under reduced pressure. The crude compound was purified by flash chromatography (SiO2, 100-200 mesh, 40% EtOAc in Pet ether) to afford the title compound as an off white solid (0.6 g, 48%): mp 68-70° C.; 1H NMR (400 MHz, CDCl3) δ 7.96 (s, 1H), 7.05 (m, 4H), 6.75 (dd, J=16.4, 10.7 Hz, 1H), 5.81 (d, J=16.4 Hz, 1H), 5.35 (d, J=10.7 Hz, 1H), 2.73 (s, 3H); ESIMS m/z 218.09 ([M+H]+).
Reaction SMILES: C([O:3][C:4](=[O:54])[C@@H:5]([O:51][CH2:52][CH3:53])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14]/[CH:15]=[C:16](/[C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27](/[C:30](/[CH3:50])=[CH:31]/[CH2:32][O:33][C:34]4[CH:39]=[CH:38][C:37]([CH2:40][C@H:41]([O:47][CH2:48][CH3:49])[C:42]([O:44]CC)=[O:43])=[CH:36][CH:35]=4)=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)\[CH3:17])=[CH:9][CH:8]=1)C.[OH-].[Na+]>C(O)C.O.C(OCC)(=O)C>[C:42]([C@@H:41]([O:47][CH2:48][CH3:49])[CH2:40][C:37]1[CH:36]=[CH:35][C:34]([O:33][CH2:32]/[CH:31]=[C:30](/[C:27]2[CH:28]=[CH:29][C:24]([C:21]3[CH:22]=[CH:23][C:18](/[C:16](/[CH3:17])=[CH:15]/[CH2:14][O:13][C:10]4[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:51][CH2:52][CH3:53])[C:4]([OH:54])=[O:3])=[CH:12][CH:11]=4)=[CH:19][CH:20]=3)=[CH:25][CH:26]=2)\[CH3:50])=[CH:39][CH:38]=1)([OH:44])=[O:43]
Reactant: CCOC(=O)[C@H](Cc1ccc(OC/C=C(\C)c2ccc(-c3ccc(/C(C)=C/COc4ccc(C[C@H](OCC)C(=O)OCC)cc4)cc3)cc2)cc1)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: CCO[C@@H](Cc1ccc(OC/C=C(\C)c2ccc(-c3ccc(/C(C)=C/COc4ccc(C[C@H](OCC)C(=O)O)cc4)cc3)cc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 53 %

Procedure:
To a solution of (E)(E)(S)(S) 2-ethoxy-3-{4-[3-(4′-{3-[4-(2-ethoxy-2-ethoxycarbonyl-ethyl)-phenoxy]-1-methyl-propenyl}-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-propionic acid ethyl ester (example 11) (367 mg 0.5 mmol) in ethanol (10 mL) was added 1N sodium hydroxide (2 mL). The reaction mixture was stirred at room temperature for 18 h, and at 60° C. 1 h. The resulting mixture was diluted with water and ethyl acetate, the aqueous layer collected and further extracted with ethyl acetate (3×). The organic layers were combined, washed with brine, dried (MgSO4) and evaporated to give 180 mg (53%) of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][CH:3]=1.[CH3:12][C:13]1[CH:14]=[C:15]([CH:19]=O)[O:16][C:17]=1[CH3:18]>C(O)(=O)C.CCO>[CH3:12][C:13]1[CH:14]=[C:15]([CH:19]=[N:9][NH:8][C:6](=[O:7])[C:5]2[CH:10]=[CH:11][C:2]([OH:1])=[CH:3][CH:4]=2)[O:16][C:17]=1[CH3:18]
Reactant: Cc1cc(C=O)oc1C
Reactant: NNC(=O)c1ccc(O)cc1
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1cc(C=NNC(=O)c2ccc(O)cc2)oc1C
Temperature: 25 °C
Yield: 91 %

Procedure:
To a solution of 4-hydroxy-benzoic acid hydrazide (0.3 g, 0.002 mol) and 4,5-dimethyl-2-furaldehyde (0.25 g, 0.002 mol) in abs. EtOH (10 mL), was added 1 drop of acetic acid. The reaction mixture was refluxed for 5 hours. The reaction mixture was cooling to room temperature and concentrated to remove solvent. The resulting residue was solidified by EtOAc to give red solid 0.47 g, in 90% yield, mp: 251.4° C. 1H NMR (DMSO-d6) δ 11.46 (s, 1H), 10.09 (s, 1H), 8.18 (s, 1H), 7.79 (d, 2H), 6.86 (d, 2H), 6.69 (s, 1H), 2.27 (s, 3H), 1.96 (s, 3H). 13C NMR (DMSO-d6) δ 163.1, 161.0, 150.3, 147.2, 137.0, 130.0, 124.4, 117.4, 116.9, 115.4, 11.8, 9.9. Anal. Calcd for C14H14N2O3 H2O: C, 60.82; H, 5.11; N, 10.13. Found: C, 60.80; H, 5.03; N, 9.48.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([CH2:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16](O)=[O:17])=[N:9][NH:8][C:7]2=[O:22].[CH3:23][O:24][CH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.C(N(C(C)C)C(C)C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([CH2:12][C:13]1[CH:21]=[CH:20][CH:19]=[C:15]([C:16]([N:28]3[CH2:29][CH2:30][CH:25]([O:24][CH3:23])[CH2:26][CH2:27]3)=[O:17])[CH:14]=1)=[N:9][NH:8][C:7]2=[O:22]
Reactant: O=C(O)c1cccc(Cc2n[nH]c(=O)c3cccc(Cl)c23)c1
Reactant: COC1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[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: COC1CCN(C(=O)c2cccc(Cc3n[nH]c(=O)c4cccc(Cl)c34)c2)CC1
Temperature: 0 °C
Reaction time: 4 h
Yield: 23.6 %

Procedure:
3-((8-chloro-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid (118) (200 mg, 0.64 mmol) and 4-methoxypiperidine (73.2 mg, 0.64 mmol) were added to DMF (5 mL), to this was added N-ethyl-N-isopropylpropan-2-amine (0.170 mL, 0.95 mmol) and then HBTU (362 mg, 0.95 mmol). The reaction mixture was stirred for four hours at 0° C. The crude mixture was purified by preparative LCMS (Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the desired material as a white crystalline solid (62.2 mg, 23.76% yield); 1H NMR (400.132 MHz, CDCl3) δ 1.62-2.00 (3H, m), 3.02-3.29 (2H, m), 3.35 (3H, s), 3.37-3.65 (3H, m), 3.87-4.08 (1H, m), 4.69 (2H, s), 7.15-7.24 (3H, m), 7.29-7.34 (1H, m), 7.65 (1H, t), 7.77-7.81 (1H, m), 8.48 (1H, m), 9.85-10.01 (1H, m); m/z (LC-MS, ESI+), RT=1.80 (M+H 412.1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7](Cl)[C:6]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=1)=[C:5]2[Cl:24].C1(C)C=CC=CC=1.[CH3:32][O-:33].[Na+].[Al]>CCCCCC.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:33][CH3:32])[C:6]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=1)=[C:5]2[Cl:24]
Reactant: C[O-]
Reactant: FC(F)(F)c1ccc(Cc2c(Cl)nc3ccc(Br)cc3c2Cl)cc1
Agent: [Al]
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: COc1nc2ccc(Br)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Temperature: 80 °C

Procedure:
To a 1 L flask containing 6-bromo-2,4-dichloro-3-(4-(trifluoromethyl)benzyl)quinoline (32.5 g, 74.7 mmol, Intermediate 5: step c) was added toluene (550 mL) followed by solid sodium methoxide (40 g, 740 mmol, 97% purity) at room temperature. The suspension was stirred at reflux (˜118° C.) in an aluminum mantle. TLC (50% hexane-DCM) and HPLC after 5.5 hours showed the reaction to be complete. The reaction mixture was filtered through Celite® while still warm (˜80° C.) and rinsed with warm toluene (˜70° C., 500 mL). The colorless filtrate was concentrated which then solidified to afford the title compound as an off white solid.
Reaction SMILES: [C:1]([CH2:6][C:7]([NH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:8])([O:3][CH2:4][CH3:5])=[O:2].[CH:15](OCC)(OCC)[O:16][CH2:17][CH3:18]>C(OC(=O)C)(=O)C>[C:1]([C:6](=[CH:15][O:16][CH2:17][CH3:18])[C:7]([NH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:8])([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)CC(=O)NC(=O)OCC
Reactant: CCOC(OCC)OCC
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C(=O)NC(=O)OCC)C(=O)OCC

Procedure:
Following the procedure of Example 1, N-(2-carbethoxyacetyl)urethane is reacted with triethyl orthoformate in acetic anhydride to give α-carbethoxy-β-ethoxy-N-ethoxycarbonylacrylamide. This is reacted with 2,4,6-trichlorophenylhydrazine, giving α-carbethoxy-β-(2,4,6-trichlorophenylhydrazino)-N-ethoxycarbonylacrylamide which is cyclized to yield 5-carbethoxy-1-(2,4,6-trichloroanilino)-2,4-pyrimidinedione.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20](Cl)[CH:21]=[C:16]3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][S:25]([N:28]1[CH2:33][CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH2:30][CH2:29]1)(=[O:27])=[O:26]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20]([C:31]4[CH2:32][CH2:33][N:28]([S:25]([CH3:24])(=[O:27])=[O:26])[CH2:29][CH:30]=4)[CH:21]=[C:16]3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(C)OB(C2=CCN(S(C)(=O)=O)CC2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc3cc(Cl)ncc3o2)CC1
Product: CC(C)(C)OC(=O)N1CCC(c2cc3cc(C4=CCN(S(C)(=O)=O)CC4)ncc3o2)CC1

Procedure:
The title compound is prepared from 4-(5-chloro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acid tert-butyl ester and 1-methanesulfonyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,2,3,6-tetrahydro-pyridine following a procedure analogous to that described for Example 1; the reaction is conducted at 150° C. LC (method 1): tR=1.27 min; Mass spectrum (ESI+): m/z=462 [M+H]+.