Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[OH:12][C:13]1[CH:18]=[CH:17][C:16]([SH:19])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl>CN(C)C=O>[OH:12][C:13]1[CH:18]=[CH:17][C:16]([S:19][C:2]2[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=2[N+:9]([O-:11])=[O:10])=[CH:15][CH:14]=1
Reactant: Oc1ccc(S)cc1
Reactant: O=[N+]([O-])c1cc(O)ccc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(O)ccc1Sc1ccc(O)cc1
Temperature: 25 °C
Yield: 44.5 %

Procedure:
A solution of 4-Chloro-3-nitro-phenol (2.0 g, 11.52 mmol), 4-hydroxythiophenol (1.45 g, 11.52 mmol) and cesium carbonate (11.26 g, 34.56 mmol) in N,N-dimethylformamide (25 mL) was heated to 100° C. for 4 hours. After cooling to room temperature, 1N aqueous Hydrochloric acid (150 mL) was added and the resultant solution extracted with ethyl acetate (2×100 mL), the combined extracts dried over magnesium sulfate, filtered and concentrated under vacuum to provide the crude title compound which was purified by chromatography on silica gel using hexanes/ethyl acetate as eluent to obtain the title product as a bright orange solid (1.35 g, 45%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1/[C:9](/[CH2:37][CH3:38])=[C:10](\[C:26]1[CH:31]=[CH:30][C:29](/[CH:32]=[CH:33]/[C:34]([OH:36])=O)=[CH:28][CH:27]=1)/[C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][O:21]1)[N:15]=[CH:14]2.C(Cl)(=O)C([Cl:42])=O>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1/[C:9](/[CH2:37][CH3:38])=[C:10](\[C:26]1[CH:27]=[CH:28][C:29](/[CH:32]=[CH:33]/[C:34]([Cl:42])=[O:36])=[CH:30][CH:31]=1)/[C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][O:21]1)[N:15]=[CH:14]2
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC/C(=C(/c1ccc(/C=C/C(=O)O)cc1)c1ccc2c(cnn2C2CCCCO2)c1)c1ccc(F)cc1Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC/C(=C(/c1ccc(/C=C/C(=O)Cl)cc1)c1ccc2c(cnn2C2CCCCO2)c1)c1ccc(F)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (E)-3-(4-((E)-2-(2-chloro-4-fluorophenyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylic acid (1 g, 1.88 mmol; Compound 407) in DCM (9.4 mL) at room temperature, oxalyl dichloride (0.33 mL, 3.76 mmol) was added. After the addition of DMF (2 drops), the mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated to afford a pale yellow solid. This material was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:12][CH3:13])=[C:4]([CH3:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[OH:14]S(O)(=O)=O>C(O)(=O)C.C(OC(=O)C)(=O)C.[O-2].[O-2].[O-2].[Cr+6]>[Cl:1][C:2]1[C:3]([O:12][CH3:13])=[C:4]([CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9])[CH:11]=[O:14]
Reactant: COc1c(C)ccc([N+](=O)[O-])c1Cl
Reactant: O=S(=O)(O)O
Agent: [Cr+6]
Agent: [O-2]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: COc1c(C=O)ccc([N+](=O)[O-])c1Cl
Temperature: 2.5 °C
Reaction time: 0.5 h

Procedure:
A solution of 3-chloro-2-methoxy-4-nitrotoluene (1.0 g, 5.0 mmol) in acetic acid (10 mL) and acetic anhydride (10 mL) was cooled to 50° C. and treated with 1 mL conc. H2SO4. Chromium trioxide (1.4 g, 14 mmol) was added in portions over 10 minutes while the reaction temperature was maintained at 0-5° C. After 30 minutes at this temperature, the mixture was poured onto ice-water (20 g) and the mixture was extracted with ethyl acetate (2×25 mL). The combined organic phases were washed with brine, dried (sodium sulfate) and concentrated. The crude bis-acetate was combined with water (10 mL), ethanol (10 mL) and concentrated sulfuric acid (1 mL) and heated to reflux for 40 minutes. Upon cooling, the mixture was diluted with water (20 mL) and extracted with ethyl acetate (2×50 mL). The combined extracts were washed with brine, dried (sodium sulfate) and concentrated. The crude mixture was chromatographed (10% ethyl acetate/hexanes) to give 3-chloro-2-methoxy-4-nitrobenzaldehyde (400 mg, 1.9 mmol): LC/MS (m/z=215).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]([N+:15]([O-:17])=[O:16])=[C:13](F)[CH:12]=[C:11]([F:19])[C:10]=2[F:20])=[C:4]([F:21])[CH:3]=1.[CH3:22][O-:23].[Na+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]([N+:15]([O-:17])=[O:16])=[C:13]([O:23][CH3:22])[CH:12]=[C:11]([F:19])[C:10]=2[F:20])=[C:4]([F:21])[CH:3]=1
Reactant: O=[N+]([O-])c1c(F)cc(F)c(F)c1Nc1ccc(Br)cc1F
Reactant: C[O-]
Agent: [Na+]
Product: COc1cc(F)c(F)c(Nc2ccc(Br)cc2F)c1[N+](=O)[O-]
Yield: 81 %

Procedure:
Intermediate I-4a was prepared from (4-bromo-2-fluoro-phenyl)-(2,3,5-trifluoro-6-nitro-phenyl)-amine (25 g, 0.069 mol) and sodium methoxide (18.6 g, 0.344 mol) using procedures analogous to Intermediate (I-3a) above to afford the product (81% yield).
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])=[N:6][CH:7]=[CH:8][CH:9]=1)([O-])=O>CCOC(C)=O>[C:12]1([CH3:17])[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[NH:10][C:5]1[C:4]([NH2:1])=[CH:9][CH:8]=[CH:7][N:6]=1
Reactant: Cc1ccccc1Nc1ncccc1[N+](=O)[O-]
Solvent: CCOC(C)=O
Product: Cc1ccccc1Nc1ncccc1N
Temperature: 25 °C
Reaction time: 16 h
Yield: 58.6 %

Procedure:
A mixture of (3-nitropyridin-2-yl)-o-tolylamine (3.96 g, 17.3 mmol) in EtOAc (200 mL) was degassed with a stream of nitrogen prior to addition of 10% Pd/C (700 mg) and was stirred at RT under a hydrogen atmosphere for 16 h. The suspension was filtered and the filtrate was concentrated in vacuo to afford the title compound as a white solid (2.02 g, 59%). 1H NMR (CDCl3, 400 MHz): δ 7.83 (1H, d, J=4.94 Hz), 7.28-7.11 (3H, m), 7.01 (1H, d, J=7.64 Hz), 6.93 (1H, t, J=7.41 Hz), 6.79 (1H, dd, J=7.63, 4.96 Hz), 5.97 (1H, s), 3.43 (2H, s), 2.30 (3H, s).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[C:10](=[CH:15]N(C)C)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)(O)O.[NH2:23][C:24]([NH2:26])=[NH:25].O.O.O.C([O-])(=O)C.[Na+]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[N:25]=[C:24]([NH2:26])[N:23]=[CH:15][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)C=C1CN(C(=O)OC(C)(C)C)CCC1=O
Reactant: N=C(N)N
Agent: CC(=O)[O-]
Agent: O=C(O)O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCc2nc(N)ncc2C1
Yield: 54.5 %

Procedure:
A solution of 1-t-Butoxycarbonyl-3-(dimethylamino)methylene-4-piperidone (7.64 g, 30.04 mmol) in methanol (190 mL) was treated with guanidine carbonate (21.65 g, 120.16 mmol), followed by sodium acetate trihydrate (32.70 g, 240.32 mmol). The reaction mixture was heated at reflux for 17 hours and the solvent was removed in vacuo. The residue was diluted with water and the mixture was swirled for a few minutes. The undissolved white solid was collected and washed with water, followed by a small amount of cold ethyl acetate to give the title compound (4.10 g, 55%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]2[CH:20]=[CH:19][N:18]3[N:21]=[CH:22][C:23]([C:24](O)=[O:25])=[C:17]3[N:16]=2)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[CH3:27][O:28][NH2:29]>>[F:1][C:2]1[CH:3]=[C:4]([C@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]2[CH:20]=[CH:19][N:18]3[N:21]=[CH:22][C:23]([C:24]([NH:29][O:28][CH3:27])=[O:25])=[C:17]3[N:16]=2)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: CON
Reactant: COc1ncc(F)cc1[C@H]1CCCN1c1ccn2ncc(C(=O)O)c2n1
Product: CONC(=O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)cnc3OC)nc12
Yield: 67 %

Procedure:
Prepared by the method described in Example 1 using (R)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (Preparation K) and O-methylhydroxylamine. The combined organic extracts were concentrated and the residue was purified by reverse phase HPLC (0-80% acetonitrile/water) to yield the title compound (29 mg, 67% yield). MS (apci) m/z=387.0 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[CH2:12](Cl)[CH:13]=[CH2:14].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:14]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1)[CH:13]=[CH2:12]
Reactant: COC(=O)c1ccc(O)cc1
Reactant: C=CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOc1ccc(C(=O)OC)cc1
Yield: 100.3 %

Procedure:
A solution of methyl 4-hydroxybenzoate (15.21 g, 0.10 mol), allyl chloride (11.48 g, 0.15 mol), and potassium carbonate (20.73 g, 0.15 mol) in N,N-dimethylformamide (40 mL) was stirred at 50° C. overnight. The reaction solution was added with water and extracted with ethyl acetate. Subsequently, the organic layer was washed with brine, dried using anhydrous sodium sulfate, and concentrated in vacuo. The obtained residue was purified using silica-gel column chromatography (hexane/ethyl acetate) and the title compound (19.27 g, yield 100%) was obtained as a pale yellow oil.
Reaction SMILES: [Br:1]Br.[CH3:3][C:4]1([CH3:17])[C:8](=[O:9])[C:7]2[C:10]([CH3:16])=[CH:11][C:12]([CH3:15])=[C:13]([CH3:14])[C:6]=2[O:5]1.S([O-])([O-])=O.[Na+].[Na+]>C(O)(=O)C>[Br:1][C:11]1[C:12]([CH3:15])=[C:13]([CH3:14])[C:6]2[O:5][C:4]([CH3:17])([CH3:3])[C:8](=[O:9])[C:7]=2[C:10]=1[CH3:16]
Reactant: BrBr
Reactant: Cc1cc(C)c2c(c1C)OC(C)(C)C2=O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1c(C)c2c(c(C)c1Br)C(=O)C(C)(C)O2
Temperature: 25 °C
Yield: 83.7 %

Procedure:
Bromine (12.3 mL, 241 mmol) was added dropwise to a solution of acetic acid (400 mL) containing 2,2,4,6,7-pentamethyl-1-benzofuran-3(2H)-one (40.9 g, 200 mmol) synthesized in Reference Example 35, and then it was stirred at room temperature. After stirring for 1 hour, the reaction solution was poured into 5% aqueous solution of sodium sulfite. The generated crystals were collected by filtration, and recrystallized from methanol to give 47.4 g of the title compound (yield: 84%).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH3:11])=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][C@H:13]2[CH3:18])[N:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.CN([CH:32]=[O:33])C.Cl>C1COCC1>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH:32]=[O:33])[N:8]2[CH3:11])=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][C@H:13]2[CH3:18])[N:3]=1
Reactant: CN(C)C=O
Reactant: C[C@@H]1COCCN1c1nc(Cl)nc2c1ncn2C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@@H]1COCCN1c1nc(Cl)nc2c1nc(C=O)n2C
Temperature: 25 °C

Procedure:
To a solution of 2-chloro-9-methyl-6-((R)-3-methylmorpholin-4-yl)-9H-purine (550 mg, 2.05 mmol) in THF (20 mL) at −78° C. was added LiHMDS (3.1 mL, 3.08 mmol, 1M solution in THF). The resulting mixture was allowed to stir for 45 min before the addition of DMF (800 μL, 10.33 mmol). The reaction mixture was warmed to r.t. over 1.5 h then poured onto 0.5M HCl. The resulting precipitate was collected by filtration and washed with H2O then Et2O affording the title compound as a yellow solid (406 mg, 67%). LCMS (method H): RT 3.35 min [M+H]+ 296.3
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](=[N:10]/[NH:11]C(OCC)=O)/[CH3:9])=[C:4]([CH3:17])[CH:3]=1.[S:18](Cl)(Cl)=O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:10]=[N:11][S:18][CH:9]=2)=[C:4]([CH3:17])[CH:3]=1
Reactant: CCOC(=O)N/N=C(\C)c1ccc(Cl)cc1C
Reactant: O=S(Cl)Cl
Product: Cc1cc(Cl)ccc1-c1csnn1
Temperature: 25 °C

Procedure:
Ethyl (2E)-2-[1-(4-chloro-2-methylphenyl)ethylidene]hydrazine carboxylate (0.63 g, 2.45 mmol) was stirred with thionyl chloride (1 mL, 13.70 mmol) at 60° C. for 1 h. The mixture was cooled to room temperature and concentrated in vacuo. 4-(4-Chloro-2-methylphenyl)-1,2,3-thiadiazole was obtained as a red solid. MS m/z=211.5; 1H NMR (CDCl3, 400 MHz) δ 2.45 (s, 3H), 7.31 (dd, J=2.2, 8.2 Hz, 1H), 7.36 (d, J=1.8 Hz, 1H), 7.60 (d, J=8.2 Hz, 1H), 8.51 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:30])[C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([O:17][CH3:18])[C:11]=2[NH:19][C:20]([C:22]2[S:23][CH:24]=[C:25]([CH2:28]Cl)[C:26]=2[Cl:27])=[O:21])=[CH:4][CH:3]=1.[CH3:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.O>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:30])[C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([O:17][CH3:18])[C:11]=2[NH:19][C:20]([C:22]2[S:23][CH:24]=[C:25]([CH2:28][N:35]3[CH2:36][CH2:37][N:32]([CH3:31])[CH2:33][CH2:34]3)[C:26]=2[Cl:27])=[O:21])=[CH:4][CH:3]=1
Reactant: CN1CCNCC1
Reactant: COc1cc(Cl)cc(C(=O)Nc2ccc(Cl)cc2)c1NC(=O)c1scc(CCl)c1Cl
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(Cl)cc(C(=O)Nc2ccc(Cl)cc2)c1NC(=O)c1scc(CN2CCN(C)CC2)c1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 64.6 %

Procedure:
To a solution of N-(4-chlorophenyl)-2-[((4-(chloromethyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide (1.0 g, 2.1 mmol) in DMF (40 mL) at 0° C. was added 1-methylpiperazine (1.2 mL, 1.1 g, 11 mmol), and the mixture stirred for 0.5 hours at 0° C., then warmed to ambient temperature. After 7 hours the reaction mixture was poured into water (150 mL) and the resulting solid collected by filtration, washed with water (50 mL) and acetonitrile (10 mL). Purification by flash chromatography on silica gel afforded 0.77 g (64% yield) of N-(4-chlorophenyl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide, as a white foam: NMR (DMSO-d6 /TFA) 10.4 (s, 1), 9.4 (s, 1), 7.2-8.1 (m, 7), 4.4 (s, 2), 3.8 (s, 3), 3.0-3.8 (br m, 8), 2.8 (s, 3) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:10][C:11](=[O:22])[N:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]#[CH:21])=[CH:16][CH:15]=2)[N:13]=1.[F:23][C:24]1[CH:29]=[CH:28][C:27](I)=[CH:26][N:25]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:10][C:11](=[O:22])[N:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]#[C:21][C:27]3[CH:26]=[N:25][C:24]([F:23])=[CH:29][CH:28]=3)=[CH:16][CH:15]=2)[N:13]=1
Reactant: Fc1ccc(I)cn1
Reactant: C#Cc1ccc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CS(C)=O
Product: O=c1[nH]c(-c2c(F)cccc2Cl)nn1-c1ccc(C#Cc2ccc(F)nc2)cc1
Yield: 23 %

Procedure:
The title compound was prepared according to the procedure described in Example-3 using 5-(2-chloro-6-fluorophenyl)-2-(4-ethynylphenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (Intermediate-2, 0.100 g, 0.319 mmol), 2-fluoro-5-iodopyridine (0.106 g, 0.479 mmol), TBAF (0.201 g, 0.638 mmol), bis(triphenylphosphine)palladium(II) chloride (0.020 g, 0.028 mmol) and DMSO (3.0 mL). The obtained product was purified with column chromatography on silica gel eluting with 2.0% MeOH:DCM to afford 0.030 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 7.30 (d, J=7.5 Hz, 1H), 7.51 (t, J=8.7 Hz, 1H), 7.58 (d, J=8.4 Hz, 1H), 7.70 (d, J=8.1 Hz, 3H), 8.03 (d, J=8.4 Hz, 2H), 8.20 (t, J=7.2 Hz, 1H), 8.49 (s, 1H), 12.73 (br s, 1H). MS (m/z): 407.33 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[C:6]([Cl:11])[C:3]=1[CH:4]=O.[CH2:12]([O:14][C:15](=[O:21])[CH2:16][C:17]([CH2:19][Cl:20])=[O:18])[CH3:13]>>[CH2:12]([O:14][C:15](=[O:21])[C:16](=[CH:4][C:3]1[C:6]([Cl:11])=[CH:7][CH:8]=[C:9]([Cl:10])[C:2]=1[Cl:1])[C:17](=[O:18])[CH2:19][Cl:20])[CH3:13]
Reactant: O=Cc1c(Cl)ccc(Cl)c1Cl
Reactant: CCOC(=O)CC(=O)CCl
Product: CCOC(=O)C(=Cc1c(Cl)ccc(Cl)c1Cl)C(=O)CCl

Procedure:
210 g of 2,3,6-trichlorobenzaldehyde were reacted with 4-chloroacetoacetic acid ethyl ester as described in Example 43. 213 g of a 3:1 isomer mixture were obtained as an oily crude product.
Reaction SMILES: [Br:1][C:2]1[C:3](I)=[C:4]([CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1)[NH2:5].[CH3:14][Si:15]([C:18]#[CH:19])([CH3:17])[CH3:16]>C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Br:1][C:2]1[C:3]([C:19]#[C:18][Si:15]([CH3:17])([CH3:16])[CH3:14])=[C:4]([CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1)[NH2:5]
Reactant: C#C[Si](C)(C)C
Reactant: Nc1cc(C(F)(F)F)cc(Br)c1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1c(N)cc(C(F)(F)F)cc1Br
Temperature: 80 °C
Reaction time: 2 h

Procedure:
3-Bromo-2-iodo-5-(trifluoromethyl)aniline (18.7 g, 51.1 mmol) was dissolved in triethylamine (400 mL). To this was added dichlorobis(triphenylphosphine)palladium(II) (3.59 g, 5.11 mmol), copper(I) iodide (0.973 g, 5.11 mmol), and trimethylsilylacetylene (5.52 g, 56.2 mmol). The reaction was stirred for 2 h at ambient temperature, at 80° C. for 2 h, and then evaporated. The residue was purified by chromatography on silica gel with 5% ethyl acetate/hexanes to give 10.67 g (62.1%) as a brown liquid. 1H-NMR (CDCl3, 400 MHz) δ 7.13 (s, 1H), 6.82 (s, 1H), 4.52 (bs, 2H), 0.29 (s, 9H); LC/MS (HPLC method 4): tR=4.208 min, 336.05(MH)+.
Reaction SMILES: O/[C:2](/[C:9]([O:11][CH3:12])=[O:10])=[C:3](/O)\[C:4]([O:6][CH3:7])=[O:5].[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl>CO>[CH3:7][O:6][C:4](=[O:5])[C:3]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[C:2]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:9]([O:11][CH3:12])=[O:10]
Reactant: Nc1ccccc1
Reactant: COC(=O)/C(O)=C(\O)C(=O)OC
Agent: Cl
Solvent: CO
Product: COC(=O)C(Nc1ccccc1)=C(Nc1ccccc1)C(=O)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
In a round bottom flask with a teflon stirbar, 25 g (142 mmol) of dimethyl dihydroxyfumarate (prepared according to a procedure described in U.S. Pat. No. 3,334,102), 29.0 g (312.5 mmol) of aniline, 0.1 mL of concentrated HCl, and 90 mL of methyl alcohol were mixed and heated to reflux for 3 hours. The reaction mixture was cooled to room temperature and left overnight in a refrigerator. The next morning, the resulting thick paste was filtered on a coarse frit, washed with a 50% (v:v) methanol-water mixture, and dried in a vacuum oven, yielding 30.1 g (65% yield) which, according to NMR analysis, was a mixture of E/Z isomers (E:Z˜1:2).
Reaction SMILES: CO[C:3](=[O:28])[CH2:4][CH:5]([C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1)[CH2:6][N:7]1[C:15]2[CH:14]=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=2[C:9]2[CH2:17][N:18]([CH3:21])[CH2:19][CH2:20][C:8]1=2.[C:29]([Li])([CH3:32])([CH3:31])[CH3:30]>C1COCC1>[CH3:21][N:18]1[CH2:19][CH2:20][C:8]2[N:7]([CH2:6][CH:5]([C:22]3[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=3)[CH2:4][C:3](=[O:28])[C:29]([CH3:32])([CH3:31])[CH3:30])[C:15]3[CH:14]=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=3[C:9]=2[CH2:17]1
Reactant: COC(=O)CC(Cn1c2c(c3cc(C)ccc31)CN(C)CC2)c1ccncc1
Reactant: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: Cc1ccc2c(c1)c1c(n2CC(CC(=O)C(C)(C)C)c2ccncc2)CCN(C)C1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 108 %

Procedure:
4-(2,8-Dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-3-pyridin-4-yl-butyricacidmethylester (1.5 g, 3.9 mmol) was dissolved in THF (50 mL) and cooled to −78° C., tert-butyl lithium (16% in pentane) (6 mL, 15.13 mmol) was added dropwise under nitrogen. The reaction mixture was stirred at −78° C. for 90 min. After complete consumption of starting material, the reaction mixture was quenched with ammonium chloride solution and the reaction mixture was allowed to come to RT and extracted with EtOAc (3×100 mL). The combined organic layer was dried over anhydrous sodium sulfate and concentrated to obtain 1.7 g of crude 6-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-2,2-dimethyl-5-pyridin-4-yl-hexan-3-one. 1H NMR (CDCl3, freebase) δ (ppm): 8.41 (d, 2H), 7.31 (d, 1H), 7.19 (s, 1H), 7.1 (d, 1H), 6.93 (d, 2H), 4.25 (dd, 1H), 3.9 (t, 2H), 3.8 (m, 1H), 3.67 (dd, 1H), 2.87 (m, 3H), 2.71 (m, 2H), 2.51 (s, 3H), 2.42 (s, 3H), 2.1 (m, 1H), 1.21 s (9H). Separation by chiral HPLC provides enantiomers II-222a-b.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:23]=[CH:22][C:17]([C:18]([O:20]C)=[O:19])=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:6][C@@H:5]1[CH3:32])(=[O:3])[CH3:2].[OH-].[Li+].C(O)(=O)C>CO>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:23]=[CH:22][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:6][C@@H:5]1[CH3:32])(=[O:3])[CH3:2]
Reactant: COC(=O)c1ccc(-c2ccc3c(c2)[C@H](NC(=O)OC(C)(C)C)C[C@H](C)N3C(C)=O)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: CC(=O)N1c2ccc(-c3ccc(C(=O)O)cc3)cc2[C@H](NC(=O)OC(C)(C)C)C[C@@H]1C
Reaction time: 24 h
Yield: 96 %

Procedure:
A solution of methyl 4-((2S,4R)-1-acetyl-4-((tert-butoxycarbonyl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)benzoate (for a preparation see Intermediate 30)(5.23 g, 11.93 mmol) in MeOH (80 mL) was treated with aqueous lithium hydroxide (1M, 17.89 mL, 17.89 mmol) and the resulting mixture, which became a suspension after 5 min was stirred. After 24 h, lithium hydroxide (17.89 mL, 17.89 mmol) was added and the mixture (which by then was a solution) was stirred at 50° C. for 3 h. The mixture was cooled to room temperature, most of the MeOH was evaporated in vacuo and the residue treated with acetic acid (2.73 mL, 47.7 mmol). After 5 min, a precipitate formed, was isolated by filtration, washed with water and dried at 45° C. under vacuum for 16 h to give 4-((2S,4R)-1-acetyl-4-((tert-butoxycarbonyl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)benzoic acid (4.88 g, 11.50 mmol, 96% yield) as a white solid. LCMS (HpH, 2 min), Rt=0.70 min, MH+=425.
Reaction SMILES: [CH:1]([N:3]([CH2:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:4]=[O:5])=[CH2:2].C(O)C[OH:15].C[O-].[Na+].C(O)C>CO>[CH:1]([N:3]([CH2:6][CH2:7][C:8]([O:10][CH2:11][CH2:12][OH:15])=[O:9])[CH:4]=[O:5])=[CH2:2]
Reactant: C=CN(C=O)CCC(=O)OCC
Reactant: OCCO
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: C=CN(C=O)CCC(=O)OCCO
Temperature: 90 °C
Reaction time: 2 h

Procedure:
The apparatus of Example 2 was charged with 17.1 grams (0.1 mol) of ethyl 3-(N-vinylformamido)propionate, 6.2 grams (0.1 mol) of ethylene glycol, and 0.15 gram of 25% sodium methoxide in methanol solution. The mixture was stirred at 90° C. for 2 hours. No evolution of ethanol was observed during the reaction period. Heating for an additional hour at 135° C. also failed to generate a volatile coproduct which indicated no conversion to the desired product.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CS([C:11]1[S:12][C:13]([C:17]#[N:18])=[C:14]([NH2:16])[N:15]=1)=O>C(#N)C>[C:1]1([S:7][C:11]2[S:12][C:13]([C:17]#[N:18])=[C:14]([NH2:16])[N:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Sc1ccccc1
Reactant: CS(=O)c1nc(N)c(C#N)s1
Solvent: CC#N
Product: N#Cc1sc(Sc2ccccc2)nc1N
Reaction time: 8 h

Procedure:
15.5 ml (16.5 g) of thiophenol are added to a suspension of 9.35 g of 2-methylsulphinyl-4-amino-5-cyanothiazole, prepared according to example I, in 250 ml of acetonitrile, while stirring. After stirring at room temperature for another 30 minutes and leaving to stand overnight, the mixture is filtered with charcoal, after which the filtrate is evaporated. The residue is taken up in methylene chloride, after which the resulting solution is washed, successively with 2N sodium hydroxide solution and water, dried, filtered and diluted with isopropanol. After evaporating the methylene chloride the desired product crystallises in a yield of 7.62 g; m.p. 176°-18° C.; Rf (CH2Cl2) 0.15.