Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][C:4]=1[Cl:10].[C:11]([O-])(=[O:13])[CH3:12].[Na+].O.C(=O)(O)[O-].[Na+]>C(O)(=O)C>[C:11]([NH:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][C:4]=1[Cl:10])(=[O:13])[CH3:12]
Reactant: CC(=O)[O-]
Reactant: Nc1ccc(O)cc1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(O)cc1Cl
Yield: 84.2 %

Procedure:
Part E. A solution of 4-amino-3-chlorophenol hydrochloride (18.6 g, 103 mmol) and sodium acetate (18.6 g, 227 mmol) in glacial acetic acid (200 mL) was heated to gentle reflux for 12 hours, then cooled and poured into 4 volumes water. This was neutralized with portionwise addition of sodium bicarbonate, and the resulting mixture was extracted with ethyl acetate (2×500 mL). The extracts were washed with brine, combined, dried over magnesium sulfate, filtered and evaporated. The resulting solid was triturated with warm ether; filtration and vacuum drying gave 4-acetamido-3-chlorophenol (16.1 g, 86.7 mmol, 84%). m.p. 128-129° C. TLC RF 0.14 (50:50 ethyl acetate-hexane). 1H NMR (300 MHz, 4:1 CDCl3.CD3OD): d 7.66 (1H, d, J=8.8 Hz), 6.88 (1H, d, J=1.7 Hz), 6.74 (1H, dd, J=8.8, 1.7 Hz), 2.19 (3H, s). MS (H2O-GC/MS): m/e 186 (100).
Reaction SMILES: C[O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19]C)[CH:14]=3)[CH:9]=2)[C:4]=1[C:21]1[CH:22]=[C:23]([NH2:27])[CH:24]=[CH:25][CH:26]=1.B(Br)(Br)Br>>[NH2:27][C:23]1[CH:22]=[C:21]([C:4]2[C:5]3[C:10](=[CH:9][C:8]([C:13]4[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[CH:14]=4)=[CH:7][CH:6]=3)[CH:11]=[CH:12][C:3]=2[OH:2])[CH:26]=[CH:25][CH:24]=1
Reactant: COc1cccc(-c2ccc3c(-c4cccc(N)c4)c(OC)ccc3c2)c1
Agent: BrB(Br)Br
Product: Nc1cccc(-c2c(O)ccc3cc(-c4cccc(O)c4)ccc23)c1

Procedure:
The compound is prepared by the reaction of 3-(2-methoxy-6-(3-methoxyphenyl)naphthalene-1-yl)benzeneamine (1 g, 2.82 mmol, 1 eq) with boron tribromide solution (14.1 ml, 14.1 mmol, 5 eq) according to method G. Purification by column chromatography was not necessary, and the desired product was obtained in quantitative yield (922 mg) after processing.
Reaction SMILES: [CH2:1]([N:3]([CH2:7][CH3:8])[CH2:4][CH2:5][OH:6])[CH3:2].S(=O)(=O)=O>>[CH2:1]([N:3]([CH2:4][CH2:5][O:6][CH2:2][CH2:1][N:3]([CH2:7][CH3:8])[CH2:4][CH3:5])[CH2:7][CH3:8])[CH3:2]
Reactant: CCN(CC)CCO
Agent: O=S(=O)=O
Product: CCN(CC)CCOCCN(CC)CC
Temperature: 25 °C
Yield: 17.1 %

Procedure:
Using the apparatus of Example 1, a solution of 2.43 moles of sodio-2-N,N-diethylaminoethoxide in 4.57 moles of N,N-diethylethanolamine at about 50° C. was added to he reactor. To this mixture was added 514 grams of Diluent II. The resulting mixture was cooled to 25° C. with stirring and then circulated through the scrubber. A vapor mixture of sulfur trioxide and nitrogen, produced by sparging nitrogen gas through liquid sulfur trioxide at a rate of about 148 cubic centimeters per minute, was passed into the gas inlet tube of the reactor over a period of about 2 hours and 10 minutes until 1.01 moles of sulfur trioxide has been added to the reactor, while the stirred mixture in the reactor was maintained at about 24° C. Upon completion of the addition of sulfur trioxide to the reactor, the mixture was stirred for one hour and then heated to a reflux temperature of 110° C. The mixture was refluxed with stirring for 11 hours, and then it was cooled and filtered through a kiesel-guhr-coated filter. The filtrate was distilled through a 35-tray Oldershaw column to give 0.39 moles of bis[2-(N,N-diethylamino)ethyl]ether as a fraction boiling at 120° C. at 15 mm. The yield of bis[2-(N,N-diethylamino)ethyl]ether was 39 percent, based on sulfur trioxide employed.
Reaction SMILES: [N:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][C@@H:11]2[CH2:15][C@H:14]([S:16][C:17]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:13][N:12]2[C:36]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][C:43]([N+:46]([O-:48])=[O:47])=[CH:42][CH:41]=2)=[O:37])[CH2:6][CH2:5]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N>N1C=CC=CC=1>[NH2:1][N:4]1[CH2:9][CH2:8][N:7]([CH2:10][C@@H:11]2[CH2:15][C@H:14]([S:16][C:17]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:13][N:12]2[C:36]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][C:43]([N+:46]([O-:48])=[O:47])=[CH:42][CH:41]=2)=[O:37])[CH2:6][CH2:5]1
Reactant: [N-]=[N+]=NN1CCN(C[C@@H]2C[C@H](SC(c3ccccc3)(c3ccccc3)c3ccccc3)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1
Agent: N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Product: NN1CCN(C[C@@H]2C[C@H](SC(c3ccccc3)(c3ccccc3)c3ccccc3)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.6 %

Procedure:
To a solution of (2S,4S) 2-[(4-azidopiperizin-1-yl)methyl]-1-(4-nitrobenzyloxycarbonyl)-4-(triphenylmethylthio)pyrrolidine (3.76 g) in pyridine (12 ml) was added triphenylphosphine (2.38 g) and the mixture was stirred at ambient temperature for 1 hour. To the reaction mixture was added concentrated ammonia (0.76 ml) and the mixture was allowed to stand overnight at ambient temperature. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in ethyl acetate (100 ml). The solution was washed with saturated aqueous sodium chloride, dried over magnesium sulfate and evaporated in vacuo to give a residue. The residue was chromatographed on silica gel (100 g) eluting with a mixture of chloroform and methanol (10:1 V/V). The fractions containing the desired compound were collected and evaporated in vacuo to give (2S,4S)-2-[(4-aminopiperizin-1-yl)methyl]-1-(4-nitrobenzyloxycarbonyl)-4-(triphenylmethylthio)pyrrolidine (2.66 g).
Reaction SMILES: [CH3:1][CH:2]([CH:4]1[CH2:9][N:8]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7][CH2:6][N:5]1[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[OH:3].[H-].[Na+].I[CH3:27]>CN(C)C=O>[CH3:27][O:3][CH:2]([CH:4]1[CH2:9][N:8]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7][CH2:6][N:5]1[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH3:1]
Reactant: CI
Reactant: CC(O)C1CN(Cc2ccccc2)CCN1Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(C)C1CN(Cc2ccccc2)CCN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.5 %

Procedure:
To a stirred mixture of 60.5 parts of α-methyl-1,4-bis(phenylmethyl)-2-piperazinemethanol and 180 parts of N,N-dimethylformamide were added portionwise 29.8 parts of a sodium hydride dispersion 50% at a temperature below 35° C. under nitrogen atmosphere. The mixture was allowed to cool and stirred for 3 hours at room temperature. After cooling to 10° C., there were added dropwise 9.4 parts of iodomethane at about 20° C. Upon completion, stirring was continued for 2 hours at room temperature. The reaction mixture was poured onto water and the product was extracted twice with 1,1'-oxybisethane. The combined extracts were washed with water, dried, filtered and evaporated, yielding 45.2 parts (71.5%) of 2-(1-methoxyethyl)-1,4-bis(phenylmethyl)piperazine as a residue (intermediate 28).
Reaction SMILES: [CH:1]1([Si:6](OC)([O:9][CH3:10])[O:7][CH3:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:13]([OH:18])([CH2:16][CH3:17])([CH3:15])[CH3:14].C[Si](C)(C)Cl>C[O-].[Na+]>[C:13]([O:18][Si:6]([CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)([O:9][CH3:10])[O:7][CH3:8])([CH2:16][CH3:17])([CH3:15])[CH3:14]
Reactant: CO[Si](OC)(OC)C1CCCC1
Reactant: CCC(C)(C)O
Agent: C[O-]
Agent: C[Si](C)(C)Cl
Agent: [Na+]
Product: CCC(C)(C)O[Si](OC)(OC)C1CCCC1
Yield: 81.7 %

Procedure:
In a 100 ml three-neck flask provided with a magnetic stirrer and a reflux condenser were charged 10.1 g (0.0531 mole) of cyclopentyl trimethoxysilane, 30.6 g (0.347 mole) of tert-amyl alcohol and 86.4 mg (1.6 m mole) of sodium methoxide, which were then reacted with each other in an oil bath of 105° C. for 4 hours under stirring. Then, trimethylchlorosilane was added to neutralize the alkali. Then, 10.7 g (0.0434 mole) of tert-amyloxy cyclopentyl dimethoxysilane were obtained by vacuum distillation. Its structure was confirmed as in Example 1. The yield was 82%.
Reaction SMILES: [N:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][N:8]=[CH:9][CH:10]=3)[C:5]=2[C:4](O)=[N:3][CH:2]=1.C(N(CC)CC)C.P(Cl)(Cl)([Cl:24])=O>>[Cl:24][C:4]1[C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[N:8][CH:7]=3)[NH:12][C:13]=2[N:1]=[CH:2][N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ncnc2[nH]c3ccncc3c12
Solvent: CCN(CC)CC
Product: Clc1ncnc2[nH]c3ccncc3c12

Procedure:
A suspension of 9H-1,3,6,9-Tetraaza-fluoren-4-ol (330 mg) and 500 μL of triethylamine were stirred vigorously overnight at 100° C. in 10 mL phosphorous oxychloride. The reaction mixture was then concentrated in vacuo and a small amount of the title compound was isolated by triturating the residue with water. The filtrate was concentrated in vacuo to give 363 mg of title compound which was used without further purification. LCMS (1): Rt 1.11 min; m/z 205 [M+H]+.
Reaction SMILES: [C:1]1([CH3:8])[CH:6]=[CH:5][CH:4]=[C:3]([CH3:7])[CH:2]=1.[C:9]1([S:15](Cl)(=[O:17])=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>[N-](S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O.[N-](S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O.C([N+]1C=CN(C)C=1)CCC.C([N+]1C=CN(C)C=1)CCC.N(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O.N(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O.[Zn+2]>[CH3:8][C:1]1[CH:6]=[CH:5][C:4]([S:15]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)(=[O:17])=[O:16])=[C:3]([CH3:7])[CH:2]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Cc1cccc(C)c1
Agent: CCCC[n+]1ccn(C)c1
Agent: O=S(=O)(NS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: O=S(=O)([N-]S(=O)(=O)C(F)(F)F)C(F)(F)F
Product: Cc1ccc(S(=O)(=O)c2ccccc2)c(C)c1
Yield: 99 %

Procedure:
Zinc(II) bis-triflimide (0.062 g, 1 mol %) was dissolved in [bmim][NTf2] (1.0 g) in a round-bottomed flask equipped with a magnetic stirrer and reflux condenser and m-xylene (2.12 g, 20 mmol) and benzene sulfonyl chloride (1.76 g, 10 mmol) were added. The mixture was heated under reflux for 18 hours and was analysed by-gas chromatographic analysis as in previous examples. All the benzene sulfonyl chloride had reacted and mostly 2,4-dimethyldiphenylsulfone had formed (yield=99%, 20:1 isomer ratio {by NMR}). The major product is shown below, the structure of the minor isomer is not known but is believed to be the 2,6-dimethyl isomer.
Reaction SMILES: Cl.[C:2]1([CH2:8][CH2:9][C:10]([NH2:12])=[NH:11])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[Na+].[N:16](=[C:18]([C:24]#[N:25])[C:19](OCC)=[O:20])[OH:17]>>[NH2:25][C:24]1[N:11]=[C:10]([CH2:9][CH2:8][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[NH:12][C:19](=[O:20])[C:18]=1[N:16]=[O:17]
Reactant: N=C(N)CCc1ccccc1
Reactant: CCOC(=O)C(C#N)=NO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Product: Nc1nc(CCc2ccccc2)[nH]c(=O)c1N=O
Reaction time: 5.25 h

Procedure:
3-Phenylpropionamidine hydrochloride (4.33 g; prepared as described by P. W. Neber and A. Uber, Leibig's Annalen der Chemie, 1928, 467, 52) was added to a solution of sodium methoxide (prepared from 2.17 g. sodium and 37 ml. anhydrous methanol). Ethyl α-oximinocyanoacetate (3.34 g.) was added, and the mixture was refluxed with stirring for 5.25 hours and left to stand overnight. The mauve solid was filtered off and washed with a small quantity of anhydrous methanol to give the crude sodium salt of 4-amino-5-nitroso-2-(2-phenylethyl)pyrimid-6-one (3.9 g.). An aliquot was dissolved in water, and the solution was filtered and acidified to pH 4 with glacial acetic acid to give 4-amino-5-nitroso-2-(2-phenylethyl)pyrimid-6-one as a turquoise solid, m.p. 253° C. (with decomposition, sintering at 188° C.).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[OH-].[K+].I[CH2:14][CH3:15]>CS(C)=O>[CH2:14]([N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[C:2]1[CH3:1])[CH3:15]
Reactant: Cc1cc2ccccc2[nH]1
Reactant: CCI
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CCn1c(C)cc2ccccc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 82.6 %

Procedure:
To a mixture of 0.20 g (1.52 mmol) of 2-methylindole, 0.38 g (6.89 mmol) of KOH in DMSO (6 mL) was added 0.24 mL (3.04 mmol) of iodoethane. The mixture was stirred at room temperature for 12 hours, quenched by the addition of 15 mL of H2O, and extracted with ethyl acetate (2×15 mL). The combined organic extracts were washed with water (10 mL), brine (20 mL), dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by column chromatography (ether/petroleum ether 0.5:9.5) to give 0.20 g (83%) of the desired product as a red oil.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7]([OH:15])=[C:8]([CH2:12][CH2:13][CH3:14])[CH:9]=[C:10]([F:11])[C:5]=2[O:4][C:3]=1C(O)=O>N1C2C(=CC=CC=2)C=CC=1.[Cu]>[CH3:1][C:2]1[C:6]2[C:7]([OH:15])=[C:8]([CH2:12][CH2:13][CH3:14])[CH:9]=[C:10]([F:11])[C:5]=2[O:4][CH:3]=1
Reactant: CCCc1cc(F)c2oc(C(=O)O)c(C)c2c1O
Agent: [Cu]
Solvent: c1ccc2ncccc2c1
Product: CCCc1cc(F)c2occ(C)c2c1O
Yield: 74.4 %

Procedure:
A mixture of 3-methyl-4-hydroxy-5-propyl-7-fluorobenzofurancarboxylic acid (0.10 gm; 0.4 mmoles) and copper(20 mg) in quinoline (50 mL) was refluxed for a period of 2.5 hours. The two phases were separated and the organic phase was dried (Na2SO4), and concentrated in vacuo. The residue was purified by preparative TLC and eluted with 5% ethylacetate in hexane to yield 3-methyl-4-hydroxy-5-propyl-7-fluorobenzofuran (62 mg; 75%), identical to the product obtained from the cyclisation reaction described above in step f.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][NH:11][C:12]([C@:14]12[CH2:49][CH2:48][C@@H:47]([C:50]([CH3:52])=[CH2:51])[C@@H:15]1[C@@H:16]1[C@@:29]([CH3:32])([CH2:30][CH2:31]2)[C@@:28]2([CH3:33])[C@@H:19]([C@:20]3([CH3:46])[C@@H:25]([CH2:26][CH2:27]2)[C:24]([CH3:35])([CH3:34])[C:23]([C:36]2[CH:45]=[CH:44][C:39]([C:40]([O:42][CH3:43])=[O:41])=[CH:38][CH:37]=2)=[CH:22][CH2:21]3)[CH2:18][CH2:17]1)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:54][C:55]([O:57][CH3:58])=[O:56].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C(#N)C>[CH2:1]([N:8]([CH2:54][C:55]([O:57][CH3:58])=[O:56])[CH2:9][CH2:10][NH:11][C:12]([C@:14]12[CH2:49][CH2:48][C@@H:47]([C:50]([CH3:52])=[CH2:51])[C@@H:15]1[C@@H:16]1[C@@:29]([CH3:32])([CH2:30][CH2:31]2)[C@@:28]2([CH3:33])[C@@H:19]([C@:20]3([CH3:46])[C@@H:25]([CH2:26][CH2:27]2)[C:24]([CH3:35])([CH3:34])[C:23]([C:36]2[CH:37]=[CH:38][C:39]([C:40]([O:42][CH3:43])=[O:41])=[CH:44][CH:45]=2)=[CH:22][CH2:21]3)[CH2:18][CH2:17]1)=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)NCCNCc3ccccc3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: C1COCCO1
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)NCCN(CC(=O)OC)Cc3ccccc3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 78 °C

Procedure:
A mixture of methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-(benzylamino)ethylcarbamoyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (50 mg, 0.071 mmol), methyl 2-bromoacetate (32.5 mg, 0.213 mmol) and potassium carbonate (29.4 mg, 0.213 mmol) in dioxane (1 mL) and acetonitrile (1 mL) was heated up at 78° C. for 3 hours. LCMS indicated the formation of desired product. The reaction mixture was quenched with distilled water, extracted with DCM (3×4 mL). All the extracts were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure to provide the title compound as a white solid (45 mg, 82%). LCMS: m/e 777.48 (M+H)+, 3.12 min (method 1).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([NH:39][C:40](=[O:49])[O:41][CH2:42][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[C:8]([C:12]([NH:14][C:15]3[CH:16]=[N:17][CH:18]=[CH:19][C:20]=3[N:21]3[CH2:26][C@H:25]([C:27]([F:30])([F:29])[F:28])[CH2:24][C@H:23]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:22]3)=[O:13])=[N:9]2)=[CH:4][CH:3]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1.CC1(C)C(C)(C)OB([C:72]2[CH2:73][CH2:74][O:75][CH2:76][CH:77]=2)O1>C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.NC1C=CC=CC=1C1C=CC=CC=1[Pd]Cl.O>[C:35]([O:34][C:32]([NH:31][C@H:23]1[CH2:24][C@@H:25]([C:27]([F:30])([F:29])[F:28])[CH2:26][N:21]([C:20]2[CH:19]=[CH:18][N:17]=[CH:16][C:15]=2[NH:14][C:12]([C:8]2[C:7]([NH:39][C:40](=[O:49])[O:41][CH2:42][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)=[CH:6][C:5]3[C:10](=[CH:11][C:2]([C:72]4[CH2:77][CH2:76][O:75][CH2:74][CH:73]=4)=[CH:3][CH:4]=3)[N:9]=2)=[O:13])[CH2:22]1)=[O:33])([CH3:38])([CH3:36])[CH3:37]
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](C(F)(F)F)CN(c2ccncc2NC(=O)c2nc3cc(Br)ccc3cc2NC(=O)OCc2ccccc2)C1
Agent: Nc1ccccc1-c1ccccc1[Pd]Cl
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1C[C@@H](C(F)(F)F)CN(c2ccncc2NC(=O)c2nc3cc(C4=CCOCC4)ccc3cc2NC(=O)OCc2ccccc2)C1
Temperature: 80 °C
Yield: 498.3 %

Procedure:
A pressure vial was charged with benzyl {7-bromo-2-[({4-[(3S,5R)-3-[(tert-butoxycarbonyl)amino]-5-(trifluoromethyl)piperidin-1-yl]pyridin-3-yl}amino)carbonyl]quinolin-3-yl}carbamate (0.032 g, 0.043 mmol), K3PO4 (0.0181 g, 0.0852 mmol), 1,4-dioxane (0.55 mL), water (0.092 mL) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran (0.013 g, 0.063 mmol). The mixture was deoxygenated with nitrogen for 10 min. Dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium (1:1) (0.0022 g, 0.0028 mmol) was added. The reaction mixture was sealed with a screw cap and heated at 80° C. for 1 h. The mixture was quenched with water and extracted with EtOAc. The combined organic extracts were dried and concentrated under reduced pressure. The residue was purified by flash chromatography on a 20 g silica gel column, eluting with 0-100% EtOAc in hexanes, to give benzyl [2-[({4-[(3S,5R)-3-[(tert-butoxycarbonyl)amino]-5-(trifluoromethyl)piperidin-1-yl]pyridin-3-yl}amino)carbonyl]-7-(3,6-dihydro-2H-pyran-4-yl)quinolin-3-yl]carbamate (0.16 g, 50%, LCMS calc. for C39H42F3N6O6[M+H]+: m/z=747.3. found: 747.4) and the corresponding benzyl carbamate deprotected product, tert-butyl [(3S,5R)-1-[3-({[3-amino-7-(3,6-dihydro-2H-pyran-4-yl)quinolin-2-yl]carbonyl}amino)pyridin-4-yl]-5-(trifluoromethyl)piperidin-3-yl]carbamate (0.13 g, 50%, LCMS calc. for C31H36F3N6O4 [M+H]+: m/z=613.3. found: 613.4).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:12][O:13][CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C(N(CC)CC)C.O>CN(C=O)C>[F:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4]([N:17]1[CH2:18][CH2:19][CH:14]([O:13][CH3:12])[CH2:15][CH2:16]1)=[O:6]
Reactant: O=C(O)c1cc(I)ccc1F
Reactant: COC1CCNCC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: COC1CCN(C(=O)c2cc(I)ccc2F)CC1
Temperature: 25 °C
Reaction time: 7 h
Yield: 8.5 %

Procedure:
2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (5.99 g, 15.79 mmol) was added portionwise to 2-fluoro-5-iodobenzoic acid (3.000 g, 11.28 mmol), 4-methoxypiperidine (1.364 g, 11.84 mmol) and triethylamine (3.93 mL, 28.19 mmol) in DMF (40 mL). The resulting solution was stirred at room temperature for 7 hours. The reaction mixture was poured into water (350 mL), extracted with Et2O (2×200 mL), the combined organic layers were washed with saturated brine (100 mL), dried over Na2SO4, filtered and evaporated to afford a dark orange gum. The crude product was purified by flash silica chromatography, elution gradient 0 to 50% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford the desired material as a colourless gum (0.348 g, 67% yield); 1H NMR (400.132 MHz, CDCl3) δ1.57-1.99 (4H, m), 3.18 (1H, m), 3.39 (3H, s), 3.50 (2H, m), 3.63 (1H, m), 3.98 (1H, m), 6.89 (1H, t), 7.69 (2H, m); m/z (LC-MS, ESI+), RT=2.05 (M+H 364.0).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[N:9]=[C:10]2[C:18](=[CH:19][C:20]=1[CH3:21])[CH:17]=[C:16]1[N:11]2[C@H:12]([CH3:23])[CH2:13][NH:14][C:15]1=O.C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+]>COC(C)(C)C>[Cl:7][C:8]1[N:9]=[C:10]2[C:18](=[CH:19][C:20]=1[CH3:21])[CH:17]=[C:16]1[N:11]2[C@H:12]([CH3:23])[CH2:13][NH:14][CH2:15]1
Reactant: Cc1cc2cc3n(c2nc1Cl)[C@H](C)CNC3=O
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: COC(C)(C)C
Product: Cc1cc2cc3n(c2nc1Cl)[C@H](C)CNC3
Temperature: 25 °C

Procedure:
To a stirred suspension of 5 mL tert-butyl methyl ether and 0.14 g (3.68 mmol) lithium aluminium hydride was added 0.23 g (0.92 mmol) (R)-6-chloro-4,7-dimethyl-3,4-dihydro-2H-2,4a,5-triaza-fluoren-1-one. The suspension was stirred under reflux for 15 min and, after cooling to room temperature, was poured into saturated aqueous sodium potassium tartrate solution and extracted with ethyl acetate. After filtration over speedex the phases were separated and the aqueous phase was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate and evaporated. The so-obtained product was used without further purification.
Reaction SMILES: C([NH:5][C:6]1[C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([C:16]([NH:18][C:19]3[CH:24]=[C:23]([C:25](=[O:37])[NH:26][C:27]4[CH:32]=[CH:31][CH:30]=[C:29](C(F)(F)F)[CH:28]=4)[CH:22]=[CH:21][C:20]=3[CH3:38])=[O:17])[C:10]=2[CH:9]=[CH:8][N:7]=1)(C)(C)C.NC1C=[C:42]([C:46](C)([CH3:49])[C:47]#[N:48])C=CC=1.NC1C=CC=CC=1>>[NH2:5][C:6]1[C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([C:16]([NH:18][C:19]3[CH:24]=[C:23]([C:25](=[O:37])[NH:26][C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([C:46]([C:47]#[N:48])([CH3:49])[CH3:42])[CH:28]=4)[CH:22]=[CH:21][C:20]=3[CH3:38])=[O:17])[C:10]=2[CH:9]=[CH:8][N:7]=1
Reactant: CC(C)(C#N)c1cccc(N)c1
Reactant: Cc1ccc(C(=O)Nc2cccc(C(F)(F)F)c2)cc1NC(=O)c1cccc2c(NC(C)(C)C)nccc12
Solvent: Nc1ccccc1
Product: Cc1ccc(C(=O)Nc2cccc(C(C)(C)C#N)c2)cc1NC(=O)c1cccc2c(N)nccc12
Yield: 20 %

Procedure:
The procedures of Steps (1), (2) and (3) of Example 2 and Step (4) of Example 1 were repeated step by step, except for using 2-(3-aminophenyl)-2-methylpropanenitrile obtained in Step (2) above instead of aniline in Step (1) of Example 2 to obtain the title compound (14 mg, 20%).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH3:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=1[OH:18].[OH-].[Na+]>>[C:1]([O:18][C:10]1[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:9]=1[CH3:8])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc([N+](=O)[O-])cc1O
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)Oc1cc([N+](=O)[O-])ccc1C
Reaction time: 0.67 h
Yield: 97.4 %

Procedure:
Acetic anhydride (1.9 ml, 20.3 mmol) was added to a mixture of 2-methyl-5-nitrophenol (2.5 g, 16.3 mmol) and 1M aqueous sodium hydroxide (24.5 ml) at ambient temperature. The mixture was stirred for 40 minutes, the solid was removed by filtration and the filtrate extracted with ethyl acetate. The organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried (MgSO4) and evaporated to yield 2-acetoxy-4-nitrotoluene (3.1 g, 100%). A mixture of this material (3.1 g, 15.9 mmol) and 10% palladium-on-charcoal catalyst (0.12 g) in ethyl acetate (50 ml) was stirred at ambient temperature under an atmosphere of hydrogen for 2 hours. The catalyst was removed by filtration and the filtrate evaporated to give 3-acetoxy-4-methylaniline (2.45 g, 94%).