Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[CH2:13][C@H:12]([OH:14])[CH:11]=[CH:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H][H]>CO>[Si:1]([O:8][C@@H:9]1[CH2:10][CH2:11][C@H:12]([OH:14])[CH2:13]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1C=C[C@@H](O)C1
Reactant: [H][H]
Solvent: CO
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CC[C@H](O)C1
Reaction time: 18.5 h
Yield: 92 %

Procedure:
Combine (+/-)-cis-4-tert-butyldimethylsilyloxy-2-cyclopentenol (2.50 g, 11.6 mmol, prepared in example 3) and Ni2B (8.5 mL of a 0.14M slurry in methanol, 10 mol %) in methanol (14 mL). Stir the slurry under an atmosphere of hydrogen for 18.5 hours. Then replace the hydrogen atmosphere with nitrogen, filter through diatomaceous earth and rinse the solids with methanol (50 mL). Concentrate the filtrate under vacuum (15 mmHg/40° C.) and purify the residue by Kugelrohr distillation (0.6 mmHg/60°-65° C.) to provide the title compound as a colorless oil (2.31 g, 92%).
Reaction SMILES: [O:1]=[C:2]1[NH:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][NH2:9].[C:10]([C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([CH2:21][CH2:22][NH:23][C:24](=[O:38])[C:25]3[CH:30]=[CH:29][C:28]([C:31]4[CH:36]=[CH:35][N:34]=[C:33](Cl)[N:32]=4)=[CH:27][CH:26]=3)[CH:19]=2)[NH:14][CH:13]=1)#[N:11]>>[C:10]([C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([CH2:21][CH2:22][NH:23][C:24](=[O:38])[C:25]3[CH:30]=[CH:29][C:28]([C:31]4[CH:36]=[CH:35][N:34]=[C:33]([NH:9][CH2:8][CH2:7][N:3]5[CH2:4][CH2:5][NH:6][C:2]5=[O:1])[N:32]=4)=[CH:27][CH:26]=3)[CH:19]=2)[NH:14][CH:13]=1)#[N:11]
Reactant: NCCN1CCNC1=O
Reactant: N#Cc1c[nH]c2ccc(CCNC(=O)c3ccc(-c4ccnc(Cl)n4)cc3)cc12
Product: N#Cc1c[nH]c2ccc(CCNC(=O)c3ccc(-c4ccnc(NCCN5CCNC5=O)n4)cc3)cc12

Procedure:
Using 2-(2-oxo-imidazolidin-1-yl)-ethylamine and N-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-chloro-pyrimidin-4-yl]-benzamide (reference example 1az) as substrates. 1H NMR (DMSO) δ 2.96 (bt, 2H); 3.24 (m, 4H); 3.47 (m, 6H); 6.26 (s, 1H); 7.18 (m, 2H); 7.27 (bt, 1H, J=5 Hz); 7.48 (m, 2H); 7.91 (d, 2H, J=9 Hz); 8.19 (m, 3H); 8.36 (bd, 1H); 8.67 (t, 1H, J=5 Hz); 12.10 (bs, 1H). MS (ion spray) m/z 495 (M+H)+.
Reaction SMILES: [C:1]1([C:7]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:8][CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li+].C[Si]([N-:35][Si](C)(C)C)(C)C>O1CCCC1>[C:24]1([C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:8][CH2:9][N:10]2[CH2:11][CH2:12][N:13]([C:16]3[CH:17]=[CH:18][C:19]([C:20](=[NH:35])[NH2:21])=[CH:22][CH:23]=3)[CH2:14][CH2:15]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: N#Cc1ccc(N2CCN(CC=C(c3ccccc3)c3ccccc3)CC2)cc1
Agent: [Li+]
Solvent: C1CCOC1
Product: N=C(N)c1ccc(N2CCN(CC=C(c3ccccc3)c3ccccc3)CC2)cc1
Reaction time: 16 h
Yield: 83.4 %

Procedure:
A solution of EXAMPLE 12A (0.515 g, 1.36 mmol) in dry tetrahydrofuran (6 mL) was treated dropwise with LiHMDS (1M, 6.8 mL, 6.8 mmol), stirred for 16 hours, quenched with 1N HCl (8 mL), and filtered. The filter cake was collected to provide the desired product (0.45 g, 71%) that was used without further purification. MS (CI) m/e 397 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([N:13]3[CH2:18][CH2:17][S:16](=[O:20])(=[O:19])[CH2:15][CH2:14]3)=[O:12])[NH:8]2)=[CH:4][C:3]=1[O:21][CH:22]1[CH2:27][CH2:26][N:25]([CH:28]([CH3:30])[CH3:29])[CH2:24][CH2:23]1.Br[CH2:32][CH2:33][O:34][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36]>>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([N:13]3[CH2:18][CH2:17][S:16](=[O:20])(=[O:19])[CH2:15][CH2:14]3)=[O:12])[N:8]2[CH2:32][CH2:33][O:34][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36])=[CH:4][C:3]=1[O:21][CH:22]1[CH2:27][CH2:26][N:25]([CH:28]([CH3:30])[CH3:29])[CH2:24][CH2:23]1
Reactant: CC(C)N1CCC(Oc2cc3cc(C(=O)N4CCS(=O)(=O)CC4)[nH]c3cc2Br)CC1
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Product: CC(C)N1CCC(Oc2cc3cc(C(=O)N4CCS(=O)(=O)CC4)n(CCO[Si](C)(C)C(C)(C)C)c3cc2Br)CC1

Procedure:
In analogy to the procedure described for the synthesis of example 1, step 1, the title compound was synthesized from [6-bromo-5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-(1,1-dioxo-1λ6-thiomorpholin-4-yl)-methanone (Example 6, step 4) and (2-bromoethoxy)-tert-butyldimethylsilane. The desired product was obtained in a yield of 50% as colorless oil. MS (m/e): 656.4 (M+H, 50%).
Reaction SMILES: C(O[C:4](=[C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=2)[NH:13][C:12]1=[O:23])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)C.[CH3:24][N:25]([CH3:36])[CH2:26][C:27]#[C:28][C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=1>>[CH3:36][N:25]([CH3:24])[CH2:26][C:27]#[C:28][C:29]1[CH:30]=[CH:31][C:32]([NH:33]/[C:4](=[C:11]2\[C:12](=[O:23])[NH:13][C:14]3[C:19]\2=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=3)/[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[CH:34][CH:35]=1
Reactant: CN(C)CC#Cc1ccc(N)cc1
Reactant: CCOC(=C1C(=O)Nc2ccc([N+](=O)[O-])cc21)c1ccccc1
Product: CN(C)CC#Cc1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 89 by reacting 3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone with 4-(3-dimethylaminoprop-1-ynyl)-aniline.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH2:12][CH2:13][C:14]3[CH:15]=[C:16]([CH:20]([S:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])[S:21][CH2:22][CH2:23][C:24](O)=[O:25])[CH:17]=[CH:18][CH:19]=3)=[N:9]2)=[CH:4][CH:3]=1.[I-].Cl[C:35]1C=CC=[CH:37][N+:36]=1C.CNC.C(O)(=O)C>ClCCl.C(#N)C.C(N(CC)CC)C.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH2:12][CH2:13][C:14]3[CH:15]=[C:16]([CH:20]([S:21][CH2:22][CH2:23][C:24](=[O:25])[N:36]([CH3:37])[CH3:35])[S:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])[CH:17]=[CH:18][CH:19]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: C[n+]1ccccc1Cl
Reactant: O=C(O)CCSC(SCCC(=O)O)c1cccc(CCc2ccc3ccc(Cl)cc3n2)c1
Agent: CNC
Agent: [I-]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)C(=O)CCSC(SCCC(=O)O)c1cccc(CCc2ccc3ccc(Cl)cc3n2)c1
Reaction time: 0.5 h

Procedure:
To a suspension of diacid (Example 25) (0.3 g) in dichloromethane (20 mL), acetonitrile (5 mL) and triethylamine (200 μL) was added 2-chloro-1-methylpyridinium iodide (180 mg). The mixture was stirred 30 min, cooled to 0° and 0.32 mL of a 2M solution of dimethylamine in toluene was added. The reaction was stirred 2 hours at room temperature. The reaction mixture was poured onto NH4OAc buffer and acetic acid (5 mL) was added. The mixture was extracted with ethyl acetate, which was dried over sodium sulfate and evaporated. Purification of the residue by flash chromatography starting with 15% and finishing with 30% of THF in toluene containing 1% of acetic acid afforded the title compound.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[Br:7][C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][C:9]=1[CH3:16].O.[OH-].[Na+]>C(OCC)C>[Br:7][C:8]1[CH:15]=[CH:14][C:11]([CH2:12][NH2:13])=[CH:10][C:9]=1[CH3:16]
Reactant: Cc1cc(C#N)ccc1Br
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: Cc1cc(CN)ccc1Br
Temperature: 0 °C

Procedure:
LiAlH4 (0.68 g) in diethyl ether (30 mL) was treated with 4-bromo-3-methylbenzonitrile (15 mmol) and refluxed for 2 hours. The mixture was cooled to 0° C. and treated in succession with water (0.7 mL), 20% NaOH (0.5 mL), and water (2.5 mL). The mixture was filtered through a celite pad and the filter cake was washed several times with diethyl ether. The filtrate was dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to provide the title compound. MS (ESI+) m/z 194 (M+H)+; MS (ESI−) m/z 192 (M−H)−; 1H NMR (DMSO, 300 MHz) δ 3.97 (s, 2H), 7.30 (m, 1H), 7.46 (m, 2H).
Reaction SMILES: C([O:3][C:4](=[O:44])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:42])[CH:17]([C:24]2[N:25]([C:35]3[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=3)[N:26]=[C:27]3[C:32]=2[CH:31]=[C:30]([F:33])[C:29]([F:34])=[CH:28]3)[CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[C:11]([F:43])[CH:10]=1)([CH3:7])[CH3:6])C.[OH-].[Li+]>C1COCC1.CO>[Cl:41][C:38]1[CH:39]=[CH:40][C:35]([N:25]2[C:24]([CH:17]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[C:16]([NH:15][C:12]3[CH:13]=[CH:14][C:9]([O:8][C:5]([CH3:7])([CH3:6])[C:4]([OH:44])=[O:3])=[CH:10][C:11]=3[F:43])=[O:42])=[C:32]3[C:27]([CH:28]=[C:29]([F:34])[C:30]([F:33])=[CH:31]3)=[N:26]2)=[CH:36][CH:37]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(NC(=O)C(c2c3cc(F)c(F)cc3nn2-c2ccc(Cl)cc2)C2CCCCC2)c(F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(Oc1ccc(NC(=O)C(c2c3cc(F)c(F)cc3nn2-c2ccc(Cl)cc2)C2CCCCC2)c(F)c1)C(=O)O

Procedure:
In analogy to the procedure described in example 7.2, [rac]-2-(4-{2-[2-(4-chloro-phenyl)-5,6-difluoro-2H-indazol-3-yl]-2-cyclohexyl-acetylamino}-3-fluoro-phenoxy)-2-methyl-propionic acid ethyl ester was treated with 1 N aqueous lithium hydroxide solution in THF and MeOH to give the title compound as red solid. MS: m/e=600.2 [M+H+].
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([OH:9])=[O:8].B(O)(O)[C:11]1[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=1>>[C:14]1([CH3:17])[CH:15]=[CH:16][C:11]([C:2]2[CH:6]=[CH:5][S:4][C:3]=2[C:7]([OH:9])=[O:8])=[CH:12][CH:13]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: O=C(O)c1sccc1Br
Product: Cc1ccc(-c2ccsc2C(=O)O)cc1

Procedure:
prepared by reaction of 3-bromo-thiophene-2-carboxylic acid with p-tolylboronic acid. LC-MS (basic): tR=0.50 min; [M−H]−=217.2.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([S:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[CH3:23][NH:24][CH2:25][CH2:26][OH:27]>>[Br:1][C:2]1[C:3]([N:24]([CH2:25][CH2:26][OH:27])[CH3:23])=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([S:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8]
Reactant: O=C(Nc1ccc(SC(F)(F)F)cc1)c1cnc(Cl)c(Br)c1
Reactant: CNCCO
Product: CN(CCO)c1ncc(C(=O)Nc2ccc(SC(F)(F)F)cc2)cc1Br

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 33.1 using 5-bromo-6-chloro-N-(4-((trifluoromethyl)thio)phenyl)nicotinamide (Stage 185.2) and 2-methylamino-ethanol to afford an off-white crystalline solid. HPLC (Condition 4) tR=5.97 min, UPLC-MS (Condition 3) tR=1.18 min, m/z=450.2 [M+H]+.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C@@H:9]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]2[S:25](=[O:27])(=[O:26])[NH:24][C:23](=[O:28])[CH2:22]2)=[C:17]([Cl:29])[CH:16]=1)[C:10]([O:12]C)=[O:11].C(N(CC)CC)C.[C:37]1([S:43](Cl)(=[O:45])=[O:44])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.[OH-].[Li+].Cl>FC(F)(F)C(O)=O.CO>[Cl:29][C:17]1[CH:16]=[C:15]([CH2:14][C@H:9]([NH:8][S:43]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)(=[O:45])=[O:44])[C:10]([OH:12])=[O:11])[CH:20]=[CH:19][C:18]=1[CH:21]1[S:25](=[O:27])(=[O:26])[NH:24][C:23](=[O:28])[CH2:22]1
Reactant: COC(=O)[C@@H](N)Cc1ccc(C2CC(=O)NS2(=O)=O)c(Cl)c1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC(c2ccc(C[C@H](NS(=O)(=O)c3ccccc3)C(=O)O)cc2Cl)S(=O)(=O)N1
Temperature: 130 °C
Reaction time: 1 h
Yield: 72.7 %

Procedure:
Methyl (2S)-2-amino-3-[3-chloro-4-(1,1-dioxido-3-oxoisothiazolidin-5-yl)-phenyl]-propanoate trifluoroacetate (145 mg, 0.314 mmol) was dissolved in trifluoroacetic acid (3 mL) and heated in the microwave at 130° C. for 180 s. The reaction was concentrated in vacuo and azetroped with toluene (5 mL). The product was dissolved in methanol (2 mL), was treated with triethylamine (170 μL, 1.2 mmol) and then benzenesulfonyl chloride (60 μL, 0.47 mmol). The solution stirred at rt for 1 h. 4 M aqueous lithium hydroxide solution (0.782 mL) was added and the solution stirred 3 h at rt. The solution was acidified with aqueous hydrochloric acid solution (1.0 N, 4.0 mL), diluted with methanol to 10 mL volume, and then purified by reverse phase HPLC to afford product as a white solid (108 mg, 73%). 1H NMR (400 MHz, CD3OD): δ 7.66–7.64 (m, 2H), 7.63–7.51 (m, 1H), 7.44–7.38 (m, 3H), 7.31–7.16 (m, 2H), 5.65–5.61 (m, 1H), 4.10–4.03 (m, 1H), 3.48–3.42 (m, 1H), 3.29–3.27 (m, 1H), 3.12–3.07 (m, 1H), 2.88–2.81 (m, 1H); LCMS found for C18H21ClN3O7S2 (M+H)+: m/z=490.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].C([CH:10]1[CH2:15][CH:14]2[O:16]C1C=C2)(OC)=O.Cl.C(Cl)Cl>O>[CH2:1]([N:3]([CH2:4][CH3:5])[C:14](=[O:16])[CH:15]=[CH2:10])[CH3:2]
Reactant: CCNCC
Reactant: COC(=O)C1CC2C=CC1O2
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: C=CC(=O)N(CC)CC
Temperature: 140 °C
Reaction time: 15 h

Procedure:
7.2 parts 30% methanolic Na-methylate solution are added to 36.5 parts diethylamine. 77 parts 2-carbomethoxy-7-oxabicyclo(2,2,1)hept-5-ene are added drop-wise at 40° C. The reaction medium is then stirred for 15 hours at this temperature and neutralised with 4 parts concentrated hydrochloric acid. 100 parts methylene chloride and 50 parts water are added, the organic phase separated off, and the aqueous phase extracted 3 times with 25 parts methylene chloride in each instance. The combined organic phases are reduced in a rotary evaporator at a bath temperature of 90° C. and under a vacuum of 20 Torr. The residue is heated under a vacuum of 20 Torr to 110° to 120° C. (bath temperature 140° C.). On conclusion of the furane separation, the sedimentation temperature increases and the product distills over at the now lowered pressure. 21 parts N,N-diethylacrylamide with a boiling point of 55° C. at 1 Torr are obtained.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[C:11]3[CH2:21][CH2:20][NH:19][CH2:18][C:12]=3[N:13]=[C:14]([S:16][CH3:17])[N:15]=2)=[CH:5][CH:4]=1.Cl[C:25]1[C:30]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:29][CH:28]=[CH:27][N:26]=1.C(N(CC)C(C)C)(C)C>O1CCOCC1.CC(N(C)C)=O>[F:23][C:2]([F:22])([F:1])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[C:11]3[CH2:21][CH2:20][N:19]([C:25]4[C:30]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:29][CH:28]=[CH:27][N:26]=4)[CH2:18][C:12]=3[N:13]=[C:14]([S:16][CH3:17])[N:15]=2)=[CH:5][CH:4]=1
Reactant: CSc1nc2c(c(Nc3ccc(C(F)(F)F)cc3)n1)CCNC2
Reactant: CS(=O)(=O)c1cccnc1Cl
Solvent: CC(=O)N(C)C
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CSc1nc2c(c(Nc3ccc(C(F)(F)F)cc3)n1)CCN(c1ncccc1S(C)(=O)=O)C2
Temperature: 150 °C
Yield: 52.2 %

Procedure:
N-(4-(Trifluoromethyl)phenyl)-5,6,7,8-tetrahydro-2-(methylthio)pyrido[3,4-d]pyrimidin-4-amine (320 mg, 0.00089 mol) and 2-chloro-3-(methylsulfonyl)pyridine (200.0 mg, 0.0009915 mol) were dissolved in dioxane (5 mL) and DMA (0.5 mL), N,N-diisopropylethylamine (0.17 g, 0.0013 mol) was added and the mixture was heated in a sealed tube via microwave at 150° C. for 30 min. Solvent was removed and the residue was purified by flash chromatography over silica gel to obtain the product as a white solid (230 mg).
Reaction SMILES: [Cl:1][C:2]1[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][C:3]=1[O:4][CH2:5][CH2:6][C:7]([OH:9])=O.F>>[Cl:14][C:13]1[C:2]([Cl:1])=[C:3]2[C:10]([C:7](=[O:9])[CH2:6][CH2:5][O:4]2)=[CH:11][CH:12]=1
Reactant: O=C(O)CCOc1cccc(Cl)c1Cl
Agent: F
Product: O=C1CCOc2c1ccc(Cl)c2Cl
Reaction time: 8 h

Procedure:
500 mg of 3-(2,3-dichlorophenoxy)propionic acid, is stirred in 50 ml. of liquid hydrogen fluoride surrounded by a solid carbon dioxide/acetone bath. This slurry is allowed to stir overnight without replenishing the cooling bath. The hydrogen fluoride is removed by a stream of air. The residual solid was then dissolved in ether and washed with 10% aqueous sodium carbonate solution. The organic layer is dried over anhydrous magnesium sulphate and the solvent is evaporated to give the required chromanone with sufficient purity.
Reaction SMILES: [NH2:1][C:2]([NH:4][C:5]1[NH:6][C:7]2[C:12]([C:13]=1[C:14]([NH2:16])=[O:15])=[CH:11][CH:10]=[C:9](Br)[CH:8]=2)=[O:3].C(=O)([O-])[O-].[K+].[K+].[C:24]1([C:30]#[CH:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O.O1CCOCC1.[Cl-].[Na+].O.[Cu]I.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>[NH2:1][C:2]([NH:4][C:5]1[NH:6][C:7]2[C:12]([C:13]=1[C:14]([NH2:16])=[O:15])=[CH:11][CH:10]=[C:9]([C:31]#[C:30][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH:8]=2)=[O:3]
Reactant: NC(=O)Nc1[nH]c2cc(Br)ccc2c1C(N)=O
Reactant: C#Cc1ccccc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: NC(=O)Nc1[nH]c2cc(C#Cc3ccccc3)ccc2c1C(N)=O
Temperature: 100 °C
Reaction time: 3.5 h
Yield: 42.5 %

Procedure:
A solution mixture of 2-aminocarbonylamino-6-bromoindole-3-carboxamide (Compound 3-1, 50 mg, 0.17 mmol), potassium carbonate (36 mg, 0.26 mmol), copper (I) iodide (3.0 mg, 0.017 mmol), phenylacetylene (22 μL, 0.20 mmol) and tetrakis(triphenylphosphine)palladium (0) (20 mg, 0.017 mmol) in water-1,4-dioxane (1:3, 5 mL) was stirred at 100° C. for 3.5 hours. Brine (5 mL) was added to the reaction mixture, and the whole was extracted with ethyl acetate (5 mL). The organic layer was dried over anhydrous magnesium sulfate and was filtered throught Celite® pad. After the solvent was evaporated under reduced pressure, the resultant solid was washed with a solution mixture of ethanol and chloroform (ethanol/chloroform=1/2, 3 mL), and dried under reduced pressure to give the title compound (23 mg) as a slightly brown solid (yield 43%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12](Cl)=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[Cl:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29][Zn+]>O1CCCC1.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>[CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12]([CH2:29][C:28]2[CH:31]=[CH:32][CH:33]=[C:26]([Cl:25])[CH:27]=2)=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Reactant: Clc1cccc(C[Zn+])c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: C1CCOC1
Product: Clc1cccc(Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)c1
Temperature: 60 °C
Reaction time: 17 h
Yield: 23 %

Procedure:
To a stirred solution of 3,4-bis(benzyloxy)-6-chloropyridazine (Intermediate 1) (1 g, 3.1 mmol) in dry tetrahydrofuran (12.2 ml) was added tetrakis(triphenylphosphine)palladium(0) (0.18 g, 0.153 mmol) and (3-chlorobenzyl)zinc(II) chloride (9.2 ml of a 0.5 M solution in tetrahydrofuran, 4.6 mmol). The reaction was stirred at 60° C. for 17 hours and then partitioned between ethyl acetate and water. The organic extracts were washed with water and brine and then dried, filtered and concentrated to give a yellow oil. The oil was purified using 0-70% ethyl acetate in petrol to afford the title compound (310 mg, 23%).
Reaction SMILES: [C:1]1([NH:7][C:8](=[O:18])[CH:9]=[CH:10][S:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:19]([O+](CC)CC)[CH3:20].F[B-](F)(F)F.[H+].ClCCl>C(Cl)(Cl)Cl>[C:1]1([N:7]=[C:8]([O:18][CH2:19][CH3:20])[CH:9]=[CH:10][S:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(C=CSc1ccccc1)Nc1ccccc1
Reactant: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CCOC(C=CSc1ccccc1)=Nc1ccccc1
Temperature: 50 °C
Reaction time: 5 h

Procedure:
N-phenyl-3-(phenylthio)acrylamide (2.0 g) was dissolved to chloroform (10 ml), and 7.8 ml of tetrafluoroboric acid triethyloxonium-dichloromethane 1 mol/L solution was added thereto dropwise under ice-cooling. It was stirred for one hour at room temperature, 50° C. for two hours and for five hours under heat refluxing. After cooling, ice-water was added to the reaction solution, then the chloroform layer was separated. The chloroform layer was washed with water, dried and distilled off the solvent. The residue was subjected to silica gel column chromatography (hexane/ethyl acetate=15/1) to obtain ethyl N-phenyl-3-(phenylthio)acrylimidate (0.15 g) as oil.
Reaction SMILES: [C:1]1([C:7]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[NH:11][C:10]([NH2:12])=[N:9][C:8]2=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[C:22]=1[N:28]=[C:29]=[O:30].O>CN(C=O)C>[CH3:27][C:23]1[CH:24]=[CH:25][CH:26]=[C:21]([CH3:20])[C:22]=1[NH:28][C:29]([N:12]=[C:10]1[NH:9][C:8](=[O:13])[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:11]1)=[O:30]
Reactant: NC1=NC(=O)C(c2ccccc2)(c2ccccc2)N1
Reactant: Cc1cccc(C)c1N=C=O
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cccc(C)c1NC(=O)N=C1NC(=O)C(c2ccccc2)(c2ccccc2)N1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
A suspension of 6.95 g (0.0306 mole) of 5,5-diphenyl-2-amino-2-imidazoline-4-one in 300 ml of dry DMF is treated with 4.5 g (0.0306 mole) of 2,6-dimethylphenylisocyanate. The reaction mixture is stirred at 40° C. for two hours. It is then poured into cold water and the resulting solids are filtered off. To the crude product is added 30 ml of water with heating; acetone is added to the heated slurry until all solids go in solution (1.5 liters of acetone). The solution is then evaporated to a volume of 300 ml., chilled, and the resulting solids are filtered off to give 1-(2,6-dimethylphenyl)-3-(5,5-diphenyl-4-oxo-2-imidazolidinylidene) urea, the pure product; no m.p. up to 350° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][N:10]=[C:9](O)[C:8]=2[CH:13]=1)([O-:3])=[O:2].P(Cl)(Cl)([Cl:16])=O>>[Cl:16][C:9]1[C:8]2[CH:13]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]=2[O:11][N:10]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=[N+]([O-])c1ccc2onc(O)c2c1
Product: O=[N+]([O-])c1ccc2onc(Cl)c2c1
Temperature: 152.5 °C

Procedure:
A mixture of 5-nitro-1,2-benzisoxazol-3-ol (4.00 g, 0.0220 mol) and phosphorus oxychloride (40.0 mL, 65.8 g, 0.429 mol) is placed in a glass bomb, heated at 150-155° C. for two hours, cooled overnight, concentrated in vacuo, diluted with methylene chloride, and brought to about pH 8 with sodium hydrogen carbonate solution. The phases are separated. The organic phase is washed sequentially with water and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain a residue. Column chromatography of the residue using silica gel and a methylene chloride/hexanes solution (1:1) gives the title product as an amber oil which is identified by NMR spectral analysis.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[C:12]([NH:14][CH2:15][CH:16]([CH3:18])[CH3:17])[C:11]([Cl:19])=[CH:10][C:9]=1[NH2:20])([CH3:4])([CH3:3])[CH3:2].C([O:26][C:27](=O)[CH2:28][C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[CH:42]=[CH:41][N:40]=[C:39]([CH3:43])[CH:38]=2)[CH:32]=1)=[O:30])(C)(C)C>>[C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[C:12]([NH:14][CH2:15][CH:16]([CH3:17])[CH3:18])[C:11]([Cl:19])=[CH:10][C:9]=1[NH:20][C:27](=[O:26])[CH2:28][C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[CH:42]=[CH:41][N:40]=[C:39]([CH3:43])[CH:38]=2)[CH:32]=1)=[O:30])([CH3:3])([CH3:2])[CH3:4]
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)ccn1
Reactant: CC(C)CNc1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Product: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(Cl)c(NCC(C)C)cc3NC(=O)OC(C)(C)C)c2)ccn1

Procedure:
The title compound was prepared from (2-amino-4-chloro-5-isobutylamino-phenyl)-carbamic acid tert-butyl ester (Example J16) (314 mg, 1.0 mmol) and 3-[3-(2-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K12) (311 mg, 1.0 mmol) according to the general procedure M. Obtained as a yellow foam (480 mg, 87%).