Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21](=[O:23])[CH3:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:24].[NH2:25][C:26]1[CH:27]=[CH:28][C:29]([O:33][CH3:34])=[C:30]([OH:32])[CH:31]=1>C1COCC1>[OH:32][C:30]1[CH:31]=[C:26]([NH:25][CH:2]=[C:3]2[C:11]3[C:6](=[CH:7][C:8]([C:12]([C:14]4[CH:15]=[C:16]([NH:20][C:21](=[O:23])[CH3:22])[CH:17]=[CH:18][CH:19]=4)=[O:13])=[CH:9][CH:10]=3)[NH:5][C:4]2=[O:24])[CH:27]=[CH:28][C:29]=1[O:33][CH3:34]
Reactant: COc1ccc(N)cc1O
Reactant: CC(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3=CO)c1
Solvent: C1CCOC1
Product: COc1ccc(NC=C2C(=O)Nc3cc(C(=O)c4cccc(NC(C)=O)c4)ccc32)cc1O
Temperature: 65 °C
Reaction time: 24 h
Yield: 71 %

Procedure:
A small screw cap test tube was charged with N-[3-(3-Hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-acetamide (prepared below, 100 mg, 0.310 mmol) and THF (2 mL). To the resulting solution was added 5-amino-2-methoxyphenol (47.49 mg, 0.341 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature. Hexanes were added to the reaction mixture. The solid precipitate that formed was washed with ˜1 mL of i-prOH yielding 73% (100 mg, 0.22 mmol) of the title compound.
Reaction SMILES: [C:1]([C:4]1[C:9]2[NH:10][C:11]3[CH:12]=[C:13]([C:17](O)=[O:18])[CH:14]=[CH:15][C:16]=3[C:8]=2[N:7]=[C:6]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[C:22]([Cl:27])[CH:21]=2)[CH:5]=1)(=[O:3])[NH2:2].[CH3:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:27][C:22]1[CH:21]=[C:20]([C:6]2[CH:5]=[C:4]([C:1]([NH2:2])=[O:3])[C:9]3[NH:10][C:11]4[CH:12]=[C:13]([C:17]([N:32]5[CH2:33][CH2:34][N:29]([CH3:28])[CH2:30][CH2:31]5)=[O:18])[CH:14]=[CH:15][C:16]=4[C:8]=3[N:7]=2)[CH:25]=[CH:24][C:23]=1[F:26]
Reactant: CN1CCNCC1
Reactant: NC(=O)c1cc(-c2ccc(F)c(Cl)c2)nc2c1[nH]c1cc(C(=O)O)ccc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN1CCN(C(=O)c2ccc3c(c2)[nH]c2c(C(N)=O)cc(-c4ccc(F)c(Cl)c4)nc23)CC1
Reaction time: 8 h

Procedure:
A mixture of 4-carbamoyl-2-(3-chloro-4-fluorophenyl)-5H-pyrido[3,2-b]indole-7-carboxylic acid 431D (55 mg, 0.143 mmol), 1-methylpiperazine (0.032 mL, 0.287 mmol), N,N-diisopropylethylamine (0.075 mL, 0.430 mmol) and HATU (109 mg, 0.287 mmol) in DMF (1 mL) was stirred for overnight. The mixture was concentrated and purified using preparative HPLC to give titled product. MS (ESI) m/z 466.16 (M+H)+. 1H NMR (DMSO-d6) δ ppm 11.82 (s, 1H), 8.62 (s, 1H), 8.53 (s, 1H), 8.50 (dd, 1H, J=7.1, 2.1), 8.34 (m, 2H), 7.99 (s, 1H), 7.79 (s, 1H), 7.62 (t, 1H, J=8.8), 7.28(d, 1H, J=8.0), 3.67 (bs, 4H), 2.37 (bs, 4H), 2.22 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([F:9])[CH:8]=1)[NH2:5].Cl.[N+]([O-])([O-])=O.[Na+].[N-:16]=[N+:17]=[N-].[Na+]>O>[F:1][C:2]1[CH:3]=[C:4]([N:5]=[N+:16]=[N-:17])[CH:6]=[C:7]([F:9])[CH:8]=1
Reactant: Nc1cc(F)cc(F)c1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: O
Product: [N-]=[N+]=Nc1cc(F)cc(F)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 90.3 %

Procedure:
3,5-Difluoroaniline (64.5 g, 0.5 mol) is added to a solution of water (206 ml) and concentrated hydrochloric acid (116 ml). The resulting solution is stirred for 10 minutes and cooled to 0° C. A solution of sodium nitrate (37.4 g, 0.54 mol) in water (125 ml) is added in a dropwise manner. After being stirred for one hour, the mixture is filtered and the filtrate is cooled to 0° C. A solution of sodium azide (40.2 g, 0.62 mol) in water (125 ml) is added in a dropwise manner, and stirring is allowed to continue for 30 minutes. The reaction mixture is extracted with ether (3×250 ml), and the combined organic extracts are washed with saturated sodium bicarbonate solution (250 ml) and then brine (250 ml), and dried over sodium sulfate. Removal of the volatiles in vacuo affords pure title compound as a yellow liquid (70 g, 90%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:13][CH:12]=1.[CH:25]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH:34]([CH3:36])[CH3:35])[C:29]=1[N:37]=[C:38]=[O:39])([CH3:27])[CH3:26]>>[CH:25]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH:34]([CH3:35])[CH3:36])[C:29]=1[NH:37][C:38](=[O:39])[N:10]([CH2:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])[C:11]1[CH:12]=[CH:13][C:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:15][CH:16]=1)([CH3:26])[CH3:27]
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Reactant: CCCCCCCCc1ccc(NCc2ccccc2OC)cc1
Product: CCCCCCCCc1ccc(N(Cc2ccccc2OC)C(=O)Nc2c(C(C)C)cccc2C(C)C)cc1
Yield: 59.8 %

Procedure:
By the reaction and treatment in the same manner as in Example 2 using (2-methoxyphenylmethyl)(4-octylphenyl)amine (1.4 g) and 2,6-diisopropylphenyl isocyanate (0.96 g) as starting materials, N′-(2,6-diisopropylphenyl)-N-(2-methoxyphenylmethyl)-N-(4-octylphenyl)urea (1.36 g) was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:15]2[CH2:16][C@H:11]([CH2:12][CH2:13][C@@H:14]2[N:17]2[CH:25]=[N:24][C:23]3[C:18]2=[N:19][CH:20]=[N:21][C:22]=3[NH2:26])[CH2:10][C:9]1=[O:27])=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[CH3:34][O:35][C:36]1[CH:44]=[CH:43][C:39]([C:40](Cl)=[O:41])=[CH:38][CH:37]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[C@H:15]2[CH2:16][C@H:11]([CH2:12][CH2:13][C@@H:14]2[N:17]2[CH:25]=[N:24][C:23]3[C:18]2=[N:19][CH:20]=[N:21][C:22]=3[NH:26][C:40](=[O:41])[C:39]2[CH:43]=[CH:44][C:36]([O:35][CH3:34])=[CH:37][CH:38]=2)[CH2:10][C:9]1=[O:27])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C(=O)C[C@H]2CC[C@H](n3cnc4c(N)ncnc43)[C@@H]1C2
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(C(=O)Nc2ncnc3c2ncn3[C@H]2CC[C@@H]3CC(=O)N(C(=O)OC(C)(C)C)[C@H]2C3)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 88 %

Procedure:
A 100 ml two-necked round-bottomed flask was loaded with 4.96 g of Boc-A lactams [sic] 15e (13.3 mmol) and 60 ml of dry CH2Cl2. 5.35 ml of dry pyridine (66.5 mmol) were then added, followed by 1.59 g of DMAP (1.3 mmol). After cooling to 0° C., 5.4 ml of 4-methoxybenzoyl chloride (39.9 mmol) were added dropwise and the mixture was stirred at 0° C. for 15 min. The ice bath was removed and the reaction mixture was stirred at room temperature for 22 h. The reaction mixture was then again cooled to 0° C. and 35 ml of MeOH were added dropwise. After 30 min at 0° C., 80 ml of a saturated solution of NH3 in MeOH were added dropwise. A white precipitate was formed, which dissolved after complete addition of the solution. After 30 min, the ice bath was removed and the reaction was stirred at room temperature for a further 2 h. The solvent was then removed under reduced pressure and the resulting residue was dissolved in 200 ml of CH2Cl2. The solution was washed successively with 150 ml of saturated NaHCO3 solution and aqueous citric acid solution (20%, 2×100 ml), washed [sic] over MgSO4, filtered and concentrated in vacuo. The resulting residue was purified by means of chromatography (5.2×18 cm silica gel; eluent: EtOAc/MeOH 40:3) to afford 5.93 g of 15f (88%).
Reaction SMILES: Br[CH:2]([CH3:9])[CH2:3][CH:4]1[O:8][CH2:7][CH2:6][O:5]1.Cl[C:11]1[N:16]=[CH:15][C:14]([F:17])=[CH:13][N:12]=1>O1CCCC1.[Zn]>[O:5]1[CH2:6][CH2:7][O:8][CH:4]1[CH2:3][CH:2]([C:11]1[N:16]=[CH:15][C:14]([F:17])=[CH:13][N:12]=1)[CH3:9]
Reactant: CC(Br)CC1OCCO1
Reactant: Fc1cnc(Cl)nc1
Agent: [Zn]
Solvent: C1CCOC1
Product: CC(CC1OCCO1)c1ncc(F)cn1
Temperature: 40 °C
Reaction time: 4 h
Yield: 22.9 %

Procedure:
To a stirring suspension of activated “Rieke” zinc in tetrahydrofuran (21 ml, 1.53M) was added 2-(2-bromopropyl)-1,3-dioxolane (6.6 g) in tetrahydrofuran (50 ml), a rise in temperature from 21° C. to 40° C. was observed, heated at 40° C. for 1 hour then allowed to cool to ambient temperature before adding 2-chloro-5-fluoropyrimidine (3 g) and [1,2-Bis(diphenylphosphino)-propane]dichloronickel(II)chloride (368 mg). The mixture was stirred at ambient temperature for 4 hours then filtered through a pad of celite and the filtrate evaporated under reduced pressure. Flash chromatography (silica gel, haxane-25% ethyl acetate in hexanes) then gave the product as a pale yellow oil (1.1 g); 1H NMR (d6-DMSO): 8.81 (s, 2H), 4.73 (dd, 1H), 3.66–3.87 (m, 4H), 3.21–3.30 (m, 1H), 2.19 (ddd, 1H), 1.83 (ddd, 1H), 1.27(d, 3H); m/z 213 (M+1).
Reaction SMILES: [C:1]1([CH3:12])[CH:6]=[CH:5][C:4]([O:7][CH2:8][C:9](O)=O)=[CH:3][CH:2]=1.[CH3:13][NH2:14]>>[C:1]1([CH3:12])[CH:6]=[CH:5][C:4]([O:7][CH2:8][CH2:9][NH:14][CH3:13])=[CH:3][CH:2]=1
Reactant: CN
Reactant: Cc1ccc(OCC(=O)O)cc1
Product: CNCCOc1ccc(C)cc1

Procedure:
Synthesized according to typical procedures C and D from 2-p-tolyloxyacetic acid and methylamine.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.[CH3:41][C:42]1[C:51]2[C:46](=[CH:47][C:48]([C:52]([F:55])([F:54])[F:53])=[CH:49][CH:50]=2)[N:45]=[C:44]([CH2:56][CH2:57][CH3:58])[C:43]=1[C:59](O)=[O:60]>C1COCC1.CC(=O)OCC.CCOC(C)=O.CCCCCC>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][C:59]([C:43]2[C:44]([CH2:56][CH2:57][CH3:58])=[N:45][C:46]3[C:51]([C:42]=2[CH3:41])=[CH:50][CH:49]=[C:48]([C:52]([F:55])([F:54])[F:53])[CH:47]=3)=[O:60])=[CH:4][CH:3]=1
Reactant: CCCc1nc2cc(C(F)(F)F)ccc2c(C)c1C(=O)O
Reactant: NCc1ccc(F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCCc1nc2cc(C(F)(F)F)ccc2c(C)c1C(=O)NCc1ccc(F)cc1
Temperature: 50 °C
Reaction time: 72 h
Yield: 76 %

Procedure:
311 μl (2.7 mmol) 4-fluorobenzylamine, 941 mg (2.5 mmol) HATU and 1 ml (7.2 mmol) NEt3 were added consecutively to a solution of 740 mg (2.5 mmol) 4-methyl-2-propyl-7-(trifluoromethyl)quinoline-3-carboxylic acid in THF (19 ml) and the mixture was then stirred for 72 h at 50° C. The mixture was then diluted with EA and washed with a 4N aq. NH4CL sol., a 1M aq. Na2CO3 sol. and brine. The organic phase was dried over MgSO4, filtered through silica gel and concentrated in a vacuum. After CC (EtOAc/hexane 1:1) of the residue, 770 mg (1.9 mmol, 76%) N-[(4-fluorophenyl)-methyl]-4-methyl-2-propyl-7-(trifluoromethyl)-quinoline-3-carboxylic acid amide (example 3) was obtained. MS: m/z 405.2 [M+H]+.
Reaction SMILES: [C:1]([CH2:4][C:5](=[O:7])[CH3:6])(=[O:3])[CH3:2].C(NC1C=CC(S([N:21]=[N+:22]=[N-])(=O)=O)=CC=1)(=O)C.C(N(CC)CC)C>C(#N)C>[N+:21](=[C:4]([C:5](=[O:7])[CH3:6])[C:1](=[O:3])[CH3:2])=[N-:22]
Reactant: CC(=O)Nc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Reactant: CC(=O)CC(C)=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(=O)C(=[N+]=[N-])C(C)=O
Temperature: 0 °C

Procedure:
A 1-L round-bottomed flask was charged with acetylacetone (S1) (10.25 mL, 100 mmol, 1.0 equiv) and acetonitrile (600 mL). p-Acetamidobenzene sulfonyl azide (p-ABSA)(J. S. Baum et al., Synth. Commun. 17, 1709 (1987) (24.0 g, 100 mmol, 1.0 equiv) was added and the reaction was cooled to 0° C. Triethylamine (NEt3) (41.8 mL, 300 mmol, 3 equiv) was added dropwise and the reaction was warmed to rt for 1 hour. The resulting suspension was filtered through a fitted funnel and concentrated. The obtained residue was triturated with 1:1 ether:petroleum ether and the precipitated white solids were removed via filtration. Solvents were removed in vacuo providing analytically pure S2 as a yellow oil in quantitative yield. Spectral data matched those reported in the literature (Z.-B. Chem et al., J. Org. Chem. 74, 903 (2009)).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]2[N:6]=[C:7]([O:9]CC)[S:8][C:4]=2[CH:3]=1.Cl>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:13]=[CH:12][C:5]2[NH:6][C:7](=[O:9])[S:8][C:4]=2[CH:3]=1
Reactant: CCOc1nc2ccc(Cl)cc2s1
Agent: Cl
Solvent: Cc1ccccc1
Product: O=c1[nH]c2ccc(Cl)cc2s1
Yield: 56 %

Procedure:
Prepared analogous to Example 5 from 6-chloro-2-ethoxy-benzothiazole and concentrated hydrochloric acid with a yield of 56% of theory. M.p.: 212°-213° C. (toluene)
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]([NH:13][CH2:14][CH2:15]O)=[N:5][C:6]([Cl:12])=[N:7]2>P(Cl)(Cl)(Cl)=O>[Br:1][C:2]1[C:3]2[C:4]3[N:5]([CH2:15][CH2:14][N:13]=3)[C:6]([Cl:12])=[N:7][C:8]=2[CH:9]=[CH:10][CH:11]=1
Reactant: OCCNc1nc(Cl)nc2cccc(Br)c12
Solvent: O=P(Cl)(Cl)Cl
Product: ClC1=Nc2cccc(Br)c2C2=NCCN12

Procedure:
A suspension of 5-bromo-2-chloro-4-(2-hydroxyethylamino)quinazoline (2.3 g, 7.6 mmol) in phosphorus oxychloride (POCl3) (60 ml) was heated at reflux for 5 h. The excess of POCl3 was evaporated and the residue partioned between dichloromethane (50 ml) and 1M aqueous sodium hydroxide (50 ml). The organic layer was washed with water (25 ml), dried over sodium sulphate and evaporated. The residue was triturated with ether (25 ml) and the precipitate collected by filtration to give the title compound as colourless crystals, m.p. 220°-23° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:14][CH2:13][CH2:12][NH:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.C([O-])([O-])=O.[K+].[K+].[CH2:21](I)[CH2:22][CH2:23][CH2:24][CH3:25]>CC#N>[CH2:21]([N:11]1[CH2:12][CH2:13][CH2:14][CH:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:10]1)[CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCI
Reactant: COc1cccc(C2CCCNC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCCN1CCCC(c2cccc(OC)c2)C1

Procedure:
To a solution of 3-(3-methoxyphenyl)piperidine (3.92 g, 0.02 mol) in CH3CN (100 ml), solid K2CO3 (5 g) was added and then the mixture was refluxed. A solution of pentyliodide (4.5 g, 0.021 mol) in CH3CN (10 ml) was added dropwise under 30 min. and then the mixture was refluxed for an additional 30 min. The solid was filtered off from the cooled mixture, and the solvent evaporated giving an oil which was chromatographed on a silica gel column with methanol as eluant. Yield 1.3 g (25%) of pure N-pentyl-3-(3-methoxyphenyl)piperidine (NMR) as an oil.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22](OC)=[O:23])[CH:17]=1)[C:10]([CH3:27])([CH3:26])[CH2:9]2)=[O:5])C.Cl>CO.O1CCCC1.[OH-].[Na+].O>[C:22](=[C:18]1[CH:19]=[CH:20][CH:21]=[C:16]([CH:11]2[C:10]([CH3:27])([CH3:26])[CH2:9][C:8]3[C:13](=[CH:14][CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=3)[NH:12]2)[CH2:17]1)=[O:23]
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(C(=O)OC)c1)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1C1=CC=CC(=C=O)C1
Temperature: 50 °C
Reaction time: 24 h
Yield: 29.7 %

Procedure:
A mixture of 2-(3-methoxycarbonyl-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (2 g, 5.45 mmol) in methanol (20 mL) and tetrahydrofuran (50 mL), 30% sodium hydroxide in water (20 mL) was stirred at 50° C. for 24 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded 2-(3-carbonyl-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (500 mg, 28%) as a white solid: LC/MS m/e calcd for C19H19NO4 (M+H)+: 326.27, observed: 326.0.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C@@H:16]2[N:20]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@:19]([CH3:32])([C:28]([O:30]C)=[O:29])[CH2:18][CH2:17]2)=[CH:12][C:11]=1[O:33][CH3:34].O[Li].O>CO.O>[CH3:27][C:24]([O:23][C:21]([N:20]1[C@@H:16]([C:13]2[CH:14]=[CH:15][C:10]([O:9][CH2:8][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])=[C:11]([O:33][CH3:34])[CH:12]=2)[CH2:17][CH2:18][C@@:19]1([CH3:32])[C:28]([OH:30])=[O:29])=[O:22])([CH3:25])[CH3:26]
Reactant: COC(=O)[C@]1(C)CC[C@H](c2ccc(OCc3ccccc3F)c(OC)c2)N1C(=O)OC(C)(C)C
Agent: [Li]O
Solvent: CO
Solvent: O
Product: COc1cc([C@H]2CC[C@@](C)(C(=O)O)N2C(=O)OC(C)(C)C)ccc1OCc1ccccc1F
Temperature: 100 °C
Yield: 96 %

Procedure:
To a solution of 1-(1,1-dimethylethyl) 2-methyl (2S,5R)-5-[4-{[(2-fluorophenyl)methyl]oxy}-3-(methyloxy)phenyl]-2-methyl-1,2-pyrrolidinedicarboxylate (D59, 160 mg, 0.34 mmol) in MeOH (1 ml) was added a solution of LiOH.H2O (29 mg, 0.68 mmol) in H2O (0.5 ml) and the mixture was heated in a microwave synthesizer for 70 min at 100° C. After evaporation of methanol, the aqueous phase was acidified to pH 3.5/4 with a solution of citric acid and extracted with ethyl acetate. The organic layer was dried (Na2SO4), filtered and evaporated affording the title compound (white solid, 150 mg, 97%); Rt (HPLC): 5.89 min. MS: (ES/−) m/z: 482 [M+Na] C25H30FNO6 requires 459.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Br[C:8]1[CH:9]=[CH:10][C:11]([C:14]#[C:15][Si:16]([CH3:19])([CH3:18])[CH3:17])=[N:12][CH:13]=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24](OB(O)O)=[CH:23][CH:22]=1.C(OCC)(=O)C>O1CCOCC1>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C:8]2[CH:9]=[CH:10][C:11]([C:14]#[C:15][Si:16]([CH3:19])([CH3:18])[CH3:17])=[N:12][CH:13]=2)=[CH:23][CH:22]=1
Reactant: OB(O)Oc1ccc(Cl)cc1
Reactant: C[Si](C)(C)C#Cc1ccc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: C[Si](C)(C)C#Cc1ccc(-c2ccc(Cl)cc2)cn1

Procedure:
In an argon atmosphere, 6.93 g (6 mmol) of tetrakistriphenylphosphine palladium and 17 mL of a 2M sodium carbonate solution are added to a solution of 20.4 g (80.25 mmol) of 5-bromo-2-trimethylsilanylethynylpyridine and 26.33 g (160 mmol) of 4-chlorophenylboric acid in 350 mL of dioxane and the reaction mixture is stirred for 5 hours at 90° C., while every 30 minutes 7 mL of 2M sodium carbonate solution is added. Then at ambient temperature, 1000 mL of ethyl acetate is added, and the mixture is extracted twice with 400 mL of sodium hydrogen carbonate solution. The organic phase is dried over magnesium sulfate. The purification is carried out by column chromatography on silica gel (eluant: petroleum ether to petroleum ether/ethyl acetate (9:1)). Yield: 7.9 g (34.4% of theory); C16H16ClNSi (M=285.85); calc.: molecular ion peak (M−H)−: 286/288; found: molecular ion peak (M−H)−: 286/288; Rf value: 0.6 (silica gel, petroleum ether/ethyl acetate (8:2)).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9](Cl)[N:8]=[C:7]([Cl:12])[N:6]=1)=[O:4].[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([NH2:26])[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14]>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([NH:26][CH:23]2[CH2:22][CH2:21][N:20]([C:18]([O:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:19])[CH2:25][CH2:24]2)[N:8]=[C:7]([Cl:12])[N:6]=1)=[O:4]
Reactant: COC(=O)c1cc(Cl)nc(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: CN(C)C=O
Product: COC(=O)c1cc(NC2CCN(C(=O)OC(C)(C)C)CC2)nc(Cl)n1

Procedure:
A mixture of 2,6-dichloro-pyrimidine-4-carboxylic acid methyl ester (3.98 g, 19.19 mmol, 1.0 equiv; commercially available) and 4-amino-piperidine-1-carboxylic acid tert-butyl ester (5.0 g, 24.94 mmol, 1.3 equiv) in anhydrous DMF (100 mL) was heated to 60° C. for 18 h. The organic phase was concentrated under reduced pressure and the crude reaction mixture extracted from a 1 M NaOH (100 mL) solution with ethyl acetate (3×50 mL). The combined organic phases were dried over MgSO4 and the product purified with silica column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane/ethyl acetate providing 3.46 g (49%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 1.42-1.51 (m, 2H), 1.47 (s, 9H), 2.00-2.05 (m, 2H), 2.90-3.01 (m, 2H), 3.92 (s, 3H), 4.05-4.10 (m, 2H), 4.19 (br s, 1H), 7.10 (s, 1H), 7.17 (br s, 1H). 13C NMR (75 MHz, CDCl3): δ28.30, 31.23, 42.41, 48.00, 52.88, 79.61, 106.38, 153.58, 154.61, 161.21, 163.75, 164.23. MS (ISP): 371.1 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]1[C:15]([CH3:16])=[C:14]([CH3:17])[S:13][C:12]=1Br)=[O:10].C(=O)([O-])[O-].[K+].[K+].O.C(OCC)(=O)C>CSC>[CH3:17][C:14]1[S:13][C:12]2[O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[NH:8][C:9](=[O:10])[C:11]=2[C:15]=1[CH3:16]
Reactant: Cc1sc(Br)c(C(=O)Nc2ccccc2O)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CSC
Product: Cc1sc2c(c1C)C(=O)Nc1ccccc1O2
Temperature: 165 °C
Reaction time: 0.33 h
Yield: 56.4 %

Procedure:
To a solution of N-(2-hydroxyphenyl)-2-bromo-4,5-dimethyl-3-thiophenecarboxamide (3.3 g) in dimethyl sulfide (50 ml) was added potassium carbonate (2.8 g) and the mixture was stirred at 160-170° C. for 20 minutes. The reaction system was cooled to room temperature and the reaction mixture was poured into water-ethyl acetate. The insoluble matter was filtrated and the filtrate was extracted with ethyl acetate, washed with water and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to give 2,3-dimethylthieno[2,3-b][1,5]benzoxazepin-4(5H)-one (1.4 g).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH:7]=[C:8]([C:19]2[NH:27][C:22]3=[N:23][CH:24]=[CH:25][CH:26]=[C:21]3[CH:20]=2)[C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[CH2:3][CH2:2]1>[Pd].CO>[O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH:8]([C:19]2[NH:27][C:22]3=[N:23][CH:24]=[CH:25][CH:26]=[C:21]3[CH:20]=2)[C:9]2[CH:10]=[CH:11][C:12]([C:15]([F:16])([F:17])[F:18])=[CH:13][CH:14]=2)[CH2:3][CH2:2]1
Reactant: FC(F)(F)c1ccc(C(=CC2CCOCC2)c2cc3cccnc3[nH]2)cc1
Agent: [Pd]
Solvent: CO
Product: FC(F)(F)c1ccc(C(CC2CCOCC2)c2cc3cccnc3[nH]2)cc1
Temperature: 50 °C
Reaction time: 6 h
Yield: 3.6 %

Procedure:
A mixture of 2-[2-(tetrahydro-pyran-4-yl)-1-(4-trifluoromethyl-phenyl)-vinyl]-1H-pyrrolo[2,3-b]pyridine (170 mg, 4.5 mmol) and 10% palladium on activated carbon (51 mg) in methanol (200 mL) was heated at 50° C. under hydrogen (50 psi) and kept for 6 h. The mixture was cooled to 25° C., the solids filtered off, washed with ethyl acetate and concentrated in vacuo. Purification using a Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 2-[2-(tetrahydro-pyran-4-yl)-1-(4-trifluoromethyl-phenyl)-ethyl]-1H-pyrrolo[2,3-b]pyridine (60 mg, 35%) as a white solid: LC/MS m/e calcd for C21H21F3N2O [M+H]+ 375.41, observed 375.4; 1H NMR (400 MHz, CDCl3) δ ppm 8.12 (d, J=4.5 Hz, 1H), 7.92 (d, J=7.6 Hz, 1H), 7.49-7.58 (m, J=8.1 Hz, 2H), 7.39-7.47 (m, J=8.1 Hz, 2H), 7.09 (dd, J=7.6, 5.1 Hz, 1H), 6.36 (s, 1H), 4.39 (t, J=7.8 Hz, 1H), 3.92 (d, J=11.1 Hz, 2H), 3.27 (t, J=11.6 Hz, 2H), 2.26 (dt, J=14.1, 7.2 Hz, 1H), 2.03 (dt, J=14.0, 7.0 Hz, 1H), 1.66 (d, J=12.4 Hz, 2H), 1.33-1.56 (m, 3H).
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:9]C(Cl)(Cl)Cl>O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C#C)C=CC=CC=1>[Br:9][C:8]#[C:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClC(Cl)(Cl)Br
Reactant: C#Cc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Product: BrC#Cc1ccccc1
Yield: 95 %

Procedure:
In a 10 mL round-bottom flask, 1.02 g of phenylacetylene (10 mmol), 2.1 g bromotrichloromethane (10.5 mmol) and 100 mg of tetra-n-butylammonium fluoride trihydrate (0.316 mmol) were stirred at 24° C. for 15 min. The temperature of the mixture rose to 33° C. in the course of the process. Analysis of the resulting mixture showed that it contained 1.72 g of 1-bromo-2-phenylacetylene (95% yield) and 0.05 g of the unconverted phenylacetylene.