Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](OS(C(F)(F)F)(=O)=O)[CH:5]=[C:6]([Cl:32])[C:7]=1[CH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([N:14]2[CH2:19][CH2:18][CH:17]([O:20][Si:21]([CH:28]([CH3:30])[CH3:29])([CH:25]([CH3:27])[CH3:26])[CH:22]([CH3:24])[CH3:23])[CH2:16][CH2:15]2)[C:10]1=[O:31].[F:41][C:42]1[CH:43]=[C:44](B(O)O)[CH:45]=[CH:46][C:47]=1[C:48]#[N:49].C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.O.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:44]2[CH:45]=[CH:46][C:47]([C:48]#[N:49])=[C:42]([F:41])[CH:43]=2)[CH:5]=[C:6]([Cl:32])[C:7]=1[CH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([N:14]2[CH2:15][CH2:16][CH:17]([O:20][Si:21]([CH:25]([CH3:26])[CH3:27])([CH:22]([CH3:23])[CH3:24])[CH:28]([CH3:30])[CH3:29])[CH2:18][CH2:19]2)[C:10]1=[O:31]
Reactant: N#Cc1ccc(B(O)O)cc1F
Reactant: CC(C)[Si](OC1CCN(N2CC[C@@H](Cc3c(Cl)cc(OS(=O)(=O)C(F)(F)F)cc3Cl)C2=O)CC1)(C(C)C)C(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)[Si](OC1CCN(N2CC[C@@H](Cc3c(Cl)cc(-c4ccc(C#N)c(F)c4)cc3Cl)C2=O)CC1)(C(C)C)C(C)C
Yield: 87.2 %

Procedure:
Purge with nitrogen for 10 minutes a mixture of (R)-trifluoro-methanesulfonic acid 3,5-dichloro-4-[2-oxo-1-(4-triisopropylsilanyloxy-piperidin-1-yl)-pyrrolidin-3-ylmethyl]-phenyl ester (0.18 g, 0.28 mmol), 3-fluoro-4-cyanophenylboronic acid (0.055 g, 0.33 mmol), sodium carbonate (0.089 g, 0.84 mmol) in THF (10 mL) and water (3 mL). Add Pd(PPh3)4 (0.016 g, 0.01 mmol) to the mixture. Stir the reaction at 80° C. for 1 hour. Cool the reaction, dilute with ethyl acetate, and wash with water and brine. Dry the organic layer (Na2SO4), remove the solvent in vacuo to afford crude product, and purify on silica gel column with 0% to 50% ethyl acetate in hexanes gradient to afford 0.151 g of the titled product. MS (m/z): 617 (M+).
Reaction SMILES: CC(C)([O-])C.[K+].[CH:7]1([CH2:14][CH2:15][C:16](=[O:23])[CH2:17][C:18](OCC)=O)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.[K].[C:25]([C:29]1[CH:34]=[CH:33][C:32](CI)=[CH:31][C:30]=1[N+:37]([O-:39])=[O:38])([CH3:28])([CH3:27])[CH3:26]>C(OCC)C.O1CCCC1>[C:25]([C:29]1[CH:34]=[CH:33][C:32]([CH2:18][CH2:17][C:16](=[O:23])[CH2:15][CH2:14][CH:7]2[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]2)=[CH:31][C:30]=1[N+:37]([O-:39])=[O:38])([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)c1ccc(CI)cc1[N+](=O)[O-]
Reactant: CCOC(=O)CC(=O)CCC1CCCCCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: [K]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)c1ccc(CCC(=O)CCC2CCCCCC2)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 68.1 %

Procedure:
454 mg (4.06 mmol) of potassium-t-butoxide were added to 10 ml of a tetrahydrofuran solution containing 1.00 g (4.16 mmol) of ethyl 5-cycloheptyl-3-oxovalerate (prepared as described in Preparation 5). The mixture was then stirred for 10 minutes to prepare the corresponding potassium salt. 1.11 g (3.47 mmol) of 2-t-butyl-5-iodomethyl-1-nitrobenzene (prepared as described in Preparation 51) were added to the mixture in an ice bath, and the mixture was stirred for 2 hours at the temperature of the ice bath. The reaction solution was diluted with diethyl ether and washed with water. The solvent was removed by distillation under reduced pressure, and the resulting residue was dissolved in 10 ml of ethanol. 1.73 ml of a 2N aqueous solution of sodium hydroxide were added, and the mixture was heated for 4 hours under reflux. The reaction mixture was then cooled in an ice bath, sufficient concentrated aqueous hydrochloric acid was added to adjust its pH to a value of 5.0, and the mixture was heated for a further 2 hours under reflux. At the end of this time, the reaction solution was diluted with diethyl ether and washed with water. The solvent was then removed by distillation under reduced pressure. The resulting residue was subjected to column chromatography through 70 g of silica gel. Elution with a 2:1 by volume mixture of methylene chloride and hexane afforded 850 mg (yield 68%) of the title compound as an oily substance.
Reaction SMILES: [CH2:1]([SnH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].[CH2:10]([CH:12]([CH2:18][CH2:19][CH2:20][CH3:21])[C:13]([O:15][CH:16]=[CH2:17])=[O:14])[CH3:11]>C1CCCCC1>[CH2:10]([CH:12]([CH2:18][CH2:19][CH2:20][CH3:21])[C:13]([O:15][CH2:16][CH2:17][Sn:5]([CH2:17][CH2:16][O:15][C:13](=[O:14])[CH:12]([CH2:10][CH3:11])[CH2:18][CH2:19][CH2:20][CH3:21])([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:1][CH2:2][CH2:3][CH3:4])=[O:14])[CH3:11]
Reactant: CCCC[SnH2]CCCC
Reactant: C=COC(=O)C(CC)CCCC
Solvent: C1CCCCC1
Product: CCCCC(CC)C(=O)OCC[Sn](CCCC)(CCCC)CCOC(=O)C(CC)CCCC
Reaction time: 0.5 h

Procedure:
2.349 g (0.01 mol) of dibutyltin dihydride, 3.405 g (0.02 mol) of distilled vinyl 2-ethylhexanoate and 2.5 g of anhydrous cyclohexane were introduced into a Pyrex® tube. The exposure to ultraviolet rays was for 8 hours 30 min at 30°-35° C. The solvent was removed under vacuum at ambient temperature.
Reaction SMILES: [CH2:1]1[O:9][CH:2]1[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:10]([NH2:13])[CH:11]=[CH2:12]>>[CH2:10]([NH:13][CH2:1][CH:2]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[OH:9])[CH:11]=[CH2:12]
Reactant: C=CCN
Reactant: c1ccc(C2CO2)cc1
Product: C=CCNCC(O)c1ccccc1

Procedure:
A mixture of styrene oxide (24 mL, 0.2 moles) and allylamine (60.8 mL, 0.8 moles) was heated to reflux under nitrogen atmosphere, for 24 hours. Upon cooling, product crystallized and was triturated with hexane. Recrystallization from hexane afforded the title compound essentially uncontaminated by the other possible regioisomer. Ms m+/z=177; H1NMR (CDCl3): δ 7.3 (br.s, 5H), 5.6-6.1 (m, 1H), 4.9-5.4 (m, 2H), 4.75 (m, 1H), 3.2 (br.d, 2H), 2.9 (br.s, 2H), 2.7 (m, 2H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:4]([N+:15]([O-:17])=[O:16])=[C:5]([CH:12]=[CH:13][CH:14]=1)[C:6]([N:8]([O:10][CH3:11])[CH3:9])=[O:7].[CH3:18][C:19]([Si:22](Cl)([CH3:24])[CH3:23])([CH3:21])[CH3:20].N1C=CN=C1.O>CN(C=O)C>[Si:22]([O:1][CH2:2][C:3]1[C:4]([N+:15]([O-:17])=[O:16])=[C:5]([CH:12]=[CH:13][CH:14]=1)[C:6]([N:8]([O:10][CH3:11])[CH3:9])=[O:7])([C:19]([CH3:21])([CH3:20])[CH3:18])([CH3:24])[CH3:23]
Reactant: CON(C)C(=O)c1cccc(CO)c1[N+](=O)[O-]
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CON(C)C(=O)c1cccc(CO[Si](C)(C)C(C)(C)C)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.5 %

Procedure:
To a solution of Intermediate 37C (1.079 g, 4.49 mmol) and TBDMS-Cl (1.016 g, 6.74 mmol) in DMF (4 mL) was added imidazole (0.612 g, 8.98 mmol). The mixture was stirred at room temperature for 1 h. Water was added, and the mixture was extracted with EtOAc. The combined extracts were washed with 10% LiCl and brine, dried over MgSO4, filtered and concentrated to dryness. The crude material was purified by flash chromatography (SiO2, 40 g column, EtOAc/hexane=0-30%) to afford Intermediate 37D (1.25 g, 79%). HPLC: RT=3.05 min (CHROMOLITH® SpeedROD column 4 6×50 mm, 10-90% aqueous methanol over 4 minutes containing 0.1% TFA, 4 mL/min, monitoring at 220 nm), MS(ES): m/z=355.0 [M+H+]. 1H NMR (400 MHz, chloroform-d) δ 7.90 (d, J=7.7 Hz, 1H), 7.70-7.62 (m, 1H), 7.47 (d, J=7.7 Hz, 1H), 4.98 (s, 2H), 3.46 (br. s., 3H), 3.36 (br. s., 3H), 0.98 (s, 9H), 0.15 (s, 6H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][CH:27]=1)[CH2:5][NH:6][C:7]([C:9]1[C:10](/[CH:22]=[CH:23]/[CH3:24])=[N:11][C:12]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[CH:13][C:14]=1[CH3:15])=[O:8]>CO.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([CH2:5][NH:6][C:7]([C:9]2[C:10]([CH2:22][CH2:23][CH3:24])=[N:11][C:12]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:13][C:14]=2[CH3:15])=[O:8])[CH:25]=[CH:26][CH:27]=1
Reactant: C/C=C/c1nc(N2CCOCC2)cc(C)c1C(=O)NCc1cccc(F)c1
Agent: [Pd]
Solvent: CO
Product: CCCc1nc(N2CCOCC2)cc(C)c1C(=O)NCc1cccc(F)c1
Reaction time: 3 h
Yield: 61.7 %

Procedure:
A solution of 300 mg (0.81 mmol) (E)-N-(3-fluorobenzyl)-4-methyl-6-morpholino-2-(prop-1-enyl)-pyridine-3-carboxylic acid amide (example 9) in MeOH (9 ml) was degassed with argon for 15 min. Then 0.065 g Pd/C (10% w/w) was added and the RM was stirred for 3 h under hydrogen atmosphere by use of an H2 balloon. Subsequently the mixture was filtered through celite and the filtrate was concentrated in vacuo. Purification of the residue by CC (hexane/acetone 17:3) provided 170 mg (0.5 mmol, 56%) N-[(3-fluorophenyl)-methyl]-4-methyl-6-morpholin-4-yl-2-propyl-pyridine-3-carboxylic acid amide (example 10). [M+H]+372.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[N:8]=[C:7]([O:13][CH3:14])[C:6]([NH:15][C:16](=[O:20])OCC)=[N:5]2.[Br:21][C:22]1[CH:23]=[C:24]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:25]=[CH:26][CH:27]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[N:8]=[C:7]([O:13][CH3:14])[C:6]([NH:15][C:16]([N:31]1[CH2:30][CH2:29][N:28]([C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([Br:21])[CH:23]=3)[CH2:33][CH2:32]1)=[O:20])=[N:5]2
Reactant: Brc1cccc(N2CCNCC2)c1
Reactant: CCOC(=O)Nc1nc2cc(Cl)c(Cl)cc2nc1OC
Product: COc1nc2cc(Cl)c(Cl)cc2nc1NC(=O)N1CCN(c2cccc(Br)c2)CC1
Yield: 72 %

Procedure:
Ethyl N-(6,7-dichloro-2-methoxyquinoxalin-3-yl)carbamate and 1-(3-bromo phenyl)piperazine were reacted by the same way with the example 176 to obtain the titled compound (yield, 72%). 1H NMR (300 MHz, CDCl3) δ 3.29-3.31 (m, 4H), 3.74-3.76 (m, 4H), 4.16 (s, 3H), 6.85-6.87 (m, 1H), 7.02-7.04 (m, 1H), 7.06-7.07 (m, 1H), 7.13-7.15 (m, 1H), 7.32 (br s, 1H), 7.86 (br s, 1H), 7.86 (br s, 1H), 7.91 (br s, 1H).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14](OC)=[CH:13][C:12]=1[N+:19]([O-:21])=[O:20])([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].[CH2:22]([Sn](CCCC)(CCCC)C=C)[CH2:23]CC>CN(C=O)C.[Cl-].[Cl-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd+2]>[CH2:7]([O:6][P:4]([CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:22]=[CH2:23])=[CH:13][C:12]=1[N+:19]([O-:21])=[O:20])([O:3][CH2:1][CH3:2])=[O:5])[CH3:8]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: CCOP(=O)(COc1ccc(OC)cc1[N+](=O)[O-])OCC
Agent: [Pd+2]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C=Cc1ccc(OCP(=O)(OCC)OCC)c([N+](=O)[O-])c1
Temperature: 60 °C

Procedure:
A solution of 2-diethylphosphonomethyloxy-5-bromonitrobenzene (1 mmole, prepared as in Example 37, Step A) in DMF (5 mL) was treated with tributyl(vinyl)tin (1.2 mmole) and palladium bis(triphenylphosphine) dichloride (0.1 mmole), and the mixture was heated at 60° C. under nitrogen for 6 h. Evaporation and chromatography gave 2-diethylphosphonomethyloxy-5-vinylnitrobenzene as an oil which was subjected to Step B of Example 38, Step B of Example 36, and Step D of Example 34 to give 2-amino-7-ethyl-6-thiocyano-4-phosphonomethoxybenzothiazole (41.1). mp >167° C.(dec.). Anal. Calcd. for C11H12N3O4PS2: C:38.26; H:3.50; N:12.17. Found: C:37.87; H:3.47; N: 11.93.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[C:5](=[O:8])[C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21](Br)[CH:20]=2)([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH:16]([F:18])[F:17])=[CH:11][CH:10]=2)[N:3]=1.[CH3:26][O:27][CH2:28][C:29]#[CH:30].O>N1CCCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[NH2:1][C:2]1[N:6]([CH3:7])[C:5](=[O:8])[C:4]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH:16]([F:18])[F:17])=[CH:11][CH:10]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:30]#[C:29][CH2:28][O:27][CH3:26])[CH:20]=2)[N:3]=1
Reactant: C#CCOC
Reactant: CN1C(=O)C(c2ccc(OC(F)F)cc2)(c2cccc(Br)c2)N=C1N
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCNC1
Product: COCC#Cc1cccc(C2(c3ccc(OC(F)F)cc3)N=C(N)N(C)C2=O)c1
Temperature: 80 °C
Yield: 63 %

Procedure:
A solution of 2-amino-5-(3-bromophenyl)-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one (0.65 g, 1.6 mmol) in pyrrolidine was treated with 3-methoxy-propyne (0.27 mL, 3.2 mmol) followed by tetrakis(triphenylphosphine) palladium(0) (90 mg, 0.08 mmole), heated to 80° C. for 4 hrs, poured into water and extracted with ethyl acetate. The extracts were combined, washed sequentially with water and brine, dried over magnesium sulfate and concentrated in vacuo. The resultant residue was purified by flash chromatography on silica gel in ethyl acetate to give the title product as a brown wax, 0.4 g (63% yield), identified by NMR and mass spectral analyses.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:11][O:12][C:13](=[O:16])[CH2:14]Br.C(=O)([O-])[O-].[Cs+].[Cs+]>>[CH3:11][O:12][C:13]([CH2:14][O:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)=[O:16]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COC(=O)COc1ccc([N+](=O)[O-])cc1

Procedure:
Prepared from 4-nitrophenol, methylbromoacetate and caesium carbonate analogously to Example XIXa.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][NH:13][CH2:12][CH:11]([C:15]([O:17][CH3:18])=[O:16])[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].[N:19]1([C:24](Cl)=[O:25])[CH2:23][CH2:22][CH2:21][CH2:20]1>>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:14][N:13]([C:24]([N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)=[O:25])[CH2:12][CH:11]([C:15]([O:17][CH3:18])=[O:16])[CH2:10]2)=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCc1ccc(C2CNCC(C(=O)OC)C2)cc1
Reactant: O=C(Cl)N1CCCC1
Product: CCc1ccc(C2CC(C(=O)OC)CN(C(=O)N3CCCC3)C2)cc1

Procedure:
6.7 g (24.1 mmol) of methyl 5-(4-ethylphenyl)piperidine-3-carboxylate and 4.2 g (31.4 mmol, 1.3 eq.) of pyrrolidine-1-carbonyl chloride were reacted according to General Method 3A. Yield: 7.6 g (91% of theory)
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@:11]3(O)[CH2:12][CH2:13][C@@H:14]2[CH3:24])[CH2:6]1)(=[O:3])[CH3:2].S(Cl)(Cl)=O>N1C=CC=CC=1.Cl>[C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C:11]3=[CH:12][CH2:13][C@@H:14]2[CH3:24])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)[C@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](C)CC[C@]32O)C1
Agent: Cl
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: CC(=O)O[C@H]1CC[C@@]2(C)[C@H](CC[C@H]3C4=CC[C@H](C)[C@@]4(C)CC[C@@H]32)C1
Reaction time: 2.5 h
Yield: 94.9 %

Procedure:
To a solution of 5.0 g of 3β-acetoxy-14β-hydroxy-17β-methyl-5β-androstane (VIII-a) in pyridine (100 mL), 3.5 g of thionyl chloride were added at 0° C. The solution was stirred at the same temperature for 2.5 hrs and then poured in 100 mL of 1N HCl and crushed ice: the mixture was extracted with ethyl ether: the organic layer was washed with a saturated aqueous solution of disodium hydrogen phosphate, dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure to give 4.5 g of 3β-acetoxy-17β-methyl-5β-androst-14-ene as a white solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11]([C:13]([CH2:17][CH3:18])(O)[CH2:14][CH3:15])=[CH:10][C:9]=2[CH:19]=1)=[O:4].[CH2:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[OH:28])[CH3:21].B(F)(F)F.CC[O:35][CH2:36][CH3:37]>>[CH3:3][C:5]([CH3:6])([CH3:19])[C:36](=[O:35])[CH2:37][O:28][C:23]1[CH:24]=[CH:25][C:26]([CH:14]([CH:13]([C:11]2[O:12][C:8]3[CH:7]=[CH:6][C:5]([C:3]([OH:2])=[O:4])=[CH:19][C:9]=3[CH:10]=2)[CH2:17][CH3:18])[CH3:15])=[CH:27][C:22]=1[CH2:20][CH3:21]
Reactant: CCOCC
Reactant: CCC(O)(CC)c1cc2cc(C(=O)OC)ccc2o1
Reactant: CCc1ccccc1O
Agent: FB(F)F
Product: CCc1cc(C(C)C(CC)c2cc3cc(C(=O)O)ccc3o2)ccc1OCC(=O)C(C)(C)C
Yield: 149.9 %

Procedure:
2-(1-Ethyl-1-hydroxy-propyl)-benzofuran-5-carboxylic acid methyl ester (1.01 g, 3.85 mmol) and 2-ethylphenol (0.706 g, 5.77 mmol) and BF3-Et2O (273 mg, 1.925 mmol) are reacted analogous to step D to give the title compound (1.30 g, 92%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22].C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[N:32]=1.CN(C)C=O>O.C(OCC)(=O)C>[F:40][C:37]([F:38])([F:39])[C:33]1[N:32]=[C:31]([CH2:30][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]3([C:21]4[C:12](=[CH:13][C:14]5[O:19][CH2:18][CH2:17][O:16][C:15]=5[CH:20]=4)[O:11][CH2:10]3)[C:2]2=[O:22])[CH:36]=[CH:35][CH:34]=1
Reactant: FC(F)(F)c1cccc(CCl)n1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C1N(Cc2cccc(C(F)(F)F)n2)c2ccccc2C12COc1cc3c(cc12)OCCO3
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.2 %

Procedure:
A heterogeneous mixture of 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one (0.41 g, 1.4 mmol), cesium carbonate (1.1 g, 3.5 mmol), 2-(chloromethyl)-6-(trifluoromethyl)pyridine (0.33 g, 1.7 mmol) and N,N-dimethylformamide (10 mL) was stirred at ambient temperature for 16 h. The mixture was diluted with water (100 mL) and ethyl acetate (100 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2×70 mL). The combined organic layers was washed with brine (100 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography and eluted with a 25% to 35% gradient of ethyl acetate in hexanes to afford 1′-{[6-(trifluoromethyl)pyridin-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]-benzodioxine-8,3′-indol]-2′(1′H)-one (0.44 g, 70%) as a colorless solid: mp 195-196° C.; 1H NMR (300 MHz, DMSO-d6) δ8.15-8.07 (m, 1H), 7.85-7.79 (m, 1H), 7.75-7.70 (m, 1H), 7.28-7.15 (m, 2H), 7.07-7.00 (m, 1H), 6.97-6.91 (m, 1H), 6.52 (s, 1H), 6.29 (s, 1H), 5.16 (ABq, J=42.6, 16.9 Hz, 2H), 4.75 (ABq, J=37.3, 9.3 Hz, 2H), 4.22-4.08 (m, 4H); 13C NMR (300 MHz, DMSO-d6) δ 176.8, 156.5, 154.6, 146.0 (q, JC-F=33.7 Hz), 144.1, 142.3, 139.4, 137.8, 131.7, 128.6, 125.4, 123.5, 123.0, 121.4 (q, JC-F=272.7 Hz), 121.1, 119.5 (m), 111.4, 109.1, 98.6, 79.5, 64.1, 63.5, 57.2, 44.2; MS (ES+) m/z 455.0 (M+1).
Reaction SMILES: [Nb:1].[P:2](=[O:6])([OH:5])([OH:4])[OH:3].[O-2].[Nb+5].[O-2].[O-2].[O-2].[O-2].[Nb+5]>>[P:2]([O-:6])([O-:5])([O-:4])=[O:3].[Nb+5:1].[P:2]([O-:6])([O-:5])([O-:4])=[O:3].[P:2]([O-:6])([O-:5])([O-:4])=[O:3].[P:2]([O-:6])([O-:5])([O-:4])=[O:3].[P:2]([O-:6])([O-:5])([O-:4])=[O:3].[Nb+5:1].[Nb+5:1]
Reactant: [Nb]
Reactant: O=P(O)(O)O
Agent: [Nb+5]
Agent: [O-2]
Product: O=P([O-])([O-])[O-]
Temperature: 150 °C

Procedure:
A mixture is prepared containing niobic acid, Nb2O5.xH2O, (60.33 g; 0.211 moles; Niobium Products Company, AD-460) and 85% phosphoric acid (602.20 g; 5.22 moles). The mixture is heated to 150° C. with stirring. The niobium oxide dissolves to form a pink solution, and upon heating a precipitate forms. The precipitate is boiled in the phosphoric acid for about 2 hours. The boiled mixture is cooled to room temperature, and the liquid phase is decanted from the precipitate. The precipitate is washed by stirring with 500 ml of water, after which the aqueous mixture is filtered. The washing and filtering cycle is repeated five times. The filtered solid is dried at 110° C. under air for 21/2 days to yield a catalyst of niobium phosphate. The elemental analysis and X-ray diffraction pattern of the catalyst are consistent with the composition NbOPO4. The P/Nb mole ratio, as determined by neutron activation analysis and X-ray fluorescence, is 1.03.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:38])[C:5]([C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]([C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[C:19]([CH3:24])[CH:18]=1)=[C:11]2[CH2:25][CH2:26][NH:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1)([CH3:7])[CH3:6])[CH3:2].C(N(CC)C(C)C)(C)C.Cl[C:49]([O:51][CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)=[O:50].C(Cl)Cl.CO>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:38])[C:5]([C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]([C:17]1[CH:18]=[C:19]([CH3:24])[CH:20]=[C:21]([CH3:23])[CH:22]=1)=[C:11]2[CH2:25][CH2:26][N:27]([C:49]([O:51][CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)=[O:50])[CH2:28][CH2:29][CH2:30][CH2:31][C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)c1ccc2[nH]c(-c3cc(C)cc(C)c3)c(CCNCCCCc3cccnc3)c2c1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)C(C)(C)c1ccc2[nH]c(-c3cc(C)cc(C)c3)c(CCN(CCCCc3cccnc3)C(=O)OCc3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of 3.00 g (max. 5.86 mmol) of crude 2-[2-(3,5-dimethylphenyl)-3-[2-[4-(pyridin-3-yl)butylamino]ethyl]-1H-indol-5-yl]-2-methylpropionic acid ethyl ester in 30 mL of dry methylene chloride was stirred under nitrogen with cooling in a dry-ice-acetone bath. To this solution was added by syringe 1.106 mL (820 mg, 6.36 mmol) of N,N-diisopropylethylamine. Then 0.956 mL (1.14 g, 6.36 mmol) of benzyl chloroformate was added dropwise by syringe over 5-10 minutes. After 20 minutes, the solution was removed from the cooling bath and allowed to warm to room temperature. After 2 hours, the solution was diluted with 50 mL of methylene chloride, transferred to a separatory funnel, and shaken with 80 mL of water. The organic phase was dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography of the residual gum on silica gel (gradient elution with 0.2-2% methanol in methylene chloride gave 2.81 g (55% overall for Steps 1 and 2) of pale, golden-yellow gum; virtually homogeneous by TLC in 95:5 CH2Cl2-MeOH. 500 MHz 1H NMR (CDCl3) was complex, owing to rotamers, but appeared to be consistent with the assigned structure. Mass spectrum (ESI): m/e=646 (M+H).
Reaction SMILES: N[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][NH:8][C:9]2=[O:12])=[CH:4][CH:3]=1.[BrH:13].N([O-])=O.[Na+]>C(#N)C.O.[Cu]Br>[Br:13][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][NH:8][C:9]2=[O:12])=[CH:4][CH:3]=1
Reactant: Nc1ccc2c(c1)C(=O)NCC2
Reactant: Br
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: O=C1NCCc2ccc(Br)cc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 63 %

Procedure:
To a solution of 7-amino-3,4-dihydro-1(2H)-isoquinolinone, (for a synthesis see Girard, Yves; Atkinson, Joseph G.; Belanger, Patrice C.; Fuentes, Jose J.; Rokach, Joshua; Rooney, C. Stanley; Remy, David C.; Hunt, Cecilia A J. Org. Chem. (1983), 48(19), 3220) (0.773 g, 4.772 mmol) in acetonitrile (10 ml) at 0° C. was added 48% aqueous hydrobromic acid (10 ml, precooled to 0° C.). The mixture was stirred at 0° C. for 0.5 h before addition of a solution of sodium nitrite (0.379 g, 5.49 mmol) in water (2 ml) over 0.4 h. The reaction was then stirred at 0° C. for 0.5 h and then copper(I) bromide (0.822 g, 5.726 mmol) was added portionwise over 10 min. The reaction mixture was then warmed to room temperature, stirred at room temperature for 0.5 h and then at 70° C. for 1 h. The reaction mixture was then cooled to 0° C., water (60 ml) was added and the mixture stirred at 0° C. for 1 h before filtering and drying in vacuo. The residue was dissolved in 10% methanol/dichloromethane, dried with magnesium sulphate and evaporated to give the desired product (0.679 g, 63%).