Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.Cl.[Br:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH2:11][CH2:12][C@@H:13]2[OH:18].C(=O)([O-])O.[Na+]>C(Cl)Cl.O1CCOCC1>[Br:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH2:11][CH2:12][C@@H:13]2[O:18][CH:6]1[CH2:5][CH2:4][CH2:3][CH2:2][O:1]1
Reactant: O[C@H]1CCc2c(Br)cccc21
Reactant: C1=COCCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: Brc1cccc2c1CC[C@@H]2OC1CCCCO1

Procedure:
3,4-dihydro-2H-pyran (10.6 mL) was dissolved in methylene chloride (16.2 mL), and to the resultant solution, a 4M hydrogen chloride solution in 1,4-dioxane (31.1 μL) was added, and to the resultant reaction mixture, (1S)-4-bromo-2,3-dihydro-1H-inden-1-ol (10.0 g) that is commercially available or can be obtained by a publicly known method was added, followed by stirring the resultant reaction mixture at room temperature for 3 hours. To the reaction mixture, a saturated sodium hydrogen carbonate aqueous solution (60 mL) was added, followed by extracting the resultant reaction mixture with methylene chloride (60 mL), and the organic phase was washed with a saturated saline (60 mL), followed by drying the organic phase over anhydrous sodium sulfate. From the organic phase, the solvent was distilled off under reduced pressure, followed by purifying the resultant residue by silica gel column chromatography (eluate; n-hexane:ethyl acetate=95:5), and from the resultant, the solvent was distilled off under reduced pressure to obtain the subject compound (15 g). The compound is a mixture of diastereomers.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19](OC)=[O:20])=[C:17]([O:25][CH3:26])[CH:16]=2)[N:10]=1.[NH:27]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[N:29]=[C:28]1[NH2:36].C[Al](C)C>C1(C)C=CC=CC=1>[NH:27]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[N:29]=[C:28]1[NH:36][C:19](=[O:20])[C:18]1[CH:23]=[CH:24][C:15]([N:11]2[C:12](=[O:14])[NH:13][C:9]([C:3]3[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])=[N:10]2)=[CH:16][C:17]=1[O:25][CH3:26]
Reactant: COC(=O)c1ccc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)cc1OC
Reactant: Nc1nc2ccccc2[nH]1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: COc1cc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)ccc1C(=O)Nc1nc2ccccc2[nH]1
Yield: 32.1 %

Procedure:
The title compound was prepared by following the procedure as described for Example-31 by using methyl 4-(3-(2-chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxybenzoate (step-2 of Intermediate-15, 0.100 g, 0.26 mmol), 1H-benzo[d]imidazol-2-amine (0.046 g, 0.34 mmol), trimethyl aluminium (2M solution in toluene) (0.5 mL) and dry toluene (5.0 mL) to afford 0.040 g of desired product. 1HNMR (DMSO-d6): δ 4.01 (s, 3H), 7.11 (m, 2H), 7.48-7.76 (m, 6H), 7.81 (s, 1H), 7.96 (d, J=9.0 Hz, 1H), 11.16 (br s, 1H), 12.28 (br s, 1H), 12.76 (br s, 1H); MS (m/z): 478.90 [M]+
Reaction SMILES: [CH3:1][C:2]1[CH:26]=[C:25]([CH3:27])[CH:24]=[C:23]([CH3:28])[C:3]=1[C:4]([O:6][CH2:7][C:8]([CH2:10][O:11][C:12](=[O:22])[C:13]1[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=1[CH3:21])=[O:9])=[O:5].C([NH:39][C@H:40]([C:48]([NH:50][C@H:51]([C:53]([OH:55])=[O:54])[CH3:52])=[O:49])[CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)(OCC1C=CC=CC=1)=O.C(O)C.[ClH:59]>[Pd]>[ClH:59].[CH3:19][C:18]1[CH:17]=[C:16]([CH3:20])[CH:15]=[C:14]([CH3:21])[C:13]=1[C:12]([O:11][CH2:10][C:8]([CH2:7][O:6][C:4](=[O:5])[C:3]1[C:23]([CH3:28])=[CH:24][C:25]([CH3:27])=[CH:26][C:2]=1[CH3:1])=[O:9])=[O:22].[NH2:39][C@H:40]([C:48]([NH:50][C@H:51]([C:53]([OH:55])=[O:54])[CH3:52])=[O:49])[CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: C[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(=O)O
Agent: [Pd]
Agent: Cc1cc(C)c(C(=O)OCC(=O)COC(=O)c2c(C)cc(C)cc2C)c(C)c1
Agent: Cl
Solvent: CCO
Product: C[C@H](NC(=O)[C@@H](N)Cc1ccccc1)C(=O)O
Reaction time: 3 h

Procedure:
To a mixture of N-CBZ-L-phenylalanyl-L-alanine 2,4,6-trimethylbenzoyloxymethyl ketone (0.38 mmol, 200 mg) in 100 mL of ethanol containing 150 μL (0.75 mmol) of 5 N HCl was added 10% palladium on charcoal (20 mg). This mixture was vigorously stirred under an atmosphere of hydrogen gas for 3 hours, the catalyst was removed by filtration through a bed of Celite, and the filtrate was rotary evaporated under reduced pressure. The residue was then precipitated from ethanol-ethyl ether, washed with ethyl ether, and dried at high vacuum to quantitatively afford the product as a powder, m.p. 123°-126° C.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][C@H:18]([CH:20]4[CH2:25][CH2:24][N:23]([C:26]#[N:27])[CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].Cl.[NH2:29][OH:30]>>[OH:30][NH:29][C:26]([N:23]1[CH2:24][CH2:25][CH:20]([C@@H:18]2[O:17][C:14]3=[CH:15][N:16]=[C:11]([C:8]4[CH2:9][CH2:10][N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:6][CH:7]=4)[CH:12]=[C:13]3[CH2:19]2)[CH2:21][CH2:22]1)=[NH:27]
Reactant: NO
Reactant: CS(=O)(=O)N1CC=C(c2cc3c(cn2)O[C@@H](C2CCN(C#N)CC2)C3)CC1
Agent: Cl
Product: CS(=O)(=O)N1CC=C(c2cc3c(cn2)O[C@@H](C2CCN(C(=N)NO)CC2)C3)CC1

Procedure:
The title compound is prepared from (R)-4-[5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2,3-dihydro-furo[2,3-c]pyridine-2-yl]-piperidine-1-carbonitrile (Intermediate 44, the configuration of the stereocenter is arbitrarily assigned) and hydroxylamine hydrochloride following a procedure analogous to that described for Intermediate 11. LC (method 6): tR=0.75 min; Mass spectrum (ESI+): m/z=422 [M+H]+.
Reaction SMILES: [CH:1]1[C:6]2=[C:7]3[C:15](=[CH:16][CH:17]=[C:5]2[CH:4]=[CH:3][CH:2]=1)[C:14]1[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=1)[NH:8]3.[H-].[Na+].Br[CH2:21][CH:22]([CH2:27][CH3:28])[CH2:23][CH2:24][CH2:25][CH3:26]>CN(C=O)C>[CH2:27]([CH:22]([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:21][N:8]1[C:7]2[C:15](=[CH:16][CH:17]=[C:5]3[CH:4]=[CH:3][CH:2]=[CH:1][C:6]3=2)[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH3:28]
Reactant: c1ccc2c(c1)ccc1c3ccccc3[nH]c21
Reactant: CCCCC(CC)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCC(CC)Cn1c2ccccc2c2ccc3ccccc3c21
Temperature: 0 °C
Reaction time: 1 h
Yield: 101.8 %

Procedure:
To 11H-benzo[a]carbazole (0.70 g; 3.22 mmol) in DMF (3 ml) is added sodium hydride (0.19 g; 4.67 mmol) at 0° C., After stirring 1 h at 0° C., 1-bromo-2-ethylhexane (1.24 g; 6.44 mmol) is added at 0° C., and the mixture is stirred at room temperature overnight. The reaction mixture is poured into ice-water, and the crude product is extracted twice with AcOEt (acetic acid ethyl ester). The combined organic layer is washed with H2O and brine, dried over MgSO4, and concentrated and dried in vacuo to give a yellow liquid as a crude product (1.08 g). The product is used for the next reaction without further purification. The structure is confirmed by 1H-NMR spectrum (CDCl3). δ [ppm]: 0.80-0.92 (m, 6H), 1.16-1.47 (m, 8H), 2.27 (m, 1H), 4.65-4.69 (m, 2H), 7.27 (td, 1H), 7.44-7.59 (m, 4H), 7.66 (d, 1H), 8.02 (d, 1H), 8.14 (d, 1H), 8.18 (d, 1H), 8.54 (d, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([OH:9])[C:6]([C:10](=[O:26])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:5][C:3]=1[OH:4].C(=O)([O-])[O-].[K+].[K+].[CH2:33]([C:35](C)=O)[CH3:34].C(Br)C=C>O>[CH2:35]([O:4][C:3]1[CH:5]=[C:6]([C:10](=[O:26])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:7]([OH:9])=[CH:8][C:2]=1[CH3:1])[CH:33]=[CH2:34]
Reactant: CCC(C)=O
Reactant: CCCCCCCCCCCCCCCC(=O)c1cc(O)c(C)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C=CCBr
Solvent: O
Product: C=CCOc1cc(C(=O)CCCCCCCCCCCCCCC)c(O)cc1C

Procedure:
Under nitrogen atmosphere a mixture of 17.5 g of the keto-compound of step 1, 10.2 g of potassium carbonate and 200 ml of methyl ethyl ketone was refluxed with stirring together with 6.9 g of allyl bromide for 1 hour. After a total refluxing time of 9 h the reaction mixture was mixed with 100 ml of water. The methyl ethyl ketone layer is separated, shaken twice with a 20% by weight sodium chloride solution and dried with sodium sulphate. The residue left after evaporation of the solvent was stirred with methanol, whereupon the precipitate formed was filtered with suction and recrystallized from methanol.
Reaction SMILES: C([Li])(C)(C)C.Br[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Si:13]([CH3:16])([CH3:15])[CH3:14])[CH:8]=1.[B:17](OC)([O:20]C)[O:18]C.Cl>CCOCC.O>[CH3:14][Si:13]([CH3:16])([CH3:15])[C:9]1[CH:8]=[C:7]([B:17]([OH:20])[OH:18])[CH:12]=[CH:11][CH:10]=1
Reactant: COB(OC)OC
Reactant: C[Si](C)(C)c1cccc(Br)c1
Agent: Cl
Agent: [Li]C(C)(C)C
Solvent: O
Solvent: CCOCC
Product: C[Si](C)(C)c1cccc(B(O)O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.4 %

Procedure:
t-Butyllithium (28 cm3, 1.7 M in pentane) was added to a solution of (21) (9.65 g, 42 mmol) in ether (200 cm3) cooled in a dry ice/acetone bath, and the reaction was stirred for 30 minutes. Trimethyl borate (20 cm3, 170 mmol) was added, and the reaction was stirred for 16 hours, gradually warming to room temperature. Aqueous hydrochloric acid (3 M, 20 cm3) was added, and the reaction was stirred for a further 2 hours. Water (200 cm3) was added, and the layers were separated. The aqueous layer was extracted with ether (3×30 cm3). The combined organic extracts were washed with brine (300 cm3) and dried over magnesium sulfate, and the solvent was removed to leave a white solid. The crude product was passed through a plug of silica using light petroleum then ether as the eluent. The ether band was collected, and the solvent was removed to leave (22) as a brown solid (7.04 g, 86%).
Reaction SMILES: [C:1]([C:3]1[C:4]([Br:16])=[C:5]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])[C:6]([Br:10])=[CH:7][C:8]=1[Br:9])#[N:2].S(=O)(=O)(O)[OH:18]>>[C:1]([C:3]1[C:4]([Br:16])=[C:5]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])[C:6]([Br:10])=[CH:7][C:8]=1[Br:9])(=[O:18])[NH2:2]
Reactant: O=S(=O)(O)O
Reactant: N#Cc1c(Br)cc(Br)c(CCC(=O)O)c1Br
Product: NC(=O)c1c(Br)cc(Br)c(CCC(=O)O)c1Br
Temperature: 60 °C
Reaction time: 2 h

Procedure:
13 g of 3-(3-cyano-2,4,6-tribromophenyl)propionic acid is suspended in 50 ml of concentrated sulfuric acid and heated initially to 60° C. for 30 minutes and thereafter to 95° C. for 2 hours. The solution is then poured on 300 g of ice and agitated for 3 hours in an ice bath. The thus-precipitated product is vacuum-filtered, washed with ice water, and dried at 50° C. under vacuum. Yield: 14 g of 3-(3-carbamoyl-2,4,6-tribromophenyl)propionic acid with 90% of theory, mp 197° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]2[N:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH2:8][CH2:7]1.[CH3:18][C:19]1([CH3:29])[CH:24]2[CH2:25][CH2:26][CH:20]1[C:21](=O)[O:22][C:23]2=[O:27]>>[N:17]1[CH:16]=[CH:15][CH:14]=[N:13][C:12]=1[N:9]1[CH2:8][CH2:7][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][N:1]2[C:23](=[O:27])[CH:24]3[C:19]([CH3:18])([CH3:29])[CH:20]([CH2:26][CH2:25]3)[C:21]2=[O:22])[CH2:11][CH2:10]1
Reactant: NCCCCN1CCN(c2ncccn2)CC1
Reactant: CC1(C)C2CCC1C(=O)OC2=O
Product: CC1(C)C2CCC1C(=O)N(CCCCN1CCN(c3ncccn3)CC1)C2=O
Yield: 30.3 %

Procedure:
Following substantially the procedure of Example 1, 0.54 g (2.34 mmol) of 1-(4-aminobutyl)-4-(2-pyrimidinyl) piperazine was reacted with 0.36 g (2.14 mmol) of 8,8-dimethyl-3-oxabicyclo[3.2.1]octan-2,4-dione. The product was chromatographed on silica gel, eluting with dichloromethane/methanol (96:4), to give 0.25 g (32% yield) of the title compound.
Reaction SMILES: [NH2:1][C@H:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][OH:4].[C:11]1(=O)[O:16][C:14](=[O:15])[C:13]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:12]12>CC#N>[OH:4][CH2:3][C@H:2]([N:1]1[C:14](=[O:15])[C:13]2[C:12](=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:11]1=[O:16])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: N[C@@H](CO)c1ccccc1
Solvent: CC#N
Product: O=C1c2ccccc2C(=O)N1[C@@H](CO)c1ccccc1
Temperature: 150 °C
Yield: 93.9 %

Procedure:
To a 2.0-5.0 mL microwave vial was added (R)-2-amino-2-phenylethan-1-ol (1.53 g, 0.0112 mol) and phthalic anhydride (1.65 g, 0.0112 mol). The reaction mixture was capped and heated to 150° C. for 2 minutes in a microwave reactor. The mixture was cooled and diluted with CH3CN (2 mL), recapped and heated in the microwave reactor a second time at 140° C. for 20 minutes. The volatiles were removed under reduced pressure and the resulting solid was suspended in EtOAc (50 mL). The organic layer was washed with 5% NaHCO3 (aq), H2O, and brine, dried with anhydrous MgSO4 and concentrated. The crude residue was purified by flash chromatography (silica gel, eluting with CH3OH in CH2Cl2 (0 to 5%) to yield 2.81 g (94%) of the title compound. LC/MS: m/z (ES+) 268 (M+H)+.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](B(O)O)=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[O:18]=[S:19]1(=[O:36])[CH2:24][CH2:23][N:22]2[CH:25]=[CH:26][CH:27]=[C:28]([C:29]3[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=3)[C:21]2=[N:20]1.C(N(CC)CC)C>CN(C=O)C.C(O[Cu]OC(=O)C)(=O)C>[Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:35][C:32]2[CH:31]=[CH:30][C:29]([C:28]3[C:21]4=[N:20][S:19](=[O:36])(=[O:18])[CH2:24][CH2:23][N:22]4[CH:25]=[CH:26][CH:27]=3)=[CH:34][CH:33]=2)=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: O=S1(=O)CCN2C=CC=C(c3ccc(O)cc3)C2=N1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(B(O)O)cc1
Agent: CC(=O)O[Cu]OC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)Oc1ccc(Oc2ccc(C3=CC=CN4CCS(=O)(=O)N=C34)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.7 %

Procedure:
A mixture of 4-(tert-butyldimethylsilyloxy)phenylboronic acid (6.11 g), 4-(2,2-dioxido-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazin-9-yl)phenol (2.23 g), triethylamine (5.61 mL), diacetoxycopper (2.93 g), and 4A MS (2.0 g) in DMF (80 mL) was stirred at room temperature overnight. The mixture was added with silica gel, concentrated in vacuo, and purified by column chromatography (silica gel, eluted with EtOAc in hexane) to give the title compound (1.82 g) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:18]=[C:19]([C:21]#[CH:22])[CH:20]=1)[C:5]([NH:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH3:17])=[O:6].[C:23]([O:27][C:28](=[O:48])[NH:29][C:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:33]([O:40][C:41]2[CH:46]=[CH:45][N:44]=[C:43](Cl)[N:42]=2)=[CH:32][CH:31]=1)([CH3:26])([CH3:25])[CH3:24].CC1C=CC(S(O)(=O)=O)=CC=1.O.ClC1N=CC=CN=1>C1COCC1>[C:23]([O:27][C:28](=[O:48])[NH:29][C:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:33]([O:40][C:41]2[CH:46]=[CH:45][N:44]=[C:43]([NH:1][C:2]3[CH:3]=[C:4]([C:5](=[O:6])[NH:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH3:17])[CH:18]=[C:19]([C:21]#[CH:22])[CH:20]=3)[N:42]=2)=[CH:32][CH:31]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)Nc1ccc(Oc2ccnc(Cl)n2)c2ccccc12
Reactant: C#Cc1cc(N)cc(C(=O)NCCOCCOCCOC)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Clc1ncccn1
Solvent: C1CCOC1
Solvent: O
Product: C#Cc1cc(Nc2nccc(Oc3ccc(NC(=O)OC(C)(C)C)c4ccccc34)n2)cc(C(=O)NCCOCCOCCOC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under N2 was charged the product from step (iv) above (301.2 g, 250.0 g active, 0.816 mol), tert-butyl(4-((2-chloropyrimidin-4-yl)oxy)naphthalen-1-yl)carbamate (see, for example, Ito, K. et al., WO 2010/067130, 17 Jun. 2010; 252.8 g, 0.680 mol), pTSA.H2O (24.7 g, 0.130 mol) and THF (7600 mL). The dark red solution was heated to reflux for 6 h then cooled to room temperature, after which HPLC analysis indicated 0.25% the product of step (iv), 22.24% the product of step (vi), 8.98% chloropyrimidine starting material and 64.08% the product of step (v). Further product from step (iv) above (27.1 g, 22.5 g active, 73.4 mmol) was charged and the reaction was heated back to reflux and stirred overnight, with HPLC analysis subsequently revealing 0.20% the product of step (iv), 30.23% the product of step (vi), 4.50% starting chloropyrimidine and 58.61% the product of step (v).
Reaction SMILES: ClC(F)(F)C(F)(F)C(Cl)F.[F:11][C:12]([F:18])([CH:15]([F:17])[F:16])[CH2:13][OH:14].[S:19](Cl)([C:22]1[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=1)(=[O:21])=[O:20]>O>[C:25]1([CH3:26])[CH:27]=[CH:28][C:22]([S:19]([O:14][CH2:13][C:12]([F:18])([F:11])[CH:15]([F:17])[F:16])(=[O:21])=[O:20])=[CH:23][CH:24]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCC(F)(F)C(F)F
Agent: FC(Cl)C(F)(F)C(F)(F)Cl
Solvent: O
Product: Cc1ccc(S(=O)(=O)OCC(F)(F)C(F)F)cc1

Procedure:
For example, to prepare 1,3-dichloro-1,1,2,2,3-pentafluoropropane, 2,2,3,3-tetrafluoropropanol, tosyl chloride, and water are reacted together to form 2,2,3,3-tetrafluoropropyl p-toluenesulfonate. Then, N-methylpyrrolidone, potassium fluoride, and the 2,2,3,3-tetrafluoropropyl p-toluenesulfonate are reacted together to form 1,1,2,2,3-pentafluoropropane. Then, chlorine and the 1,1,2,2,3-pentafluoropropane are reacted to form 1,1,3-trichloro-1,2,2,3,3-pentafluoropropane. Finally, isopropanol and the 1,1,3-trichloro-1,2,2,3,3-pentafluoropropane are reacted to form 1,3-dichloro-1,1,2,2,3-pentafluoropropane.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[CH2:7][OH:8])([O-:3])=[O:2].N1C=CC=CC=1.[C:21](Cl)(=[O:30])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>C(C(C)=O)C>[C:21]([O:8][CH2:7][C:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=1)(=[O:30])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: O=[N+]([O-])c1cc(CO)cc([N+](=O)[O-])c1
Reactant: CCCCCCCCC(=O)Cl
Solvent: c1ccncc1
Solvent: CCC(C)=O
Product: CCCCCCCCC(=O)OCc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Temperature: 70 °C
Yield: 75.1 %

Procedure:
39.6 g (0.2mol) of 3,5-dinitrobenzyl alcohol, 23.7 g (0.3 mol) of pyridine and 200 ml of methyl ethyl ketone were introduced into a reactor and dissolved by stirring under a nitrogen gas stream at about 70° C. 35.3 g (0.2 mol) of pelargonic acid chloride was dissolved in 100 ml of methyl ethyl ketone and the resultant solution was added dropwise into the reactor as described above. After the completion of the addition, the mixture was refluxed and stirred under nitrogen for about 2 hours. Then the reactor was cooled by allowing to stand and pyridine hydrochloride was removed by filtration. The filtrate was concentrated and purified by using a column to give 50.8 g of 3,5-dinitrobenzyl pelargonate. 33.8 g of 3,5-dinitrobenzyl pelargonate and 4 g of a catalyst (5% palladium carried on active carbon) were introduced into a hydrogenation apparatus and reduced with hydrogen. After filtration and concentration, 27.8 g (0.1 mol) of 3,5-diaminobenzyl pelargonate was obtained.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].Cl.[NH:7]1[CH2:12][CH2:11][CH2:10][CH:9]([CH2:13][NH:14][C:15]([C:17]2[CH:18]=[N:19][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=3)=[N:21][CH:22]=2)=[O:16])[CH2:8]1.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][S:2]([N:7]1[CH2:12][CH2:11][CH2:10][CH:9]([CH2:13][NH:14][C:15]([C:17]2[CH:22]=[N:21][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=3)=[N:19][CH:18]=2)=[O:16])[CH2:8]1)(=[O:4])=[O:3]
Reactant: O=C(NCC1CCCNC1)c1cnc(-c2cccc(F)c2)nc1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N1CCCC(CNC(=O)c2cnc(-c3cccc(F)c3)nc2)C1
Temperature: 0 °C

Procedure:
Methanesulfonyl chloride (0.523 mmol) is added to a stirred solution of 2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid (piperidin-3-ylmethyl)-amide hydrochloride (0.523 mmol) and triethylamine (2.62 mmol) in DCM (20 mL) at 0° C. The mixture is stirred at 0° C. for an hour, and then stirred at room temperature overnight. The reaction mixture is washed with water (20 mL). The organic layer is separated, dried (MgSO4), filtered and concentrated in vacuo. The residue is purified by silica gel column chromatography eluting with EtOAc to afford 2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid (1-methanesulfonyl-piperidin-3-ylmethyl)-amide as a solid. MS: 393 (M+H); 1H NMR (300 MHz, CD3OD): δ 1.43-1.95 (m, 4H), 2.10-2.23 bs, H), 3.04-3.50 (m, 5H), 3.60-3.78 (m, H), 6.71-6.90 (bs, N—H), 7.18-7.23 (m, H), 7.42-7.57 (m, H), 8.18-8.37 (q, 2H), 9.20 (s, 2H).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11]([CH:13]3[CH2:18][NH:17][S:16](=[O:20])(=[O:19])[NH:15][CH2:14]3)[CH:10]=[CH:9][C:8]=2[NH:21][C:22]([C:24]2[N:25](COCC[Si](C)(C)C)[CH:26]=[C:27]([C:29]#[N:30])[N:28]=2)=[O:23])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.C(N)CN.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>CN(C=O)C>[C:1]1([C:7]2[CH:12]=[C:11]([CH:13]3[CH2:18][NH:17][S:16](=[O:19])(=[O:20])[NH:15][CH2:14]3)[CH:10]=[CH:9][C:8]=2[NH:21][C:22]([C:24]2[NH:25][CH:26]=[C:27]([C:29]#[N:30])[N:28]=2)=[O:23])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)Nc1ccc(C2CNS(=O)(=O)NC2)cc1C1=CCCCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CN(C)C=O
Solvent: NCCN
Product: N#Cc1c[nH]c(C(=O)Nc2ccc(C3CNS(=O)(=O)NC3)cc2C2=CCCCC2)n1
Temperature: 60 °C
Reaction time: 12 h
Yield: 68 %

Procedure:
To a solution of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid [2-cyclohex-1-enyl-4-(1,1-dioxo-1λ6-[1,2,6]thiadiazinan-4-yl)-phenyl]-amide (as prepared in the previous step, 17.8 mg, 0.0320 mmol) in DMF (35 μL) and ethylenediamine (13 μL, 0.18 mmol), solid tetrabutylammonium fluoride (TBAF) (25 mg, 0.090 mmol) was added. The resulting solution was stirred at 60° C. for 12 h. The reaction mixture was concentrated in vacuo and the resulting residue purified on silica (20-100% EtOAc-hexane) to afford the title compound (9.3 mg, 68%): 1H-NMR (CD3OD; 400 MHz): δ 8.19 (d, 1H, J=8.7 Hz), 8.05 (s, 1H), 7.18 (dd, 1H, J=8.7, 2.2 Hz), 7.08 (d, 1H, J=2.2 Hz), 5.81 (br s, 1H), 3.62 (m, 2H), 3.35 (m, 2H), 2.93 (m, 1H), 2.24-2.34 (m, 4H), 1.82-1.90 (m, 4H). Mass spectrum (ESI, m/z): Calcd. for C20H22N6O3S, 427.1 (M+H), found 427.2.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[Cl:8][C:9]1[CH:10]=[CH:11][C:12]2[O:16][CH:15]=[CH:14][C:13]=2[C:17]=1[CH2:18][CH2:19][CH2:20][NH2:21].ClC1C(CCCN)=CC2OC=CC=2C=1.N1C=CC=CC=1>C1COCC1>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]2[O:16][CH:15]=[CH:14][C:13]=2[C:17]=1[CH2:18][CH2:19][CH2:20][NH:21][C:1](=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: NCCCc1c(Cl)ccc2occc12
Agent: NCCCc1cc2occc2cc1Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(=O)NCCCc1c(Cl)ccc2occc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Acetic anhydride (1.95 ml) was added dropwise to a solution of 3-(5-chloro-benzofuran-4-yl)-propylamine mixture with 3-(5-chloro-benzofuran-6-yl)-propylamine (2.86 g) and pyridine (2.2 ml) in dry THF (70 ml) at 0° under nitrogen. The mixture was stirred at room temperature for 3 h, then evaporated to dryness in vacuo . The residue was purified by HPLC (CN-PK5-10530 column). Eluting with 5% isopropanol/heptane gave the title compound as a colourless solid (1.37 g) mp 82-83° C.