Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([O:13][CH2:14][CH3:15])=[CH:6][C:5]=1[NH2:16].CO[CH:20](OC)[N:21]([CH3:23])[CH3:22]>O>[CH3:20][N:21]([CH:23]=[N:16][C:5]1[CH:6]=[C:7]([O:13][CH2:14][CH3:15])[C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:4]=1[C:3]([O:2][CH3:1])=[O:17])[CH3:22]
Reactant: CCOc1cc(N)c(C(=O)OC)cc1[N+](=O)[O-]
Reactant: COC(OC)N(C)C
Solvent: O
Product: CCOc1cc(N=CN(C)C)c(C(=O)OC)cc1[N+](=O)[O-]
Temperature: 100 °C
Yield: 91 %

Procedure:
A 3-L round-bottomed flask under N2 equipped with an overhead stirrer, a condenser and a thermocouple is charged with 2-amino-4-ethoxy-5-nitrobenzoic acid methyl ester (80 g, 333 mmol) and N,N-dimethylformamide dimethyl acetal (500 mL). The reaction mixture is heated to reflux (100° C.). Once the thick slurry becomes homogeneous and the reaction is complete, the reaction mixture is cooled to 25 to 30° C. The reaction mixture is diluted with water (3 L) and the resulting suspension is filtered. The filter cake is washed with water (3×500 mL) and dried under vacuum (50 mm Hg) at 55° C. to provide the title compound as an off-white solid (89.6 g, 91% yield, >90% purity by NMR integration). 1H NMR (300 MHz, DMSO-d6): 8.23 (s, 1H), 7.81 (s, 1H), 6.71 (s, 1H), 4.22 (q, J=7 Hz), 3.68 (s, 3H), 3.09 (s, 3H), 2.97 (s, 3H), 1.40 (t, J=7 Hz, 3H).
Reaction SMILES: [N+:1]([C:4]1[C:12]2[S:11][C:10]([C:13]([OH:15])=O)=[CH:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:16](Cl)[CH2:17][Cl:18].[CH:20]1[CH:21]=C[C:23]2[N:28](O)N=[N:26][C:24]=2[CH:25]=1.C(N(CC)CC)C>CN(C=O)C>[ClH:18].[N:28]12[CH2:17][CH2:16][CH:25]([CH2:20][CH2:21]1)[C@@H:24]([NH:26][C:13]([C:10]1[S:11][C:12]3[C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=[CH:7][C:8]=3[CH:9]=1)=[O:15])[CH2:23]2
Reactant: ClCCCl
Reactant: O=C(O)c1cc2cccc([N+](=O)[O-])c2s1
Reactant: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cl
Product: O=C(N[C@H]1CN2CCC1CC2)c1cc2cccc([N+](=O)[O-])c2s1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2.0 g (8.96 mmol) of 7-nitro-1-benzothiophene-2-carboxylic acid and 1.78 g (8.96 mmol) of R-3-aminoquinuclidine dihydrochloride are initially charged in 25 ml of DMF. At 0° C., 2.06 g (10.75 mmol) of EDC, 1.45 g (10.75 mmol) of HOBt and 4.50 ml (32.26 mmol) of triethylamine are added to the solution. The mixture is stirred at RT for 18 h. The reaction is terminated by addition of a 10% strength aqueous sodium bicarbonate solution, and ethyl acetate is added. The resulting precipitate is filtered off with suction. The mother liquor is extracted twice with ethyl acetate. The organic phases are combined and concentrated. Both the precipitate and the concentrated mother liquor are purified by silica gel column chromatography (mobile phase: dichloromethane/methanol/25% ammonia 100:10:2). The product fractions are concentrated, dissolved in a mixture of methanol and 1N hydrochloric acid, then again concentrated and dried under high vacuum. The resulting solid is triturated with acetonitrile, filtered off with suction and dried at 50° C. under reduced pressure. 1.10 g (32.8% of theory) of the title compound are obtained.
Reaction SMILES: [CH:1]([NH:5][CH:6]([CH2:8][CH3:9])[CH3:7])([CH2:3][CH3:4])[CH3:2].[C:10](Cl)([Cl:12])=[O:11]>ClC1C=CC=CC=1>[CH:1]([N:5]([CH:6]([CH2:8][CH3:9])[CH3:7])[C:10]([Cl:12])=[O:11])([CH2:3][CH3:4])[CH3:2]
Reactant: O=C(Cl)Cl
Reactant: CCC(C)NC(C)CC
Solvent: Clc1ccccc1
Product: CCC(C)N(C(=O)Cl)C(C)CC
Yield: 100 %

Procedure:
A mixture of 129.0 g of di-sec.-butylamine and 129.0 g of chlorobenzene was reacted with phosgene in accordance with Example 1. When the phosgenation was complete, the mixture was heated under reflux for a further hour, the residual phosgene was then removed by blowing out with nitrogen, and, after the solvent had been removed under a moderate vacuum, the main product was collected by distillation. N,N-di-sec.-butylcarbamoyl chloride was obtained in this manner in a yield of 186.0 g and in a purity of 99.8%. The yield of 100% strength carbamoyl chloride was 185.6 g, corresponding to 96.9% of theory. A residue of 2.5 g (corresponding to 1.2% of the theoretical yield) remained in the distillation flask.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11](B1OC(C)(C)C(C)(C)O1)=[CH:10][CH:9]=2)=[O:5])[CH3:2].I[C:25]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][CH:26]=1>>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:25]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][CH:26]=1)=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: N#Cc1ccc(I)cc1
Reactant: CCOC(=O)c1cc2cc(B3OC(C)(C)C(C)(C)O3)ccc2[nH]1
Product: CCOC(=O)c1cc2cc(-c3ccc(C#N)cc3)ccc2[nH]1

Procedure:
The sub-title compound was prepared in accordance with Example 8(b) from 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indole-2-carboxylic acid ethyl ester (see Example 8(a)) and 4-iodobenzonitrile.
Reaction SMILES: [CH3:1][C:2]([CH2:7][CH2:8][CH:9]=[C:10]([CH3:22])[CH2:11][CH2:12][CH:13]=[C:14]([CH3:21])[CH2:15][CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19])=[CH:3][C:4]([OH:6])=O.[OH:23][CH:24]1[CH2:29][CH2:28][CH2:27][NH:26][CH2:25]1>>[CH3:1][C:2]([CH2:7][CH2:8][CH:9]=[C:10]([CH3:22])[CH2:11][CH2:12][CH:13]=[C:14]([CH3:21])[CH2:15][CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19])=[CH:3][C:4]([N:26]1[CH2:27][CH2:28][CH2:29][CH:24]([OH:23])[CH2:25]1)=[O:6]
Reactant: OC1CCCNC1
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CC(=O)O
Product: CC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CC(=O)N1CCCC(O)C1
Yield: 95.3 %

Procedure:
The procedure of Example 1 was repeated except that 6.1 g of 3,7,11,15-tetramethyl-2,6,10,14-hexadecatetraenoic acid and 3.0 g of 3-hydroxypiperidine were used as starting materials. 7.4 g (yield 96%) of the title compound was obtained as a colorless oil.
Reaction SMILES: [CH:1]([C:3]1[O:7][C:6]([C:8]([OH:10])=[O:9])=[CH:5][CH:4]=1)=[O:2].C(N(CC)CC)C.ClC(OCC)=O.[CH2:24](O)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O1CCCC1.O>[CH2:24]([O:9][C:8]([C:6]1[O:7][C:3]([CH:1]=[O:2])=[CH:4][CH:5]=1)=[O:10])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=Cc1ccc(C(=O)O)o1
Reactant: OCc1ccccc1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1ccc(C(=O)OCc2ccccc2)o1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
500 mg of 5-formylfuran-2-carboxylic acid was dissolved in 10 mL of tetrahydrofuran, added with 990 μl of triethylamine, cooled to 0° C., and then added with 374 μl of ethyl chloroformate. After stirring at this temperature for 30 minutes, 406 μl of benzylalcohol was added and stirred at room temperature overnight. Adding water to stop the reaction, the solution was extracted with ethyl acetate. The organic phase was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated, and purified by silica gel column chromatography, to afford 508 mg of the title compound as white crystals.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:15]=[CH:14][C:7]2[C:8](=[O:13])[O:9][C:10](=O)[NH:11][C:6]=2[CH:5]=1.[CH2:16](Br)[CH:17]=C.O>CN(C)C=O>[CH2:10]([NH:11][C:6]1[C:7](=[CH:14][CH:15]=[C:4]([F:3])[CH:5]=1)[C:8]([OH:9])=[O:13])[CH:16]=[CH2:17]
Reactant: O=c1[nH]c2cc(F)ccc2c(=O)o1
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCNc1cc(F)ccc1C(=O)O
Reaction time: 1 h

Procedure:
Sodium hydride (0.41 g of 80% suspension in oil) was added to a solution of 7-fluoro-1H-3,1-benzoxazine-2,4-dione (2.5 g) in dimethylformamide (30 ml). The mixture was cooled to keep the temperature below 30° and then stirred for 1 hour until a clear solution was obtained. A solution of allyl bromide (1.2 ml) in dimethylformamide (30 ml) was added dropwise with cooling and the mixture stirred at room temperature overnight. The mixture was poured into water and extracted with dichloromethane. The extract was washed with water, dried and evaporated and the residue added to aqueous sodium carbonate (10%; 20 ml) and stirred for 3 hours, acidified with hydrochloric acid to pH 3, filtered and the solid washed with water and dried to give N-allyl-4-fluoroanthranilic acid, mp 136°-139°. (Compound 21).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:28][Si:29]([C:32]#[CH:33])([CH3:31])[CH3:30]>C1COCC1.C(N(CC)CC)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[CH3:8][C:4]1[CH:3]=[C:2]([C:33]#[C:32][Si:29]([CH3:31])([CH3:30])[CH3:28])[CH:7]=[CH:6][N:5]=1
Reactant: Cc1cc(I)ccn1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc(C#C[Si](C)(C)C)ccn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-Iodo-2-methyl-pyridine (9.5 g, 41.8 mmol) was dissolved in 150 mL dry THF and 18 mL triethyl amine. This mixture was evacuated and backfilled with argon several times to remove oxygen from the solution. Triphenylphosphine (341 mg, 1.25 mmol) and bis(triphenylphosphine)palladium(II)chloride (1.47 g, 2.09 mmol) were added and the reaction mixture was stirred at RT for 1 h. Copper(I)iodide (248 mg, 1.3 mmol) and trimethylsilylacetylen (6.39 g, 6.50 mmol) were added. The reaction mixture was stirred at RT overnight. The solvent was evaporated. The residue was taken up in 500 mL water and extracted three times with ethyl acetate (500 mL each). The combined organic extracts were dried with magnesium sulfate, filtered and evaporated. The crude product was purified by flash chromatography on silica gel (heptane/ethyl acetate gradient 100:0→0:100). The desired product was obtained as a light brown liquid (8.18 g, 99%).
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1([Li])C=CC=CC=1.[Cl:31][C:32]1[CH:37]=[CH:36][N:35]=[C:34]([C:38]([CH:40]2[CH2:42][CH2:41]2)=O)[C:33]=1[O:43][CH:44]([F:46])[F:45]>CCOCC>[Cl:31][C:32]1[CH:37]=[CH:36][N:35]=[C:34]([C:38]([CH:40]2[CH2:42][CH2:41]2)=[CH:2][O:3][CH3:4])[C:33]=1[O:43][CH:44]([F:46])[F:45]
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(c1nccc(Cl)c1OC(F)F)C1CC1
Agent: [Cl-]
Agent: [Li]c1ccccc1
Solvent: CCOCC
Product: COC=C(c1nccc(Cl)c1OC(F)F)C1CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 18.6 %

Procedure:
0.82 g of (methoxymethyl) triphenyl phosphonium chloride was suspended in 8 ml of anhydrous ether, to which was dropped 2.71 ml of 0.88 M phenyllithium and the resulting mixture was stirred at a room temperature for 15 minutes. 6 ml of ether solution of 0.53 g of (4-chloro-3-difluoromethyl-2-pyridyl)cyclopropylketone (X) was dropped thereto and the resulting mixture was stirred at a room temperature for 2 hours. The resulting residue was separated by filtering and washed with ether, and thereafter, the ether filtrate and ether used for washing were collected together and the collected solution was washed with water, and thereafter, dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent; hexane:ethyl acetate=4:1) to obtain 0.11 g of 2-(4-chloro-3-difluoromethyl-2-pyridyl)-2-cydopropyl-1-methoxyethene (XI).
Reaction SMILES: C([O:8][CH2:9][C@H:10]1[CH2:13][C@H:12]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([NH2:23])=[C:17]3[C:16]([C:24]3[CH:29]=[CH:28][C:27]([O:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:26][CH:25]=3)=[N:15]2)[CH2:11]1)C1C=CC=CC=1.B(Cl)(Cl)Cl.N>ClCCl.CO>[NH2:23][C:22]1[N:21]=[CH:20][N:19]=[C:18]2[N:14]([C@H:12]3[CH2:11][C@H:10]([CH2:9][OH:8])[CH2:13]3)[N:15]=[C:16]([C:24]3[CH:25]=[CH:26][C:27]([O:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:28][CH:29]=3)[C:17]=12
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2[C@H]1C[C@H](COCc2ccccc2)C1
Agent: ClB(Cl)Cl
Agent: N
Solvent: CO
Solvent: ClCCl
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2[C@H]1C[C@H](CO)C1
Temperature: -78 °C
Reaction time: 7 h

Procedure:
A solution of trans 1-{3-[(benzyloxy)methyl]cyclobutyl}-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.244 g, 0.00051 mol) in dichloromethane (10 mL) was cooled to −78° C. and a solution of 1.0 M boron trichloride in dichloromethane (1.53 mL, 0.00153 mol) was added dropwise, keeping the temperature less than −70° C. The reaction mixture was stirred seven hours at −78° C., after which time a 8 M solution of ammonia in methanol (1.5 mL) was added. The solvent was removed in vacuo. The residue was purified by flash column chromatography on silica using dichloromethane/methanol (93:7). The solvent was removed in vacuo to give to give trans 3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]cyclobutylmethanol (0.192 g, 0.00049 mol) as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][C@@H:13]([NH:16]C(=O)C(F)(F)F)[C@@H:12]1[CH:23]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:24]([CH3:26])[CH3:25])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].O>C(O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][C@@H:13]([NH2:16])[C@@H:12]1[CH:23]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:24]([CH3:25])[CH3:26])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C(C)C)[C@H]1[C@H](NC(=O)C(F)(F)F)CCN1C(=O)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(C(C)C)[C@H]1[C@H](N)CCN1C(=O)OCc1ccccc1
Yield: 72 %

Procedure:
Intermediate 6 (31 g), potassium carbonate (71 g), water (930 ml) and ethanol (930 ml) were warmed at 60° C. for 3 h. The ethanol was removed in vacuo and the aqueous residue extracted with ethyl acetate (3×300 ml). The combined extracts were washed with brine and dried (MgSO4) and concentrated in vacuo to give the title compound as a brown oil (17.5 g).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][NH:17][S:18]([CH:21]([CH3:23])[CH3:22])(=[O:20])=[O:19])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)=[O:2].[BH4-].[Na+].C(OCC)(=O)C.O>C(O)C>[OH:2][CH2:1][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][NH:17][S:18]([CH:21]([CH3:23])[CH3:22])(=[O:20])=[O:19])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: CC(C)S(=O)(=O)NCCc1ccc(-c2ccc(C=O)cc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)S(=O)(=O)NCCc1ccc(-c2ccc(CO)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of 0.5 g (1.5 mmol) of material from Example 119 in 20 mL of ethyl alcohol was added 0.056 g (1.5 mmol) of sodium borohydride. The mixture was stirred at ambient temperature for 2 hr and then 10 mL of ethyl acetate and 10 mL of water was added. The organic layer was separated and the aqueous layer was extracted two times with 5 mL each of ethyl acetate. The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo to afford 0.5 g (100%) of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]1[CH:15]=[CH:14][S:13][C:12]=1Br)=[O:10].C(=O)([O-])[O-].[K+].[K+].O.C(OCC)(=O)C>CS(C)=O>[S:13]1[C:12]2[O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[NH:8][C:9](=[O:10])[C:11]=2[CH:15]=[CH:14]1
Reactant: O=C(Nc1ccccc1O)c1ccsc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: O=C1Nc2ccccc2Oc2sccc21
Temperature: 155 °C
Reaction time: 0.42 h
Yield: 45.5 %

Procedure:
To a solution of N-(2-hydroxyphenyl)-2-bromo-3-thiophenecarboxamide (16 g) in dimethyl sulfoxide (160 ml) was added potassium carbonate (15 g) and the mixture was stirred at 150-160° C. for 25 minutes. The reaction system was cooled to room temperature and the reaction mixture was poured into water-ethyl acetate. The precipitated crystals were collected by filtration and washed with water and diisopropyl ether to give thieno[2,3-b][1,5]benzoxazepin-4(5H)-one (5.3 g).
Reaction SMILES: [F:1][C@H:2]1[C@H:8]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:7][CH2:6][C@@H:5]([C:17]2[N:21]([CH3:22])[N:20]=[CH:19][C:18]=2[N+:23]([O-])=O)[O:4][CH2:3]1.[Br:26][C:27]1[N:32]=[C:31]([C:33](O)=[O:34])[CH:30]=[CH:29][C:28]=1[F:36]>>[Br:26][C:27]1[N:32]=[C:31]([C:33]([NH:23][C:18]2[CH:19]=[N:20][N:21]([CH3:22])[C:17]=2[C@H:5]2[O:4][CH2:3][C@@H:2]([F:1])[C@H:8]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:7][CH2:6]2)=[O:34])[CH:30]=[CH:29][C:28]=1[F:36]
Reactant: Cn1ncc([N+](=O)[O-])c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](F)CO1
Reactant: O=C(O)c1ccc(F)c(Br)n1
Product: Cn1ncc(NC(=O)c2ccc(F)c(Br)n2)c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](F)CO1

Procedure:
Following the procedure for Example 65, starting from tert-butyl N-[(3S,4R,7S)-3-fluoro-7-(2-methyl-4-nitro-pyrazol-3-yl)oxepan-4-yl]carbamate (intermediate 80) and replacing 2-bromo-5-(tert-butoxycarbonylamino)thiazole-4-carboxylic acid with 6-bromo-5-fluoro-pyridine-2-carboxylic acid (see US2010/56576 A1) gave tert-butyl ((3S,4R,7S)-7-(4-(6-bromo-5-fluoropicolinamido)-1-methyl-1H-pyrazol-5-yl)-3-fluorooxepan-4-yl)carbamate.
Reaction SMILES: F[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[C:6]([C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14])[N:5]=[C:4]([CH3:19])[N:3]=1.[C-:20]#[N:21].[Na+].O.C(OCC)(=O)C>C(#N)C>[CH3:19][C:4]1[N:3]=[C:2]([C:20]#[N:21])[C:7]([C:8]([F:11])([F:10])[F:9])=[C:6]([C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14])[N:5]=1
Reactant: [C-]#N
Reactant: Cc1nc(F)c(C(F)(F)F)c(C(F)(F)C(F)(F)F)n1
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Cc1nc(C#N)c(C(F)(F)F)c(C(F)(F)C(F)(F)F)n1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
5.0 g (16.8 mmol) of 4-fluoro-2-methyl-6-(pentafluoroethyl)-5-(trifluoromethyl)pyrimidine are dissolved in 40 ml of acetonitrile. 986 mg (20.1 mmol) of sodium cyanide are added and the reaction mixture is stirred for 18 hours at 50° C. A further 493 mg (10.7 mmol) of sodium cyanide are added and the reaction mixture is stirred under reflux for three hours. After adding 100 ml of water and 100 ml of ethyl acetate, the organic phase is separated off. The aqueous phase is extracted three times with ethyl acetate. The combined organic phases are washed twice with water and with a saturated sodium chloride solution, then dried over sodium sulphate, filtered and the solvent is removed on a rotary evaporator. This gives 4.71 g of 2-methyl-6-(pentafluoroethyl)-5-(trifluoromethyl)pyrimidine-4-carbonitrile (92%) as a dark oil.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([O:18][Si](CC)(CC)CC)[CH2:16]I)=[CH:11][C:10]=1[NH:26][S:27]([CH3:30])(=[O:29])=[O:28])C1C=CC=CC=1.[NH2:31][CH2:32][CH2:33][C:34]1[CH:57]=[CH:56][C:37]([NH:38][CH:39]2[CH2:44][CH2:43][N:42]([C:45]([NH:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55])=[O:46])[CH2:41][CH2:40]2)=[CH:36][CH:35]=1.C(N(CC)C(C)C)(C)C>O1CCCC1>[CH2:48]([NH:47][C:45]([N:42]1[CH2:41][CH2:40][CH:39]([NH:38][C:37]2[CH:36]=[CH:35][C:34]([CH2:33][CH2:32][NH:31][CH2:16][C@H:15]([OH:18])[C:12]3[CH:13]=[CH:14][C:9]([OH:8])=[C:10]([NH:26][S:27]([CH3:30])(=[O:28])=[O:29])[CH:11]=3)=[CH:57][CH:56]=2)[CH2:44][CH2:43]1)=[O:46])[CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55]
Reactant: CCCCCCCCNC(=O)N1CCC(Nc2ccc(CCN)cc2)CC1
Reactant: CC[Si](CC)(CC)O[C@@H](CI)c1ccc(OCc2ccccc2)c(NS(C)(=O)=O)c1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCCCNC(=O)N1CCC(Nc2ccc(CCNC[C@H](O)c3ccc(O)c(NS(C)(=O)=O)c3)cc2)CC1

Procedure:
N-(2-(Benzyloxy)-5-{(1R)-2-iodo-1-[(triethylsilyl)oxy]ethyl}phenyl)methanesulfonamide (E. J. Corey and J. O. Link, J. Org. Chem., 1991, 56, 422 and WO 9737646) (1.0 g, 1.93 mmol) was refluxed in anhydrous tetrahydrofuran (30 mL) with 4-[4-(2-aminoethyl)anilino]-N-octyl-1-piperidinecarboxamide (1.48 g, 3.98 mmol) and N,N-diisopropylethylamine (0.69 mL). The reaction was stirred at reflux for 7 days. The solvent was removed in vacuo and the residue was purified by flash chromatography on silica gel Merck-60 (eluant: 20:1 chloroform-methanol containing 2% triethylamine) to furnish the title compound (0.92 g, 1.14 mmol).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:12]2[NH:13][C:14]3[C:15]([OH:20])=[CH:16][CH:17]=[CH:18][C:19]=3[C:11]=2[CH2:10][CH2:9][N:8]([C:21](=[O:29])[C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH:7]=1)=[O:5])[CH3:2].[C:30](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[CH2:1]([O:3][C:4]([C:6]1[C:12]2[NH:13][C:14]3[C:15]([O:20][CH3:30])=[CH:16][CH:17]=[CH:18][C:19]=3[C:11]=2[CH2:10][CH2:9][N:8]([C:21](=[O:29])[C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=CN(C(=O)c2ccc(F)cc2)CCc2c1[nH]c1c(O)cccc21
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: CCOC(=O)C1=CN(C(=O)c2ccc(F)cc2)CCc2c1[nH]c1c(OC)cccc21
Temperature: 60 °C
Reaction time: 13 h
Yield: 55.1 %

Procedure:
A mixture of 3-(4-fluorobenzoyl)-7-hydroxy-1,2,3,6-tetrahydroazepino[4,5-b]indole-5-carboxylic acid ethyl ester (65 mg, 0.16 mmol), potassium carbonate (54 mg, 0.39 mmol), methyl iodide (0.4 mL, 6.4 mmol) and dry acetone (5 mL) was stirred at 60° C. for 13 hours. The potassium carbonate solid was filtered off, and the filtrate was concentrated in vacuo. The residue was purified by chromatography on silica gel eluting with hexane-EtOAc (90:10) to give the title compound as a yellow solid (36 mg, 55%); 1H-NMR (CDCl3): δ 10.56 (1H, s), 7.98 (1H, s), 7.64-7.59 (2H, m), 7.18-7.12 (3H, m), 7.03 (1H, t), 6.64 (1H, d), 4.28-4.19 (4H, m), 3.96 (3H, s), 3.26-3.24 (2H, m), 1.24 (3H, t); MS (ES): 409 (MH+).
Reaction SMILES: [CH2:1]=O.[NH2:3][CH2:4][CH2:5][CH:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1.[Cl:12][C:13]1[CH:14]=[C:15]([CH:30]=[CH:31][C:32]=1[Cl:33])[CH2:16][N:17]([CH3:29])[C:18](=[O:28])[CH:19]=[C:20]1[C:24](=[O:25])OC(C)(C)[O:21]1>CO>[Cl:12][C:13]1[CH:14]=[C:15]([CH:30]=[CH:31][C:32]=1[Cl:33])[CH2:16][N:17]([CH3:29])[C:18]([C:19]1[CH2:1][N:3]([CH2:4][CH2:5][CH:6]2[CH2:11][CH2:10][O:9][CH2:8][CH2:7]2)[C:24](=[O:25])[C:20]=1[OH:21])=[O:28]
Reactant: C=O
Reactant: CN(Cc1ccc(Cl)c(Cl)c1)C(=O)C=C1OC(C)(C)OC1=O
Reactant: NCCC1CCOCC1
Solvent: CO
Product: CN(Cc1ccc(Cl)c(Cl)c1)C(=O)C1=C(O)C(=O)N(CCC2CCOCC2)C1
Temperature: 60 °C
Reaction time: 6 h
Yield: 76.8 %

Procedure:
A mixture of paraformaldehyde (18 mg, 0.563 mmol) and 4-(2-aminoethyl)tetrahydropyran (65 mg, 0.5 mmol) in anhydrous methanol (3 mL) was warmed to 60° C. To the resulting clear homogeneous solution was added N-(3,4-dichloro-benzyl)-2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-methyl-acetamide (172 mg, 0.5 mmol) and stirring continued for 18 h at 60° C. and an additional 6 h at room temperature. The crude reaction mixture was purified by preparative HPLC on a C18 column using water/methanol (0.1% TFA) as the eluent. The fractions containing the desired product were combined, the methanol removed under vacuum and the remaining aqueous solution extracted with ethyl acetate. The combined ethyl acetate extracts were dried over anhydrous Na2SO4, filtered and concentrated to give the title compound as a white solid (164 mg, 77% yield). 1HNMR (500 MHz, CDCl3) δ: 10.15 (1H, br s), 7.41 (1H, d, J=8.2 Hz), 7.35 (1H, s), 7.11 (1H, d, J=8.2 Hz), 4.60 (2H, s), 4.13 (2H, s), 3.93 (2H, dd, J=11, 3.7 Hz), 3.54 (2H, t, J=7.1 Hz), 3.34 (2H, t, J=11.9 Hz), 3.03 (3H, s), 1.65–1.24 (7H, m). HRMS calcd for C20H25Cl2N2O4 (M+H): 427.1191. found: 427.1179.