Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:8]=1[C:9]([O:11][CH3:12])=[O:10])(=O)=O.C(=O)([O-])[O-].[K+].[K+].O1CCCC1.[F:31][C:32]([F:43])([F:42])[C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1>[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.O>[CH3:17][C:16]1[CH:15]=[CH:14][CH:13]=[C:8]([C:9]([O:11][CH3:12])=[O:10])[C:7]=1[C:36]1[CH:37]=[CH:38][C:33]([C:32]([F:43])([F:42])[F:31])=[CH:34][CH:35]=1
Reactant: COC(=O)c1cccc(C)c1OS(=O)(=O)C(F)(F)F
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cccc(C)c1-c1ccc(C(F)(F)F)cc1

Procedure:
To a solution of methyl 2-trifluoromethanesulfonyloxy-3-methylbenzoate (900 g, in toluene), potassium carbonate (629.6 g), tetrahydrofuran (2700 mL) and deionized water (5400 mL) under nitrogen is added tetrakis (triphenylphosphine) palladium (0) (104.6 g). To this is added the above solution of p-trifluoromethylphenylboronic acid and the mixture is heated at reflux for 2 days. The reaction mixture is filtered and evaporated to dryness. The residue is partitioned between water and ethyl acetate. The ethyl acetate layer is separated and evaporated to dryness. The residue is taken up in heptane-ethyl acetate (9:1), the mixture is filtered and the filtrate is evaporated to dryness to give methyl 6-methyl-4′-trifluoromethylbiphenyl-2-carboxylate as an oil.
Reaction SMILES: [C:1]([N:4]([CH2:9][C:10]([OH:12])=[O:11])[CH2:5][C:6]([OH:8])=[O:7])(=O)C.C(N)(=O)C.[P:17]([OH:20])([OH:19])[OH:18].C=O>Cl>[P:17]([CH2:1][N:4]([CH2:9][C:10]([OH:12])=[O:11])[CH2:5][C:6]([OH:8])=[O:7])([OH:20])([OH:19])=[O:18]
Reactant: CC(=O)N(CC(=O)O)CC(=O)O
Reactant: OP(O)O
Agent: C=O
Agent: CC(N)=O
Agent: Cl
Product: O=C(O)CN(CC(=O)O)CP(=O)(O)O
Yield: 63 %

Procedure:
A crude reaction mixture of N-acetyliminodiacetic acid was prepared from acetamide (5.90 g; 0.10 mol)) by the process described in French Pat. No. 2,523,576. This crude product was dissolved in a 20% aqueous hydrochloric acid solution and the resulting mixture was added to a 250 ml 3-necked flask equipped with an addition funnel and thermometer. Phosphorous acid (8.61 g; 0.105 mol) was added and the solution was heated to a temperature of 106° C.-107° C. When this temperature had been reached, formaldehyde (8.23 g of a 44% aqueous solution; 0.212 mole) was added to the mixture in the flask over a period of 30 minutes. After addition of formaldehyde was complete, the temperature was maintained at 106°-107° C. for an additional period of 3.5 hour. The reaction mixture was concentrated under reduced pressure and a precipitate formed. The product was collected by filtration to yield 14.4 g of N-phosphonomethyliminodiacetic acid (63% yield based on the starting amount of acetamide).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:14]C(=O)C)[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=1.[ClH:18]>C(OCC)C>[ClH:18].[NH2:14][C@@H:3]([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=1)[CH2:2][OH:1]
Reactant: CC(=O)N[C@H](CO)Cc1cccc([N+](=O)[O-])c1
Agent: Cl
Solvent: CCOCC
Product: N[C@H](CO)Cc1cccc([N+](=O)[O-])c1

Procedure:
The process is performed as in Example 2, starting with 5.8 g of N-[(1S)-2-hydroxy-1-(3-nitrobenzyl)ethyl]acetamide in 60 cm3 of aqueous 6N hydrochloric acid, for 10 hours at a temperature in the region of 100° C. After cooling the medium, the precipitate is filtered off and then washed with 30 cm3 of acetone and 3 times 50 cm3 of ether, and dried in an oven under reduced pressure (10 Pa) at a temperature in the region of 60° C. The filtrate is concentrated under reduced pressure (5 kPa) at about 50° C. The residue obtained is taken up in 30 cm3 of diethyl ether and the crystals are filtered off, washed with twice 30 cm3 of ether and dried in an oven under the same conditions as above. The 2 crops crystallized are combined. 5.65 g of (2S)-2-amino-3-(3-nitrophenyl)-1-propanol hydrochloride are obtained in the form of a beige-colored solid melting at 188° C.
Reaction SMILES: [NH2:1][CH:2]1[NH:6][C:5](=[O:7])[CH2:4][S:3]1.[OH:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[C:16]=1[OH:17])[CH:12]=O.N1CCCCC1>C(O)(=O)C>[OH:8][C:9]1[CH:10]=[C:11]([CH:12]=[C:4]2[S:3][CH:2]([NH2:1])[NH:6][C:5]2=[O:7])[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[C:16]=1[OH:17]
Reactant: O=Cc1cc(O)c(O)c([N+](=O)[O-])c1
Reactant: NC1NC(=O)CS1
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: NC1NC(=O)C(=Cc2cc(O)c(O)c([N+](=O)[O-])c2)S1
Temperature: 100 °C

Procedure:
A solution containing 0.58 g (0.005 mol) of 2-aminothiazolidin-4-one, 0.92 g (0.005 mol) of 3,4-dihydroxy-5-nitrobenzaldehyde and 0.05 ml of piperidine in 5 ml of acetic acid was heated for 24 h at 100° C. The product was filtered and washed with ethanol. Yield 1.2 g (86%), mp 250° C. (decomp.).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([CH3:18])[CH2:13][S:14](Br)(=[O:16])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:19]([NH2:21])[CH3:20].Cl>O1CCCC1>[CH2:19]([NH:21][S:14]([CH2:13][CH:12]([NH:11][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10])[CH3:18])(=[O:16])=[O:15])[CH3:20]
Reactant: CC(CS(=O)(=O)Br)NC(=O)OCc1ccccc1
Reactant: CCN
Agent: Cl
Solvent: C1CCOC1
Product: CCNS(=O)(=O)CC(C)NC(=O)OCc1ccccc1
Reaction time: 1 h

Procedure:
A solution (5 ml) of 1.44 g (3.3 mmol) of 2-(benzyloxycarbonylamino)propane-1-sulfonyl bromide in tetrahydrofuran was added dropwise to 70% aqueous ethylamine solution (10 ml) under ice-cooling. The reaction was carried out at room temperature for 1 hour, after which the reaction mixture was poured into diluted hydrochloric acid, followed by three runs of extraction with ethyl acetate. The extract solution was washed with saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain crude N-ethyl-2-(benzyloxycarbonylamino)propane-1-sulfonamide, and this crude product was used without further purification in the subsequent reaction.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:5]=1[S:14](Cl)(=[O:16])=[O:15])([O-:3])=[O:2].[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:5]=1[S:14]([NH:1][C:4]1[CH:5]=[CH:6][CH:7]=[C:22]2[C:23]=1[N:18]=[CH:19][CH:20]=[CH:21]2)(=[O:16])=[O:15])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(C(F)(F)F)cc1S(=O)(=O)Cl
Reactant: c1ccncc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(C(F)(F)F)cc1S(=O)(=O)Nc1cccc2cccnc12
Yield: 32 %

Procedure:
In a similar fashion using route 14 general procedure 27, 8-aminoqunoline (550 mg, 3.8 mmol), 2-nitro-5-trifluoromethyl-benzenesulfonyl chloride (Intermediate 453) (1.43 g, 4.9 mmol), DMAP (cat.), pyridine (4 ml) and DCM (5 ml) gave the title compound (490 mg, 32%) after purification by column chromatography with n-hexane/EtOAc (90:10) as the eluent.
Reaction SMILES: C[N:2]([CH:4]=[C:5]1[C:10](=O)[CH2:9][CH2:8][CH2:7][C:6]1=[O:12])C.[C:13]1([NH:19]N)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CO>[C:13]1([N:19]2[C:10]3[CH2:9][CH2:8][CH2:7][C:6](=[O:12])[C:5]=3[CH:4]=[N:2]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NNc1ccccc1
Reactant: CN(C)C=C1C(=O)CCCC1=O
Solvent: CO
Product: O=C1CCCc2c1cnn2-c1ccccc1
Yield: 26.1 %

Procedure:
To a stirred solution of 2-((dimethylamino)methylene)cyclohexane-1,3-dione (14 g, 83 mmol) in methanol (150 mL) was added phenyl hydrazine (8.92 g, 83 mmol). The reaction mixture was refluxed for 6 hours. The reaction was then concentrated under reduced pressure followed by the addition of n-butanol (130 mL) and glacial acetic acid (2 mL). The reaction mixture was refluxed for 3 hours. On the completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was triturated with ether (100 mL) to give a precipitate, which was filtered and dried under reduced pressure to give the desired product (4.6 g, 30%) as a solid. 1H NMR (DMSO-d6, 400 MHz): δ 9.06 (s, 1H), 7.59-7.51 (m, 4H), 7.45-7.40 (m, 1H), 3.00 (t, J=6.4 Hz, 2H), 2.58 (t, J=6.4 Hz, 2H), 2.21 (quintet, J=6.4 Hz, 2H). LCMS [M+H]: 213.
Reaction SMILES: O=[C:2]1[CH2:8][O:7][CH2:6][CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3]1.CCN(CC)CC.Cl.[NH2:24][OH:25]>C1COCC1>[OH:25][N:24]=[C:2]1[CH2:8][O:7][CH2:6][CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCOCC(=O)C1
Reactant: NO
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCOCC(=NO)C1
Temperature: 25 °C
Yield: 102.2 %

Procedure:
A solution of tert-butyl 6-methylene-1,4-oxazepane-4-carboxylate 38.2 (1.23 g, 5.74 mmol) in 1,4-dioxane (20 mL) and H2O (20 mL) was treated with sodium periodate (2.46 g, 11.49 mmol) and a solution of 2.5% OsO4 in t-BuOH (0.36 mL, 0.028 mmol). The reaction mixture was stirred at room temperature for 18 hrs. The resulting yellow-white suspension was diluted with H2O and extracted with EtOAc (2×50 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo to provide a brown oil (1.30 g) that was used immediately without further purification. The crude tert-Butyl 6-oxo-1,4-oxazepane-4-carboxylate (4.4 g, 20.4 mmol) was dissolved in THF (100 mL) and treated with Et3N (11.4 mL, 81.8 mmol) and hydroxylamine hydrochloride (3.1 g, 45.0 mmol). The mixture was stirred at room temperature over the weekend. The mixture was concentrated in vacuo to dryness and the residue was suspended between EtOAc and water. The aqueous layer was extracted with EtOAc. The organics were washed with brine, dried over MgSO4, filtered and concentrated in vacuo to yield (4.8 g) of a semisolid product 38.3. LCMS m/z=253.1 [M+Na], 461.3 [2M] with two equal peaks observed (oxyme steroisomers presumably). Used without further purification.
Reaction SMILES: [CH3:1][C:2]1[C:7](=[O:8])[CH2:6][CH:5]([C:9]([CH3:11])=[CH2:10])[CH2:4][CH:3]=1.[CH3:12][SH:13]>C(N(CC)CC)C>[CH3:1][C:2]1[C:7](=[O:8])[CH2:6][CH:5]([C:9]([CH3:11])=[CH2:10])[CH2:4][CH:3]=1.[CH3:12][S:13][CH:3]1[CH:2]([CH3:1])[C:7](=[O:8])[CH2:6][CH:5]([C:9]([CH3:11])=[CH2:10])[CH2:4]1
Reactant: CS
Solvent: C=C(C)C1CC=C(C)C(=O)C1
Solvent: CCN(CC)CC
Product: C=C(C)C1CC(=O)C(C)C(SC)C1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
15.0 g of carvone are mixed with 0.5 g of triethylamine. 20 ml of methyl mercaptan are condensed in this mixture at room temperature. After standing overnight in the autoclave, the mixture is heated to 50°C for a further 2 hours. After removal of the excess methyl mercaptan, the reaction product is fractionally distilled in vacuum. After a small fore-run of unreacted carvone, there are obtained 14.9 g of 6-methylthio-p-menth-8-en-2-one in the form of a mixture of two isomers in the ratio 1:4 (boiling point 105°-107°/0.2 mm Hg, nD20 1.5067), corresponding to a yield of 78% of the theory. The odour of the mixture is reminiscent of boiled white cabbage with a caraway and onion peel note.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1.[CH3:26][S:27]([CH2:30][C:31](O)=[O:32])(=[O:29])=[O:28]>>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:20][CH2:21][C@H:22]([NH:25][C:31](=[O:32])[CH2:30][S:27]([CH3:26])(=[O:29])=[O:28])[CH2:23][CH2:24]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Reactant: CS(=O)(=O)CC(=O)O
Agent: Cl
Product: CS(=O)(=O)CC(=O)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1

Procedure:
The title compound, white solid (25.3 mg, 68.7%), MS (ISP) m/z=451.1 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperidin-1-yl)-ethyl]-cyclohexylamine hydrochloride (intermediate A) (30 mg, 0.0818 mmol) and 2-(methylsulfonyl)acetic acid.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:5][CH:4]=1)=[O:2]>[Pd].CO>[C:11]1([CH2:10][CH2:9][C:6]2[CH:5]=[CH:4][C:3]([CH:1]=[O:2])=[CH:8][CH:7]=2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=Cc1ccc(C=Cc2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Product: O=Cc1ccc(CCc2ccccc2)cc1

Procedure:
4-(2-Phenylethyl)benzaldehyde is prepared by catalytic hydrogenation of 4-formylstilbene over 20% palladium on carbon in methanol.
Reaction SMILES: [NH2:1][C:2]1[C:12]2[CH2:11][CH2:10][N:9]([C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])[CH2:8][CH2:7][C:6]=2[CH:5]=[CH:4][C:3]=1[Cl:19].Br[CH2:21][C:22]1[CH:36]=[CH:35][C:25]2[N:26]=[C:27]([CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)[S:28][C:24]=2[CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[Cl:19][C:3]1[CH:4]=[CH:5][C:6]2[CH2:7][CH2:8][N:9]([C:13](=[O:18])[C:14]([F:17])([F:15])[F:16])[CH2:10][CH2:11][C:12]=2[C:2]=1[NH:1][CH2:21][C:22]1[CH:36]=[CH:35][C:25]2[N:26]=[C:27]([CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)[S:28][C:24]=2[CH:23]=1
Reactant: BrCc1ccc2nc(C3CCCCC3)sc2c1
Reactant: Nc1c(Cl)ccc2c1CCN(C(=O)C(F)(F)F)CC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=C(N1CCc2ccc(Cl)c(NCc3ccc4nc(C5CCCCC5)sc4c3)c2CC1)C(F)(F)F
Temperature: 100 °C

Procedure:
Using a method similar to the General Procedure 5-4, combine 6-amino-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (60 mg, 0.21 mmol), 6-bromomethyl-2-cyclohexyl-benzothiazole (0.1 g, 0.31 mmol), potassium carbonate (58 mg, 0.42 mmol) and anhydrous toluene (2 mL) in a sealed tube and heat at 100° C. for 72 h to obtain 7-chloro-6-[(2-cyclohexyl-benzothiazol-6-yl-methyl)-amino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a colorless oil.
Reaction SMILES: Cl[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:8][CH2:9][CH3:10])[CH:7]=1.[CH:11]12[CH2:18][NH:17][CH2:16][CH:15]1[CH2:14][NH:13][CH2:12]2.CC(C)([O-])C.[K+]>COCCOC>[CH2:9]([O:8][C:6]1[CH:7]=[C:2]([N:13]2[CH2:14][CH:15]3[CH:11]([CH2:18][NH:17][CH2:16]3)[CH2:12]2)[CH:3]=[N:4][CH:5]=1)[CH3:10]
Reactant: CCOc1cncc(Cl)c1
Reactant: C1NCC2CNCC12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Product: CCOc1cncc(N2CC3CNCC3C2)c1

Procedure:
Obtainable by stirring a mixture of 3-chloro-5-ethoxypyridine (1 eq.), 3.7-Diazabicyclo[3.3.0]octane (1 eq.), potassium-tert-butoxide (2 eq.) and 1.2-dimethoxyethane as solvent. Workup-procedure A/B.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C@H:17]([NH:19][C:20]([C:22]1([NH:25][C:26](=[O:31])[C:27]([F:30])([F:29])[F:28])[CH2:24][CH2:23]1)=[O:21])[CH3:18].Br[C:33]1[CH:34]=[CH:35][CH:36]=[C:37]2[C:42]=1[N:41]=[CH:40][CH:39]=[CH:38]2.C(=O)([O-])[O-].[Cs+].[Cs+].CCOC(C)=O>O1CCOCC1.[Pd].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>[F:1][C:2]1[CH:7]=[C:6]([C:33]2[CH:34]=[CH:35][CH:36]=[C:37]3[C:42]=2[N:41]=[CH:40][CH:39]=[CH:38]3)[CH:5]=[CH:4][C:3]=1[C@H:17]([NH:19][C:20]([C:22]1([NH:25][C:26](=[O:31])[C:27]([F:29])([F:30])[F:28])[CH2:23][CH2:24]1)=[O:21])[CH3:18]
Reactant: C[C@@H](NC(=O)C1(NC(=O)C(F)(F)F)CC1)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1F
Reactant: Brc1cccc2cccnc12
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: C[C@@H](NC(=O)C1(NC(=O)C(F)(F)F)CC1)c1ccc(-c2cccc3cccnc23)cc1F
Temperature: 25 °C

Procedure:
N-{(1R)-1-[2-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethyl}-1-[(trifluoroacetyl)amino]cyclopropanecarboxamide (250 mg, 0.563 mmol), 8-bromoquinoline (117 mg, 0.563 mmol), cesium carbonate (367 mg, 1.13 mmol), and bis(tri-t-butylphosphine) palladium(0) (10 mg, 0.03 mmol) were stirred in 1 mL of anhydrous dioxane overnight at 90° C. in a sealed tube. The reaction mixture was cooled to room temperature and diluted w/EtOAc. The organic layer was separated, washed with water and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by silica gel chromatography eluting with 10% to 95% EtOAc/hexanes to provide (N-[(1R)-1-(2-fluoro-4-quinolin-8-ylphenyl)ethyl]-1-[(trifluoroacetyl)amino]cyclopropanecarboxamide. ES MS, M+H+ found: 475. Proton NMR (400 MHz, CDCl3) δ 1.2 (m, J=2.4 Hz, 2H), 1.58 (d, J=6.8 Hz, 3H), 1.7 (m, J=2.9 Hz, 2H), 3.86 (s, 3H), 5.33 (q, J=7.2 Hz, 1H), 6.64 (d, J=8.8 Hz, 1H), 6.84 (s, 1H), 7.08 to 7.19 (m, 3H), 7.34 (m, 3H), 7.47 (m, J=4.5 Hz, 1H), 7.81 (m, J=5 Hz, 1H), 7.9 (d, J=9 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](I)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH2:10]([OH:18])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]#[CH:17]>[Cu]I.C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:17]#[C:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][OH:18])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Clc1ccc(I)cc1Cl
Reactant: C#CCCCCCCO
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: OCCCCCCC#Cc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 3,4-dichloroiodobenzene (2.16 g), oct-7-yn-1-ol (1.20 g), tetrakis (triphenylphosphine)palladium (0) (0.185 g), copper (I) iodide (0.046 g) and triethylamine (15 ml) was stirred at room temperature for 16 h. The solid was filtered off and the filtrate evaporated under reduced pressure. The residual oil was dissolved in ethyl acetate (15 ml) and washed with water (10 ml), 2M hydrochloric acid (2×10 ml) and brine (10 ml). Drying over magnesium sulfate and removal of the solvent under reduced pressure gave an oil that was purified by flash chromatography on silica gel using dichloromethane as eluent. This gave 8-(3,4-dichlorophenyl)oct-7-yn-1-ol (1.89 g). 1H-NMR (CDCl3) δ 1.2-1.75 (8H, m), 2.40 (2H, t), 3.66 (2H, t), 7.19 (1H, dd), 7.35 (1H, d) and 7.47 (1H, dd).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C:13]([OH:15])=O)[CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:16][NH:17][O:18][CH3:19].Cl.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1([C:13](=[O:15])[N:17]([O:18][CH3:19])[CH3:16])[CH2:10][CH2:11][CH2:12]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCC1
Reactant: CNOC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)C1(NC(=O)OC(C)(C)C)CCC1
Yield: 87 %

Procedure:
To a solution of 1-tert-butoxycarbonylamino-cyclobutanecarboxylic acid (3 g, 13.94 mmol) in dry DMF (50 mL) was added N,O-dimethylhydroxylamine×HCl (1.36 g, 13.94 mmol) and DIEA (9.21 mL, 55.75 mmol). The reaction flask was cooled to 0° C. and after 10 minutes HATU (5.30 g, 13.94 mmol) was added to the solution (which turned yellow on addition). After 2 hrs the DMF was removed by rotary evaporation at reduced pressure. The residue was dissolved in EtOAc (100 mL) and washed twice with 10% citric acid (aq) and saturated NaHCO3(aq) solution. The organic phase was dried with Na2SO4, filtered and evaporated on silica. The product was purified by flash chromatography (heptane: ethyl acetate (1:1) to give the product as a colourless oil that slowly crystallizes (3.13 g) in 87% yield.
Reaction SMILES: C1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[CH2:36]([N:38]([S:73]([C:76]1[S:77][CH:78]=[CH:79][CH:80]=1)(=[O:75])=[O:74])[C:39]1[CH:40]=[CH:41][CH:42]=[C:43]2[C:47]=1[NH:46][C:45]([C:48]([NH:50][CH2:51][CH2:52][S:53]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=O)=[CH:44]2)[CH3:37]>ClCCl>[S:53]1[CH2:52][CH2:51][N:50]=[C:48]1[C:45]1[NH:46][C:47]2[C:43]([CH:44]=1)=[CH:42][CH:41]=[CH:40][C:39]=2[N:38]([CH2:36][CH3:37])[S:73]([C:76]1[S:77][CH:78]=[CH:79][CH:80]=1)(=[O:75])=[O:74]
Reactant: CCN(c1cccc2cc(C(=O)NCCSC(c3ccccc3)(c3ccccc3)c3ccccc3)[nH]c12)S(=O)(=O)c1cccs1
Agent: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: CCN(c1cccc2cc(C3=NCCS3)[nH]c12)S(=O)(=O)c1cccs1
Reaction time: 0.17 h
Yield: 33.7 %

Procedure:
To a solution of triphenylphosphine oxide (2.34 g) in dichloromethane (25 mL) was slowly added trifluoromethanesulfonic anhydride (0.71 mL) at 0° C. The mixture was stirred for 10 min, and 7-[ethyl(2-thienylsulfonyl)amino]-N-[2-(tritylthio)ethyl]-1H-indole-2-carboxamide (0.89 g) was added. The reaction mixture was stirred at room temperature for 3 hr and concentrated. Saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography and the title compound (0.18 g, yield 33%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). melting point 206-207° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:21])=[C:6]([C@:8]2([CH3:20])[C:14]([F:16])([F:15])[C:13]([CH3:18])([CH3:17])[O:12][CH2:11][C:10](=[S:19])[NH:9]2)[CH:7]=1.[C:22]([C:24]1[CH:25]=[CH:26][C:27]([C:30](O)=[O:31])=[N:28][CH:29]=1)#[N:23]>>[C:22]([C:24]1[CH:25]=[CH:26][C:27]([C:30]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([F:21])=[C:6]([C@:8]3([CH3:20])[C:14]([F:16])([F:15])[C:13]([CH3:17])([CH3:18])[O:12][CH2:11][C:10](=[S:19])[NH:9]3)[CH:7]=2)=[O:31])=[N:28][CH:29]=1)#[N:23]
Reactant: N#Cc1ccc(C(=O)O)nc1
Reactant: CC1(C)OCC(=S)N[C@](C)(c2cc(N)ccc2F)C1(F)F
Product: CC1(C)OCC(=S)N[C@](C)(c2cc(NC(=O)c3ccc(C#N)cn3)ccc2F)C1(F)F

Procedure:
The compound was prepared in an analogous manner as described for intermediate B14A from (R)-5-(5-amino-2-fluorophenyl)-6,6-difluoro-5,7,7-trimethyl-[1,4]oxazepane-3-thione (intermediate A17B) (150 mg, 0.47 mmol) and commercially available 5-cyano-pyridine-2-carboxylic acid [CAS No. 53234-55-2] (105 mg, 0.71 mmol). The compound was obtained as a light brown oil (280 mg, 99%, 75% purity). MS (ISP): m/z=449.2 [(M+H)+].
Reaction SMILES: FC(F)(F)C(O)=O.[NH:8]1[CH2:13][CH2:12][CH2:11][CH:10]([NH:14][C:15]([N:17]2[CH2:22][CH2:21][C:20]3[NH:23][N:24]=[C:25]([C:26]4[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=4)[C:19]=3[CH2:18]2)=[O:16])[CH2:9]1.[F:32][C:33]1[CH:40]=[CH:39][CH:38]=[CH:37][C:34]=1[CH:35]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Na]>C(O)(=O)C.ClCCl>[F:32][C:33]1[CH:40]=[CH:39][CH:38]=[CH:37][C:34]=1[CH2:35][N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([NH:14][C:15]([N:17]2[CH2:22][CH2:21][C:20]3[NH:23][N:24]=[C:25]([C:26]4[CH:27]=[CH:28][N:29]=[CH:30][CH:31]=4)[C:19]=3[CH2:18]2)=[O:16])[CH2:9]1
Reactant: O=C(NC1CCCNC1)N1CCc2[nH]nc(-c3ccncc3)c2C1
Reactant: O=Cc1ccccc1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [Na]
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=C(NC1CCCN(Cc2ccccc2F)C1)N1CCc2[nH]nc(-c3ccncc3)c2C1
Reaction time: 16 h

Procedure:
In a flask, dichloromethane (0.295 mL) and acetic acid (2 drops) was added to N-(piperidin-3-yl)-3-(pyridin-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxamide trifluoroacetate salt (0.021 g, 0.05 mmol) and 2-fluorobenzaldehyde (0.0124 g, 0.1 mmol). The reaction was sonicated for 1 hr. Sodium triacetoxyborohydride (0.050 g, 0.25 mmol) was added in one portion. The reaction was stirred for an additional 16 hours. Saturated sodium bicarbarbonate (1 mL) was added. The reaction was stirred for an additional 5 minutes and was extracted with dichloromethane (3×1 mL). The extracts were combined, dried with anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting crude product was purified by prep LC/MS. LC-MS: 435.68 [M+H]. LC/MS RT=1.82 min.