Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH:2]([C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]([CH3:15])([CH3:14])[CH3:13])[N:7]=1)[C:3](=O)[CH3:4].[NH2:16][C:17]([NH2:19])=[S:18]>C(O)C>[C:12]([C:8]1[N:7]=[C:6]([C:2]2[S:18][C:17]([NH2:19])=[N:16][C:3]=2[CH3:4])[CH:11]=[CH:10][N:9]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: NC(N)=S
Reactant: CC(=O)C(Br)c1ccnc(C(C)(C)C)n1
Solvent: CCO
Product: Cc1nc(N)sc1-c1ccnc(C(C)(C)C)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-Bromo-1-(2-tert-butyl-pyrimidin-4-yl)-propan-2-one (1 g, 37 mmol) is stirred in ethanol (40 ml) at 70° C. Thiourea (280 mg, 37 mmol) is added and stirring continued for 1 hour at 70° C. After cooling to room temperature the mixture is filtered to afford the titled compound as the hydrobromide salt. If required, the product is dissolved in 1M aqueous hydrochloric acid and the solution is brought to pH 8 by addition of sodium hydroxide solution to precipitate the titled compound as the free base.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([CH2:13][C:14]([OH:16])=[O:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CI.[C:19]([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:19][O:15][C:14](=[O:16])[CH2:13][CH:10]1[CH2:11][CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(CC(=O)O)C1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)CC1CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 2-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)acetic acid (500 mg, 2.18 mmol, Astatec Pharmaceutical Technology Co.) in DMF (10 mL) was added methyl iodide (1634, 2.62 mmol, Sigma-Aldrich) and K2CO3 (904 mg, 6.53 mmol). These ingredients were stirred at a temperature of about 25° C. for 1 h after which the reaction mixture was quenched with water (20 mL), extracted three times with EtOAc (20 mL for each extraction), washed twice with water (20 mL for each wash), washed with saturated aqueous NaCl (10 mL), dried (MgSO4), and concentrated under reduced pressure to provide tert-butyl 3-(2-methoxy-2-oxoethyl)pyrrolidine-1-carboxylate as an oil. To a mixture of tert-butyl 3-(2-methoxy-2-oxoethyl)pyrrolidine-1-carboxylate (2.18 mmol) in dioxane (10 mL) at a temperature of about 25° C. was added 4N HCl in dioxane (10.8 mmol). Then the reaction mixture was stirred at 50° C. for 2 h. Thereafter, the mixture was concentrated under reduced pressure to provide 380 mg of the hydrochloride of methyl 2-(pyrrolidin-3-yl)acetate as a colorless oil (yield 96% for two steps), the identity of which was confirmed using 1H NMR and LC/MS.
Reaction SMILES: [F:1][C:2]1[CH:19]=[C:18]([I:20])[CH:17]=[CH:16][C:3]=1[NH:4][C:5]1[C:6]([C:13]([OH:15])=O)=[CH:7][N:8]([CH3:12])[C:9](=[O:11])[CH:10]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:33][CH2:34][CH:35]([OH:38])[CH2:36][OH:37]>C1COCC1.CN(C=O)C>[OH:38][CH:35]([CH2:36][OH:37])[CH2:34][NH:33][C:13]([C:6]1[C:5]([NH:4][C:3]2[CH:16]=[CH:17][C:18]([I:20])=[CH:19][C:2]=2[F:1])=[CH:10][C:9](=[O:11])[N:8]([CH3:12])[CH:7]=1)=[O:15]
Reactant: Cn1cc(C(=O)O)c(Nc2ccc(I)cc2F)cc1=O
Reactant: NCC(O)CO
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cn1cc(C(=O)NCC(O)CO)c(Nc2ccc(I)cc2F)cc1=O
Yield: 33 %

Procedure:
4-(2-Fluoro-4-iodoanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxylic acid and CDI were dissolved in anhydrous THF/DMF (5:1) and treated with 3-amino-1,2-propandiol as for example 34. After workup, the residue was further purified by flash chromatography on silica gel (5% MeOH/CH2Cl2—10% MeOH/CH2Cl2 gradient elution) to give N-(2,3-dihydroxypropyl)-4-(2-fluoro-4-iodoanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide (33%) as a pale cream solid; m.p. (EtOAc/Hexane) 96-101° C. (glue-liquid). 1H NMR [400 MHz, CH3OD] δ 8.17 (s, 1H), 7.61 (dd, J=9.9, 1.9 Hz, 1H), 7.59-7.55 (m, 1H), 7.22 (t, J=8.4, 1H), 5.78 (s, 1H), 3.85-3.79 (m, 1H), 3.56 (dd, J=5.4, 2.3 Hz, 2H), 3.51 (s, 3H), 3.53-3.50 (m, 1H), 3.39-3.33 (m, 1H). HRMS (FAB+) calcd for C16H18FIN3O4 462.0326 (M+), found 462.0332. HPLC 84.8% (254 nm).
Reaction SMILES: C([O:3][C:4](=[O:39])[CH:5]([C:7]1[CH:8]=[C:9]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:16]=2[CH2:25][N:26]2[C@@H:30]([CH3:31])[C@@H:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[O:28][C:27]2=[O:38])[C:10]([O:13][CH3:14])=[CH:11][CH:12]=1)[CH3:6])C.[OH-].[Li+]>CO>[CH3:14][O:13][C:10]1[C:9]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:23])([F:22])[F:24])=[CH:17][C:16]=2[CH2:25][N:26]2[C@@H:30]([CH3:31])[C@@H:29]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[O:28][C:27]2=[O:38])=[CH:8][C:7]([CH:5]([CH3:6])[C:4]([OH:39])=[O:3])=[CH:12][CH:11]=1
Reactant: CCOC(=O)C(C)c1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN2C(=O)O[C@H](c3ccccc3)[C@@H]2C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(C(C)C(=O)O)cc1-c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2ccccc2)[C@@H]1C
Temperature: 65 °C
Reaction time: 3 h

Procedure:
To 2-[6-methoxy-2′-((4S,5R)-4-methyl-2-oxo-5-phenyl-oxazolidin-3-ylmethyl)-4′-trifluoromethyl-biphenyl-3-yl]-propionic acid ethyl ester (0.05 g, 0.09 mmol) in MeOH (2 mL) was added lithium hydroxide (1N; 1 mL, 1.0 mmol), and the reaction was stirred at 65° C. for 3 hours. The crude material was purified by preparative HPLC to give the title compound. M+H is 514.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:20][OH:21])[CH:5]=[C:6]([F:19])[C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:14]=1.Cl[C:23]1[CH:24]=[C:25]2[N:32](C(OC(C)(C)C)=O)[C@@H:31]([CH3:40])[CH2:30][N:26]2[C:27](=[O:29])[N:28]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([F:19])[C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]([C:15]([F:16])([F:17])[F:18])=[CH:13][CH:14]=1)[CH2:20][O:21][C:23]1[CH:24]=[C:25]2[NH:32][C@@H:31]([CH3:40])[CH2:30][N:26]2[C:27](=[O:29])[N:28]=1
Reactant: OCc1cc(F)c(Oc2ccc(C(F)(F)F)nc2)c(F)c1
Reactant: C[C@H]1Cn2c(cc(Cl)nc2=O)N1C(=O)OC(C)(C)C
Product: C[C@H]1Cn2c(cc(OCc3cc(F)c(Oc4ccc(C(F)(F)F)nc4)c(F)c3)nc2=O)N1

Procedure:
The title compound was prepared by a procedure similar to that described for E9 starting from (3,5-difluoro-4-((6-(trifluoromethyl)pyridin-3-yl)oxy)phenyl)methanol and (S)-tert-butyl 7-chloro-2-methyl-5-oxo-2,3-dihydroimidazo[1,2-c]pyrimidine-1(5H)-carboxylate.
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].Cl[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=1[N+:23]([O-:25])=[O:24].C([O-])(O)=O.[Na+]>CN(C=O)C.CCOC(C)=O.[F-].[Cs+]>[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:3]([O:11][CH2:12][CH3:13])=[O:10])=[C:16]([N+:23]([O-:25])=[O:24])[CH:17]=1
Reactant: COc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CCOC(=O)CC(=O)OCC
Agent: O=C([O-])O
Agent: [Cs+]
Agent: [F-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C(=O)OCC)c1ccc(OC)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a suspension of sodium hydride (2.81 g; 117.28 mmol; 2.2 eq) in DMF (35 mL) under nitrogen is added slowly at 0° C. over 20 min diethyl malonate (17.89 mL; 117.28 mmol; 2.2 eq) followed by cesium fluoride (404.91 mg; 2.67 mmol; 0.05 eq) and 1-chloro-4-methoxy-2-nitrobenzene (10 g; 53.31 mmol; 1 eq; commercially available from ACROS). The resulting reaction mixture is stirred at room temperature for 45 min then heated at 105° C. overnight. The reaction is quenched by addition of water and DMF is removed under reduced pressure. The residue obtained is taken up in EtOAc then an aqueous solution of NaHCO3 is added. The organic phase is separated and dried over MgSO4. The solvent is removed under reduced pressure to afford 25 g of a brown oil which is purified on silica gel (800 g) using cyclohexane/EtOAc (95/5) as eluent affording 4.7 g (28%) of the title compound as a yellow oil. HPLC (max plot) 89%; Rt 4.25 min. LC/MS: (ES+): 312.1, (ES−): 310.1.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[Cl:5][C:6]1[CH:11]=[C:10]([F:12])[C:9]([F:13])=[CH:8][C:7]=1[C:14](=[O:25])[C:15](=[CH:21]OCC)[C:16]([O:18][CH2:19][CH3:20])=[O:17]>C(O)C>[Cl:5][C:6]1[CH:11]=[C:10]([F:12])[C:9]([F:13])=[CH:8][C:7]=1[C:14](=[O:25])[C:15](=[CH:21][NH:4][CH:1]1[CH2:3][CH2:2]1)[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(F)cc1Cl
Reactant: NC1CC1
Solvent: CCO
Product: CCOC(=O)C(=CNC1CC1)C(=O)c1cc(F)c(F)cc1Cl
Reaction time: 1 h

Procedure:
A 3.9 ml portion of cyclopropylamine was added dropwise to a solution of 16.25 g of 2-chloro-α-(ethoxymethylene)-4,5-difluoro-β-oxobenzenepropanoic acid, ethyl ester in 45 ml of ethanol, producing an exotherm. The solution was stirred for 1 hour, evaporated to dryness and the residue crystallized from hexane, giving 14.6 g of the desired compound, mp 55°-58° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[F:13])[C:7]([OH:9])=[O:8])([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[F:13])[C:7]([OH:9])=[O:8]
Reactant: O=C(O)c1ccc(F)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: Nc1cc(C(=O)O)ccc1F
Reaction time: 6 h

Procedure:
A mixture of 3-nitro-4-fluorobenzoic acid (1.85 g, 10.0 mmol) in MeOH (10 mL) and 5% Pd/C (100 mg) was stirred under an atmosphere of hydrogen and for 6 h. The catalyst was removed by filtration, washed with methanol and the volatiles were removed in vacuo to give compound 8A, 3-amino-4-fluorobenzoic acid, as a light yellow solid (1.50 g, 9.67 mmol, 97%).
Reaction SMILES: [NH2:1][C:2]1[C:9]([F:10])=[CH:8][C:7]([Br:11])=[CH:6][C:3]=1[CH:4]=O.[NH2:12][C:13](N)=[O:14]>>[Br:11][C:7]1[CH:6]=[C:3]2[C:2](=[C:9]([F:10])[CH:8]=1)[N:1]=[C:13]([OH:14])[N:12]=[CH:4]2
Reactant: NC(N)=O
Reactant: Nc1c(F)cc(Br)cc1C=O
Product: Oc1ncc2cc(Br)cc(F)c2n1
Temperature: 180 °C
Yield: 82.3 %

Procedure:
A stirred mixture of 2-amino-5-bromo-3-fluorobenzaldehyde (2.17 g, 10 mmol) and urea (9 g, 150 mmol) was heated at 180° C. for 2 h. LCMS showed the reaction was completed. The reaction mixture was cooled to RT, and the resulting precipitate was filtered and washed with water (500 mL*3). The moisture trapped was completely removed by the co-evaporation with toluene three times. The title compound (2 g, 83%) was obtained as a yellow solid. MS (ES+) C8H4BrFN2O requires: 242, 244. Found: 243, 245 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[C:10]2([CH3:11])[CH:5]([CH:6]([OH:12])[CH2:7][CH2:8][CH2:9]2)[CH2:4][CH:3]1[CH2:13][CH2:14][O:15][CH2:16][CH2:17][CH2:18][C:19]([OH:22])([CH3:21])[CH3:20].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl>[CH3:1][C:2]1([CH3:23])[C:10]2([CH3:11])[CH:5]([C:6](=[O:12])[CH2:7][CH2:8][CH2:9]2)[CH2:4][CH:3]1[CH2:13][CH2:14][O:15][CH2:16][CH2:17][CH2:18][C:19]([OH:22])([CH3:21])[CH3:20]
Reactant: CC(C)(O)CCCOCCC1CC2C(O)CCCC2(C)C1(C)C
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(C)(O)CCCOCCC1CC2C(=O)CCCC2(C)C1(C)C
Yield: 77.4 %

Procedure:
260 mg (0.80 mmol) of 48 is reacted with 240 mg (1.12 mmol) of pyridinium chlorochromate in 16 ml of methylene chloride analogously to 30., and 201 mg of the title compound is obtained as colorless oil.
Reaction SMILES: C[O:2][C:3](=[O:40])[C:4]([CH3:39])([CH3:38])[CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([N:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C@H:19]([N:26]([C:34](=[O:36])[CH3:35])[C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)[CH2:18][C@@H:17]2[CH3:37])=[O:15])=[CH:10][CH:9]=1.[OH-].[Na+]>CO.O1CCCC1.O>[C:34]([N:26]([C:27]1[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=1)[C@H:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:16]([C:14]([C:11]2[CH:12]=[CH:13][C:8]([CH2:7][CH2:6][CH2:5][C:4]([CH3:39])([CH3:38])[C:3]([OH:40])=[O:2])=[CH:9][CH:10]=2)=[O:15])[C@@H:17]([CH3:37])[CH2:18]1)(=[O:36])[CH3:35]
Reactant: COC(=O)C(C)(C)CCCc1ccc(C(=O)N2c3ccccc3[C@H](N(C(C)=O)c3ccc(Cl)cc3)C[C@@H]2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(CCCC(C)(C)C(=O)O)cc2)c2ccccc21
Temperature: 60 °C
Yield: 60 %

Procedure:
5-(4-{(2S,4R)-4-[acetyl(4-chloro-phenyl)-amino]-2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl}-phenyl)-2,2-dimethyl-pentanoic acid methyl ester (500 mg, 0.89 mmol, 1 eq.) was dissolved in methanol/tetrahydrofuran (2/1) (4 ml). A solution of sodium hydroxide (71 mg, 1.8 mmol, 2 eq.) in water (1 ml) was added and reaction mixture heated to 60° C. for 20 h. The mixture was concentrated and the residue was acidified with a 1N HCl aqueous solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated to give the crude acid. Purification by silica gel chromatography gave pure 5-(4-{(2S,4R)-4-[acetyl(4-chloro-phenyl)-amino]-2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl}-phenyl)-2,2-dimethyl-pentanoic acid (292 mg, 60%).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7](N)[CH:8]=[N:9]2)=[CH:4][C:3]=1[O:13][CH3:14].Cl.N([O-])=[O:17].[Na+].S(=O)(=O)(O)O.C(=O)([O-])O.[Na+]>O>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([OH:17])[CH:8]=[N:9]2)=[CH:4][C:3]=1[O:13][CH3:14]
Reactant: COc1cc2cc(N)cnc2cc1F
Reactant: O=N[O-]
Agent: Cl
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Product: COc1cc2cc(O)cnc2cc1F
Temperature: 4 °C
Reaction time: 2 h
Yield: 72.2 %

Procedure:
A mixture of 7-fluoro-6-methoxy-quinolin-3-ylamine (prepared according to procedures described in FR2862301, 830 mg, 4.3 mmol, 1.0 eq) and concentrated hydrochloric acid (12N, 3.0 g, 30.2 mmol, 7.0 eq) is stirred at 4° C. before the addition of sodium nitrite (313 mg, 4.7 mmol, 1.1 eq) in water (24 mL). After 2 hours stirring at 4° C., the resulting mixture is added dropwise to a stirred solution of concentrated sulfuric acid (8.2 mL) and water (24 mL) at 90° C. within 10 minutes. After 1 hour stirring at 90° C. the reaction mixture is cooled down to room temperature, neutralized with sodium hydrogen carbonate and extracted with ethyl acetate (3×80 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a crude product that is recrystallized in methanol to afford 7-fluoro-6-methoxy-quinolin-3-ol as an off-white solid (0.60 g, 72% yield).
Reaction SMILES: I[C:2]1[C:3]([O:20][CH3:21])=[CH:4][C:5]([CH:17]([CH3:19])[CH3:18])=[C:6]([CH:16]=1)[O:7][C:8]1[C:9]([NH2:15])=[N:10][C:11]([NH2:14])=[N:12][CH:13]=1.C(NC(C)C)(C)C.[C:29]([CH:31]1[CH2:33][CH2:32]1)#[CH:30]>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.O>[CH:31]1([C:29]#[C:30][C:2]2[C:3]([O:20][CH3:21])=[CH:4][C:5]([CH:17]([CH3:19])[CH3:18])=[C:6]([CH:16]=2)[O:7][C:8]2[C:9]([NH2:15])=[N:10][C:11]([NH2:14])=[N:12][CH:13]=2)[CH2:33][CH2:32]1
Reactant: COc1cc(C(C)C)c(Oc2cnc(N)nc2N)cc1I
Reactant: C#CC1CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Solvent: O
Product: COc1cc(C(C)C)c(Oc2cnc(N)nc2N)cc1C#CC1CC1
Temperature: 70 °C
Yield: 89.4 %

Procedure:
5-(5-Iodo-2-isopropyl-4-methoxy-phenoxy)-pyrimidine-2,4-diamine (873 g, 2 mmol), bis(triphenylphosphine)palladium dichloride (140 mg, 0.2 mmol), and CuI (19 mg, 0.1 mmol) were added to 15 mL of degassed diisopropylamine under nitrogen in a screw cap flask. Ethynylcyclopropane (0.25 mL, 3 mmol) was added, and the flask was sealed and heated to 70° C. for 18 hours. The reaction mixture was cooled, poured into water, and extracted into dichloromethane. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was chromatographed on 100 g of flash silica (2%-3% MeOH/CH2Cl2) to give 605 mg of 5-(5-cyclopropylethynyl-2-isopropyl-4-methoxy-phenoxy)-pyrimidine-2,4-diamine. MP 225.5-226.8° C.; MS (M+H)=339.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.C(=O)([O-])[O-].[K+].[K+].F[C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=1>N1C=CC=CC=1.[Cu-]=O>[N:1]1([C:13]2[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: O=Cc1ccc(F)cc1
Reactant: c1nc[nH]n1
Agent: O=[Cu-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Product: O=Cc1ccc(-n2cncn2)cc1

Procedure:
To a solution of 2-methoxy-N-(3,5-dimethylbenzoyl) glycine methyl ester (16.7 g, 66.5 mmol) in toluene (70 ml) under nitrogen atmosphere is added phosphorus thrichloride (6.0 ml, 68.7 mmol) at room temperature. The reaction mixture is heated at 70° C. for 16 h. Then, trimethyl phosphite (8.1 ml, 68.7 mmol) is added dropwise to the stirred mixture at 70° C. and stirring is continued for further 2 h at 70° C. The solvent is evaporated in vacuo. The residue is diluted with hexane, filtered, and washed with ethyl acetate. The combined filtrate is concentrated in vacuo and the crude material is purified by column chromatography on silica with ethyl acetate to give trimethyl 2-(3,5-dimethylbenzoyl)amino-phosphonoacetate. A mixture of 1,2,4-triazole (4.06 g, 58.7 mmol), potassium carbonate (9.05 g, 65.5 mmol), 4-fluorobenzaldehyde (6.3 ml, 58.7 mmol), and copper(I) oxide (0.26 g, 1.82 mmol) in pyridine (30 ml) is heated under nitrogen atmosphere at reflux overnight. After pyridine is distilled, the residue is diluted with chloroform, filtered, and washed with chloroform. The combined filtrate is washed with water, dried over magnesium sulfate, and concentrated in vacuo. The crude material is purified by column chromatography on silica with hexane/ethyl acetate (1:2) to give 4-(1,2,4-triazol-1-yl)-benzaldehyde and with ethyl acetate/methanol (19:1) to give 4-(1,3,4-triazol-1-yl)-benzaldehyde.
Reaction SMILES: C(OC([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16]([N:18]([CH3:20])[CH3:19])=[O:17])=O)C1C=CC=CC=1.[H][H]>C(O)C.[C].[Pd]>[CH3:19][N:18]([CH3:20])[C:16]([C@@H:12]1[CH2:13][CH2:14][CH2:15][NH:11]1)=[O:17]
Reactant: [H][H]
Reactant: CN(C)C(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CN(C)C(=O)[C@@H]1CCCN1
Yield: 99 %

Procedure:
In 86 ml of ethanol was dissolved 4.3 g of compound (88) and after adding thereto 210 mg of 10% palladium-carbon, the mixture was stirred vigorously for 90 minutes in a hydrogen stream. After filtering off the catalyst, ethanol was distilled off under reduced pressure to provide 2.19 g of crude (S)-N,N-dimethyl-2-pyrrolidinecarboxamide (89).
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].Br[C:10]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:11]=1[CH:12]=[O:13].[CH:19]1(B(O)O)[CH2:21][CH2:20]1>N#N.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>[Br:18][C:15]1[CH:16]=[CH:17][C:10]([CH:19]2[CH2:21][CH2:20]2)=[C:11]([CH:14]=1)[CH:12]=[O:13]
Reactant: OB(O)C1CC1
Reactant: O=Cc1cc(Br)ccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: O=P([O-])([O-])[O-]
Product: O=Cc1cc(Br)ccc1C1CC1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
To a mixed solution of toluene (2250 ml) and distilled water (250 ml) at 0° C. is added finely ground potassium phosphate tribasic (699.23 g, 3.29 mol) portionwise over 10 minutes. This mixture is then allowed to warm to room temperature, followed by the addition of 2,5-dibromobenzaldehyde (235.0 g, 890 mmol) and cyclopropylboronic acid (68.92 g, 801 mmol). After stirring at room temperature for 50 minutes under a blanket of nitrogen tetrakis(triphenylphosphine)palladium (102.89 g, 89 mmol) is added over 10 minutes, washing residual solid with toluene (50 ml). The reaction mixture is then stirred at 80° C. for 22 hours, followed by cooling to room temperature and addition of distilled water (500 ml). The mixture is filtered through a pad of silica (washing with additional ethyl acetate) and the aqueous phase is extracted with ethyl acetate (2×300 ml). The combined organic extracts are washed with brine (500 ml), dried with anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography on silica gel (iso-hexane/ethyl acetate as eluant) followed by distillation under reduced pressure to afford 5-bromo-2-cyclopropylbenzaldehyde as a yellow oil.
Reaction SMILES: Br[C:2]1[NH:3][C:4]2[C:9]([C:10]=1C1CCCCC1)=[CH:8][CH:7]=[C:6]([C:17]([NH:19]S(N(C)C)(=O)=O)=[O:18])[CH:5]=2.COC1C=CC(B(O)O)=C(C=O)C=1.[Li+].[Cl-].C([O-])([O-])=O.[Na+].[Na+]>CCO.C1(C)C=CC=CC=1.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>[NH:3]1[C:4]2[C:9](=[CH:8][CH:7]=[C:6]([C:17]([NH2:19])=[O:18])[CH:5]=2)[CH:10]=[CH:2]1
Reactant: CN(C)S(=O)(=O)NC(=O)c1ccc2c(C3CCCCC3)c(Br)[nH]c2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: COc1ccc(B(O)O)c(C=O)c1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: NC(=O)c1ccc2cc[nH]c2c1
Temperature: 70 °C
Reaction time: 0.17 h

Procedure:
To a slurried solution of 2-bromo-3-cyclohexyl-N-[(dimethylamino)sulfonyl]-indole-6-carboxamide (54.0 g, 126 mmol), 4-methoxy-2-formylphenylboronic acid (29.5 g, 164 mmol) and LiCl (13.3 g, 315 mmol) in EtOH/toluene (1:1, 1 L) was added a solution of Na2CO3 (40.1 g, 379 mmol) in water (380 mL). The reaction mixture was stirred 10 min. and then Pd(PPh3)4 (11.3 g, 10.0 mmol) was added. The reaction solution was flushed with nitrogen and heated at 70° C. (internal monitoring) overnight and then cooled to rt. The reaction was diluted with EtOAc (1 L) and EtOH (100 mL), washed carefully with 1N aqueous HCl (1 L) and brine (500 mL), dried (MgSO4), filtered and concentrated. The residual solids were stirred with Et2O (600 mL) for 1 h and collected by filtration to yield 1H-indole-6-carboxamide, 3-cyclohexyl-N-[(dimethylamino)sulfonyl]-2-(2-formyl-4-methoxyphenyl)- (52.8 g, 109 mmol, 87%) as a yellow powder which was used without further purification. 1HNMR (300 MHz, d6-DMSO) δ 11.66 (s, 1H), 8.17 (s, 1H), 7.75 (d, J=8.4 Hz, 1H), 7.74 (d, J=8.4 Hz, 1H), 7.59 (dd, J=1.4, 8.4 Hz, 1H), 7.23-7.16 (m, 2H), 7.08 (dd, J=2.6, 8.4 Hz, 1H), 6.54 (d, J=8.8 Hz, 1H), 3.86 (s, 3H), 3.22-3.08 (m, 1H), 2.91 (s, 6H), 2.00-1.74 (m, 7H), 1.60-1.38 (m, 3H). 13CNMR (75 MHz, CDCl3) δ 165.7, 158.8, 147.2, 139.1, 134.3, 132.0, 123.4, 122.0, 119.2, 118.2, 114.8, 112.3, 110.4, 109.8, 79.6, 45.9, 37.2 (2), 34.7, 32.0 (2), 25.9 (2), 24.9. LCMS: m/e 482 (M−H)−, ret time 2.56 min, column A, 4 minute gradient.