Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:4]([CH2:20][CH3:21])[CH2:5][CH2:6][CH2:7][CH2:8][NH:9]C(=O)OCC2C=CC=CC=2)[CH2:3][CH2:2]1.[ClH:22]>>[ClH:22].[CH:1]1([N:4]([CH2:20][CH3:21])[CH2:5][CH2:6][CH2:7][CH2:8][NH2:9])[CH2:3][CH2:2]1
Reactant: CCN(CCCCNC(=O)OCc1ccccc1)C1CC1
Agent: Cl
Product: CCN(CCCCN)C1CC1
Temperature: 22.5 °C

Procedure:
The mixture of benzyl 4-(cyclopropyl(ethyl)amino)butylcarbamate (Step 1) in HCl (6 N) was heated to reflux for 1 hour and cooled to 20-25° C. The reaction mixture was concentrated, and the residue was dried under reduced pressure to give N1-cyclopropyl-N1-ethylbutane-1,4-diamine HCl salt.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:22](=[O:23])[N:21]([CH2:24][CH3:25])[C:12]2[N:13]=[C:14](S(C)(=O)=O)[N:15]=[CH:16][C:11]=2[CH:10]=1.[CH3:26][O:27][C:28]1[CH:29]=[C:30]([CH:32]=[C:33]([O:37][CH3:38])[C:34]=1[O:35][CH3:36])[NH2:31]>C(O)(=O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:22](=[O:23])[N:21]([CH2:24][CH3:25])[C:12]2[N:13]=[C:14]([NH:31][C:30]3[CH:32]=[C:33]([O:37][CH3:38])[C:34]([O:35][CH3:36])=[C:28]([O:27][CH3:26])[CH:29]=3)[N:15]=[CH:16][C:11]=2[CH:10]=1
Reactant: COc1cc(N)cc(OC)c1OC
Reactant: CCn1c(=O)c(-c2c(Cl)cccc2Cl)cc2cnc(S(C)(=O)=O)nc21
Solvent: CC(=O)O
Solvent: O
Product: CCn1c(=O)c(-c2c(Cl)cccc2Cl)cc2cnc(Nc3cc(OC)c(OC)c(OC)c3)nc21
Temperature: 160 °C

Procedure:
A mixture of 0.150 g (0.38 mmol) of 6-(2,6-dichlorophenyl)-8-ethyl-2-methanesulfonyl-8H-pyrido[2,3-d]pyrimidin-7-one of Example 68 and 0.500 g (2.70 mmol) of 3,4,5-trimethoxyaniline was heated in a 160° C. oil bath for 5 minutes. The dark solution was cooled and dissolved in 2 mL of warm glacial acetic acid. This solution was diluted to 15 mL volume with water to precipitate a violet solid. The solid was filtered, washed well with water, and dried; wt 0.140 g. Purification was effected by filtration of an ethyl acetate (30 mL) solution through a layer of silica gel and washing the silica gel with ethyl acetate. The filtrate was concentrated to 3 mL volume. The crystals that separated on inducement were filtered and washed with 1 mL of ethyl acetate and 1 mL of ether; wt 0.054 g; mp 275°-278° C.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[CH:9]=[C:8]([CH3:11])[O:7][C:6]=2[C:5]([Cl:12])=[CH:4][C:3]=1[F:13].C(N(CC)C1C=CC=CC=1)C.[C:25](Cl)(=[O:28])[O:26][CH3:27]>O1CCCC1.C(OCC)(=O)C>[Cl:12][C:5]1[C:6]2[O:7][C:8]([CH3:11])=[CH:9][C:10]=2[C:2]([NH:1][C:25]([O:26][CH3:27])=[O:28])=[C:3]([F:13])[CH:4]=1
Reactant: Cc1cc2c(N)c(F)cc(Cl)c2o1
Reactant: COC(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)c1ccccc1
Solvent: C1CCOC1
Product: COC(=O)Nc1c(F)cc(Cl)c2oc(C)cc12
Temperature: 25 °C
Yield: 87.1 %

Procedure:
A mixture of 4-amino-7-chloro-5-fluoro-2-methylbenzo[b]furan (3.4 g) and N,N-diethylaniline (2.6 g) was dissolved in tetrahydrofuran (20 ml), and methyl chlorocarbonate (1.6 g) was dropwise added thereto at room temperature. The resultant mixture was heated under reflux for 3 hours. After cooling to room temperature, the reaction mixture was dissolved in ethyl acetate and washed with 10% hydrochloric acid. After removal of N,N-diethylaniline, the reaction mixture was dried and concentrated. The residue was washed with hexane to give 7-chloro-5-fluoro-4-methoxycarbonylamino-2-methylbenzo[b]furan (3.8 g; yield, 87%). m.p., 168°-169° C.
Reaction SMILES: [H][H].[C:3]([O:6][C:7]12[CH2:16][CH:11]3[CH2:12][CH:13]([CH2:15][C:9]([N+:17]([O-])=O)([CH2:10]3)[CH2:8]1)[CH2:14]2)(=[O:5])[CH3:4]>>[C:3]([O:6][C:7]12[CH2:16][CH:11]3[CH2:12][CH:13]([CH2:15][C:9]([NH2:17])([CH2:10]3)[CH2:8]1)[CH2:14]2)(=[O:5])[CH3:4]
Reactant: CC(=O)OC12CC3CC(C1)CC([N+](=O)[O-])(C3)C2
Reactant: [H][H]
Product: CC(=O)OC12CC3CC(CC(N)(C3)C1)C2
Yield: 70 %

Procedure:
An autoclave was charged, 10 mmole of 1-acetyloxy-3-nitroadamantane obtained by the method of Example 14, 5% Pd-C (10 mole % of Pd relative to a substrate), 1 ml of dilute hydrochloric acid and 10 ml of methanol. The mixture was stirred for 2 hours at 80° C. in an atmosphere of hydrogen at 30 atm. As a result, the conversion of 1-acetyloxy-3-nitroadamantane was 90%, and 1-acetyloxy-3-aminoadamantane (yield 70%) was formed.
Reaction SMILES: [I:1][C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[BH4-].[Na+]>CO>[OH:13][CH2:12][C:11]1[C:2]([I:1])=[N:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: O=Cc1cc2ccccc2nc1I
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1cc2ccccc2nc1I
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 84.4 %

Procedure:
To a stirred solution of 2-iodo-3-quinolinecarboxaldehyde (595 mg, 2.10 mmol) in 40 mL of CH3OH at 0° C. was added NaBH4 (86 mg, 2.31 mmol), and the mixture was stirred at 0° C. for 30 min. After concentrating the mixture to approximately one-half of its original volume, water (30 mL) was added and the mixture was allowed to stand at 5° C. overnight. The solids were filtered and the crude product (570) mg, 95%) was recrystallized from methanol to give 3-hydroxymethyl-2-iodoquinoline (505 mg, 84%) as colorless needles: mp 189°-190° C. 1H NMR (300 MHz, CDCl3) δ8.19 (s, 1H), 7.99 (d, 1H, J=9 Hz), 7.87 (d, 1H, J=9 Hz), 7.68 (m, 1H), 7.58 (t, 1H, J=9 Hz), 5.45 (t, 1H, J=6 Hz), 4.66 (d, 2H, J=6 Hz); IR (nujol) 3350, 1580, 1320, 1125, 1060, 995, 755, 720, cm-1.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH:11]2[CH:18]3[CH2:19][CH:14]4[CH2:15][CH:16]([CH2:20][CH:12]2[CH2:13]4)[CH2:17]3)=[O:9])[CH2:4]1.Cl[C:22]([O:24][CH2:25][CH:26]([CH3:28])[CH3:27])=[O:23]>>[CH2:25]([O:24][C:22]([NH:2][C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH:11]2[CH:12]3[CH2:13][CH:14]4[CH2:15][CH:16]([CH2:17][CH:18]2[CH2:19]4)[CH2:20]3)=[O:9])[CH2:4]1)=[O:23])[CH:26]([CH3:28])[CH3:27]
Reactant: CC(C)COC(=O)Cl
Reactant: N[C@@H]1CCN(C(=O)OC2C3CC4CC(C3)CC2C4)C1
Agent: Cl
Product: CC(C)COC(=O)N[C@@H]1CCN(C(=O)OC2C3CC4CC(C3)CC2C4)C1

Procedure:
The title compound was prepared from (R)-2-adamantyl 3-aminopyrrolidine-1-carboxylate HCl salt and isobutyl chloroformate following a procedure analogous to that described in Example 3 Step 2. LC-MS Method 1 tR=2.1 min, m/z=365; 1H NMR (CDCl3) 0.97 (d, 6H), 1.58 (d, 2H), 1.70-2.05 (14H), 2.18 (m, 1H), 2.80 (1H), 3.29 (dd, 1H), 3.53 (m, 2H), 3.70 (m, 1H), 3.84 (m, 1H), 4.28 (1H), 4.80 (1H), 4.83 (s, 1H)
Reaction SMILES: [CH3:1][Si:2]([CH3:20])([CH3:19])[O:3][Si:4]([CH3:18])([CH3:17])[O:5][Si:6]([CH3:16])([CH3:15])[O:7][Si:8]([CH3:14])([CH3:13])OC(=O)C.[C:21]([OH:26])(=[O:25])[C:22]([CH3:24])=[CH2:23]>>[CH3:1][Si:2]([CH3:19])([CH3:20])[O:3][Si:4]([CH3:18])([CH3:17])[O:5][Si:6]([CH3:16])([CH3:15])[O:7][Si:8]([CH3:13])([CH3:14])[O:25][C:21](=[O:26])[C:22]([CH3:24])=[CH2:23]
Reactant: CC(=O)O[Si](C)(C)O[Si](C)(C)O[Si](C)(C)O[Si](C)(C)C
Reactant: C=C(C)C(=O)O
Product: C=C(C)C(=O)O[Si](C)(C)O[Si](C)(C)O[Si](C)(C)O[Si](C)(C)C

Procedure:
5 g of nonamethyl-1-acetoxy-tetrasiloxane prepared as described in reference example of EP-0839869 and 2.31 g of commercial methacrylic acid (ATOFINA Norsocryl® MAA) are mixed at room temperature. Acetic acid is then distilled under reduced pressure (45° C./13 hPa) to afford nonamethyl-1-methacryloyloxy-tetrasiloxane.
Reaction SMILES: [NH2:1][C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4].[NH2:9][C@H:10]([C:14]([OH:16])=O)[CH:11]([CH3:13])[CH3:12].[CH3:17][Si](Cl)(C)C>CO>[CH3:17][O:7][C:6](=[O:8])[C@H:2]([CH:3]([CH3:5])[CH3:4])[NH:1][C:14](=[O:16])[C@H:10]([CH:11]([CH3:13])[CH3:12])[NH2:9]
Reactant: CC(C)[C@H](N)C(=O)O
Reactant: C[Si](C)(C)Cl
Solvent: CO
Product: COC(=O)[C@@H](NC(=O)[C@@H](N)C(C)C)C(C)C

Procedure:
The title compound is prepared by the procedure of Example 7 using 0.50 g of L-valine-L-valine, 10 ml of methyl alcohol and 0.689 ml of trimethylsilyl chloride to give 0,657 g of the desired product.
Reaction SMILES: [C:1]1([C:7]2[S:11][C:10]([NH2:12])=[N:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]>CN(C=O)C>[C:24]([O:23][C:21](=[O:22])[CH2:20][NH:12][C:10]1[S:11][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8][N:9]=1)([CH3:27])([CH3:26])[CH3:25]
Reactant: Nc1nnc(-c2ccccc2)s1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CNc1nnc(-c2ccccc2)s1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1 g (5.6 mmol) of 5-phenyl-[1,3,4]thiadiazol-2-ylamine was dissolved in 20 ml of DMF, and 3.1 g (22.6 mmol) of potassium carbonate and 1.1 g (5.6 mmol) of tert-butyl bromoacetate were added. The reaction mixture was stirred at room temperature for 16 h. After evaporation of the solvent under reduced pressure, ethyl acetate was added to the residue. The solution was washed with water, dried with sodium sulfate, filtered, and the solvent was removed under reduced pressure. The product was purified by silica gel chromatography. Yield: 300 mg.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[CH:26][C:6]([CH2:7][N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][N:16]=3)[CH2:10][C:9]2([CH3:25])[CH3:24])=[CH:5][CH:4]=1>[Ni].CO.C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[N:16]=[CH:17][C:18]([NH2:21])=[CH:19][CH:20]=3)[CH2:10][C:9]2([CH3:25])[CH3:24])=[CH:26][CH:27]=1
Reactant: COc1ccc(CN2CCN(Cc3ccc([N+](=O)[O-])cn3)CC2(C)C)cc1
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(CN2CCN(Cc3ccc(N)cn3)CC2(C)C)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 77.7 %

Procedure:
A suspension of 1-(4-methoxy-benzyl)-2,2-dimethyl-4-(5-nitro-pyridin-2-ylmethyl)-piperazine (Step 112.2) (0.640 g, 1.72 mmol) and Raney Nickel (0.150 g) in MeOH/THF (1:1, v/v; 50 mL) was stirred for 20 h at rt, under a hydrogen atmosphere. The mixture was filtered through a pad of celite and the filtrate was concentrated. The residue was purified by silica gel column chromatography (DCM/NH3aq, 99:1→DCM/MeOH/NH3aq, 97:2:1) to afford 455 mg of the title compound as a yellow foam. Title compound: ESI-MS: 341.3 [M+H]+; tR=1.71 min (System 1); TLC: Rf=0.30 (DCM/MeOH, 9:1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[NH:11][C:12](=[O:19])[O:13][CH2:14][CH2:15][CH2:16][CH2:17]Cl.[K].CC(C)([O-])C>CN(C=O)C>[CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13][C:12]1=[O:19]
Reactant: Cc1cc([N+](=O)[O-])ccc1NC(=O)OCCCCCl
Agent: CC(C)(C)[O-]
Agent: [K]
Solvent: CN(C)C=O
Product: Cc1cc([N+](=O)[O-])ccc1N1CCCCOC1=O
Temperature: 90 °C
Reaction time: 4 h

Procedure:
20.2 g (63.4 mmol) 4-chlorobutyl (2-methyl-4-nitro-phenyl)-carbamate are dissolved in 500 ml DMF and added to a suspension of 7.8 g (69.8 mmol) potassium-tert.-butoxide in 500 ml DMF. The reaction solution is stirred for four hours at 90° C.; then the solvent is eliminated in vacuo using the rotary evaporator. The residue is combined with water and extracted three times with ethyl acetate. The combined organic phases are extracted twice with sat. ammonium chloride solution, then dried over sodium sulphate and filtered. The filtrate is evaporated to dryness i. vac. The residue is purified by reversed phase HPLC.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][C:3]=1[O:12][CH3:13].[CH3:14][C:15](OC(C)=O)=[O:16]>OP(O)(O)=O>[C:15]([O:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][C:3]=1[O:12][CH3:13])(=[O:16])[CH3:14]
Reactant: COc1cc(CC(=O)O)ccc1O
Reactant: CC(=O)OC(C)=O
Agent: O=P(O)(O)O
Product: COc1cc(CC(=O)O)ccc1OC(C)=O

Procedure:
A mixture of (4-hydroxy-3-methoxyphenyl)acetic acid (380 mg, 2.088 mmol) and H3PO4 (2 drops) in about 20 mL of Hac/Ac2O (v/v=1:1) was refluxed overnight, and then concentrated to dryness in vacuo. The residue was diluted with water (50 mL), and the result mixture was extracted with ethyl acetate (2*50 mL). The combined organic phase was washed with brine (100 mL) and dried over Na2SO4 and concentrated to give [4-(acetyloxy)-3-methoxyphenyl]acetic acid. 1H-NMR (400 MHz, CDCl3) δ ppm 6.97 (d, J=7.8 Hz, 1H), 6.84˜6.89 (m, 2H), 3.81 (s, 3H), 3.61 (s, 2H), 2.29 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@H:12]([CH2:28][CH:29]=O)[CH2:13][N:14]2[C:18]3=[N:19][CH:20]=[CH:21][CH:22]=[C:17]3[C:16]([CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:15]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]2[CH:28]=[CH:29][C:15]3[N:14]([C:18]4[N:19]=[CH:20][CH:21]=[CH:22][C:17]=4[C:16]=3[CH2:23][C:24]([O:26][CH3:27])=[O:25])[CH2:13]2)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: COC(=O)Cc1cn(C[C@@H](CC=O)NS(=O)(=O)c2ccc(F)cc2)c2ncccc12
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1
Product: COC(=O)Cc1c2n(c3ncccc13)C[C@H](NS(=O)(=O)c1ccc(F)cc1)C=C2
Reaction time: 10 h
Yield: 70.6 %

Procedure:
To a mixture of methyl [1-((2R)-2-{[(4-fluorophenyl)sulfonyl]amino}-4-oxobutyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]acetate (0.69 g, 1.6 mmol) in toluene (50 mL) was added PPTS (0.41 g, 1.6 mmol, 1.2 equiv.). After a period of 10 h at 90° C., the reaction mixture was quenched with saturated sodium bicarbonate and extracted with ethyl acetate. The organic phase was separated, dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by combiflash (10% ethyl acetate in hexane to 100% ethyl acetate) to give 469 mg of the title compound.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([O:11][C:12](=[O:44])[CH2:13][C@H:14]([NH:21][S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[O:31][CH2:32][CH2:33][C:34]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:37]=[N:36][CH:35]=1)(=[O:24])=[O:23])[C:15](N(OC)C)=[O:16])([CH3:10])([CH3:9])[CH3:8].C1COCC1.C(OCC)C>C(OCC)C>[C:7]([O:11][C:12](=[O:44])[CH2:13][C@H:14]([NH:21][S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[O:31][CH2:32][CH2:33][C:34]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:37]=[N:36][CH:35]=1)(=[O:24])=[O:23])[CH:15]=[O:16])([CH3:10])([CH3:8])[CH3:9]
Reactant: CON(C)C(=O)[C@H](CC(=O)OC(C)(C)C)NS(=O)(=O)c1ccccc1OCCc1cncc2ccccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C[C@@H](C=O)NS(=O)(=O)c1ccccc1OCCc1cncc2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To lithium aluminum hydride (0.45 mL of 1.0 M solution in diethyl ether) in diethyl ether (7 mL) at −65° C. was added (S)-3-[2-(2-isoquinolin-4-yl-ethoxy)-benzenesulfonylamino]-N-methoxy-N-methyl-succinamic acid tert-butyl ester in 1:1 THF/diethylether (4 mL). After 1 hour, the reaction was quenched by addition of 1.0N sodium hydroxide (2 mL) and the reaction was warmed to room temperature. The organic layer was separated and evaporated. The resulting residue was chromatographed on silica gel eluting with 10% diethyl ether in ethyl acetate to give (S)-3-[2-(2-isoquinolin-4-yl-ethoxy)-benzenesulfonylamino]-4-oxo-butyric acid tert-butyl ester as a colorless foam (39 mg). MS (APCI) m/z 485.1 (M+1).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:8]1([CH3:13])[O:12][CH2:11][CH2:10][O:9]1)[C:4]([O:6][CH3:7])=[O:5].[CH:14]1[CH:19]=[C:18]2[CH:20]=[CH:21][C:22]3[C:27](=O)[O:26][C:24](=[O:25])[C:23]=3[C:17]2=[CH:16][CH:15]=1>>[O:25]=[C:24]1[C:23]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:19][C:18]=3[CH:20]=[CH:21][C:22]=2[C:27](=[O:26])[N:1]1[CH2:2][CH:3]([C:8]1([CH3:13])[O:9][CH2:10][CH2:11][O:12]1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: O=C1OC(=O)c2c1ccc1ccccc21
Reactant: COC(=O)C(CN)C1(C)OCCO1
Product: COC(=O)C(CN1C(=O)c2ccc3ccccc3c2C1=O)C1(C)OCCO1

Procedure:
Methyl 3-(1,3-dioxo-1,3-dihydro-benzo[e]isoindol-2-yl)-2-(2-methyl-[1,3]dioxolan-2-yl)propionate was prepared (0.45 g, 58%) in the same manner as described in the above example 5 (1) from methyl 3-amino-2-(2-methyl-[1,3]dioxolan-2-yl)propionate (0.40 g, 2.11 mmol) and 1,2-naphthalic anhydride (0.55 g, 2.75 mmol), and the obtained product was identified with the following NMR data.
Reaction SMILES: [BrH:1].Br.Br.N1CCCC1=O.[C:10]([C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:22])[CH3:21])=[CH:16][CH:15]=1)([CH3:13])([CH3:12])[CH3:11].O>O1CCCC1>[Br:1][CH2:21][C:20]([C:17]1[CH:16]=[CH:15][C:14]([C:10]([CH3:13])([CH3:11])[CH3:12])=[CH:19][CH:18]=1)=[O:22]
Reactant: CC(=O)c1ccc(C(C)(C)C)cc1
Reactant: Br
Agent: O=C1CCCN1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)c1ccc(C(=O)CBr)cc1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
Pyrrolidone trihydrobromide (3.27 g, 10.0 mmol) was added to a solution of 1-(4-tert-butylphenyl)ethanone obtained (1.61 g, 9.13 mmol) in tetrahydrofuran (30 mL) and the mixture was heated to an external temperature of 60° C. and stirred for 30 min. After cooling, water was added thereto and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate and then the desiccant was filtered off, followed by concentration under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane only→hexane:ethyl acetate=9:1) to afford the title compound as a colorless oil (472 mg).
Reaction SMILES: [F:1][C:2]1([F:29])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:28])[CH3:27])[CH2:22][CH2:21]2)=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[Cl:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1>>[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([N:11]2[C:12]3[C:17](=[CH:16][C:15]([O:19][CH:20]4[CH2:25][CH2:24][N:23]([CH:26]([CH3:27])[CH3:28])[CH2:22][CH2:21]4)=[CH:14][CH:13]=3)[CH:18]=[C:10]2[C:8]([N:5]2[CH2:6][CH2:7][C:2]([F:1])([F:29])[CH2:3][CH2:4]2)=[O:9])=[CH:33][CH:32]=1
Reactant: CC(C)N1CCC(Oc2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Reactant: OB(O)c1ccc(Cl)cc1
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc(C(=O)N2CCC(F)(F)CC2)n3-c2ccc(Cl)cc2)CC1

Procedure:
In analogy to the procedure described for the synthesis of example 6, the title compound was synthesized from (4,4-difluoro-piperidin-1-yl)-[5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-methanone (intermediate 1) and 4-chlorophenylboronic acid. The title compound was obtained in 93% yield as light yellow foam. MS (m/e): 516.2 (MH+, 100%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([C:10]#[N:11])=[C:6](N)[CH:5]=1.N([O-])=O.[Na+].[BrH:18]>S(=O)(=O)(O)O.C(O)(=O)C.[Cu](Br)Br>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([C:10]#[N:11])=[C:6]([Br:18])[CH:5]=1
Reactant: COC(=O)c1ccc(C#N)c(N)c1
Reactant: Br
Agent: Br[Cu]Br
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: COC(=O)c1ccc(C#N)c(Br)c1
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 56 %

Procedure:
Add 3-amino-4-cyano-benzoic acid methyl ester (1.1 g, 6.24 mmol) to a stirred solution of sodium nitrite (511 mg, 7.4 mmol) in concentrated sulfuric acid (5 ml) and glacial acetic acid (5 ml) at 40° C. After 30 min at 40° C., pour the resulting orange solution into a cold solution of copper bromide (1.42 g, 9.89 mmol) in 48% hydrobromic acid (5 ml). When the evolution of nitrogen is finished, heat the mixture to 90° C. for 30 min. Cool down to room temperature and pour the mixture onto crushed ice. Filter out the resulting dark solid, wash with water. Take this solid up in chloroform and filter the inorganic solid. Concentrate the filtrate to yield a crude yellow residue. Purification by flash chromatography (Silica gel-hexane/EtOAc) yields the title compound (56%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[NH:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)[C:3]=12.N1C=CN=C1.[CH3:23][C:24]([Si:27](Cl)([CH3:29])[CH3:28])([CH3:26])[CH3:25]>CN(C=O)C.O>[Si:27]([O:17][C:14]1[CH:15]=[CH:16][C:11]([C:10]2[C:3]3[C:4](=[N:5][CH:6]=[N:7][C:2]=3[NH2:1])[NH:8][N:9]=2)=[CH:12][CH:13]=1)([C:24]([CH3:26])([CH3:25])[CH3:23])([CH3:29])[CH3:28]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Nc1ncnc2[nH]nc(-c3ccc(O)cc3)c12
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(-c2n[nH]c3ncnc(N)c23)cc1
Reaction time: 16 h
Yield: 92.7 %

Procedure:
To a stirred solution of compound (4) (5.25 g, 23.1 mmol) and imidazole (3.85 g, 57.8 mmol) in dry DMF (70 mL) was added TBDMSCl (4.19 g, 27.7 mmol). After 16 hr, further aliquots of imidazole (1.93 g, 28.9 mmol) and TBDMSCl (2.10 g, 13.9 mmol) were added and the mixture stirred for 4 hr. The reaction mixture was diluted with water (200 mL) and the resulting precipitate was collected by filtration, washed with water (200 mL) and heptane (300 mL) to afford the title compound (5) (7.31 g, 93%) as a brown solid: m/z 344 (M+H)+ (ES+).
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.C[O:31][C:32](=[O:83])[C@@H:33]([O:78][C:79]([CH3:82])([CH3:81])[CH3:80])[C:34]1[C:63]([CH3:64])=[C:62]([C:65]2C=CN=C[CH:66]=2)[C:61]2=[N:71][C:58]3=[CH:59][N:60]2[C:35]=1[N:36]1[CH2:76][CH2:75][C:39]([CH3:77])([O:40][CH2:41][CH2:42][CH2:43][CH2:44][C@H:45]([CH3:74])[O:46][C:47]2[CH:48]=[CH:49][C:50]([F:73])=[CH:51][C:52]=2[C:53]2[CH:72]=[C:57]3[CH:56]=[CH:55][CH:54]=2)[CH2:38][CH2:37]1.CN1CC(=O)OB(C2C=CN=CC=2)OC(=O)C1.BrC1C2=NC3=CN2C(N2CCC(C)(OCCCC[C@H](C)OC4C=CC(F)=CC=4C4C=C3C=CC=4)CC2)=C([C@H](OC(C)(C)C)C(OC)=O)C=1C.N#N.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CC([O-])=O.CC([O-])=O.[Pd+2].O1CCOCC1>[C:79]([O:78][C@@H:33]([C:34]1[C:63]([CH3:64])=[C:62]([CH:65]=[CH2:66])[C:61]2=[N:71][C:58]3=[CH:59][N:60]2[C:35]=1[N:36]1[CH2:37][CH2:38][C:39]([CH3:77])([O:40][CH2:41][CH2:42][CH2:43][CH2:44][C@H:45]([CH3:74])[O:46][C:47]2[CH:48]=[CH:49][C:50]([F:73])=[CH:51][C:52]=2[C:53]2[CH:72]=[C:57]3[CH:56]=[CH:55][CH:54]=2)[CH2:75][CH2:76]1)[C:32]([OH:83])=[O:31])([CH3:80])([CH3:81])[CH3:82]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)c(-c2ccncc2)c2nc3cn2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1ccc(F)cc1-c1cccc-3c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CN1CC(=O)OB(c2ccncc2)OC(=O)C1
Solvent: C1COCCO1
Product: C=Cc1c(C)c([C@H](OC(C)(C)C)C(=O)O)c2n3cc(nc13)-c1cccc(c1)-c1cc(F)ccc1O[C@@H](C)CCCCOC1(C)CCN2CC1
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
Methyl(2S)-2-(tert-butoxy)-2-[(22S)-17-fluoro-4,22,28-trimethyl-5-(pyridin-4-yl)-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetate 2-Dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (1.672 mg, 4.07 μmol, 0.2 equiv), Pd(OAc)2 (0.457 mg, 2.036 μmol, 0.1 equiv), 6-methyl-2-(pyridin-4-yl)-1,3,6,2-dioxazaborocane-4,8-dione (5.72 mg, 0.024 mmol, 1.2 equiv) and methyl(2S)-2-[(22S)-5-bromo-17-fluoro-4,22,28-trimethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]-2-(tert-butoxy)acetate (15 mg, 0.020 mmol, 1.0 equiv) were mixed in a one drum vial with a stir bar. The vial was vacuumed and back filled with N2 triple times. Then to this mixture was added dioxane (339 μl) and potassium phosphate tribasic (76 μl, 0.153 mmol, 7.5 equiv). The resulted solution was degassed by N2 for 5 mins. Then it was stirred at 80° C. for 1.5 hours. It was diluted by EA and washed by NaHCO3. concentrated, to afford the pure enough product. LCMS (ESI, M+1): 735.4.