Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OC(C(F)(F)F)=O.[F:8][C:9]1[CH:26]=[CH:25][C:12]([CH2:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17](=[O:24])[NH:16][N:15]=2)=[CH:11][C:10]=1[C:27]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)=[O:28].[CH3:35][C:36]([CH3:43])([CH3:42])[C:37](=[O:41])[C:38](O)=[O:39].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>[F:8][C:9]1[CH:26]=[CH:25][C:12]([CH2:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17](=[O:24])[NH:16][N:15]=2)=[CH:11][C:10]=1[C:27]([N:29]1[CH2:34][CH2:33][N:32]([C:38](=[O:39])[C:37](=[O:41])[C:36]([CH3:43])([CH3:42])[CH3:35])[CH2:31][CH2:30]1)=[O:28]
Reactant: O=C(c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F)N1CCNCC1
Reactant: CC(C)(C)C(=O)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)C(=O)C(=O)N1CCN(C(=O)c2cc(Cc3n[nH]c(=O)c4ccccc34)ccc2F)CC1
Temperature: 25 °C
Reaction time: 44 h
Yield: 48.2 %

Procedure:
4-(4-fluoro-3-(piperazine-1-carbonyl)benzyl)phthalazin-1(2H)-one TFA salt (310 mg, 0.65 mmol), 3,3-dimethyl-2-oxobutanoic acid [1.37 g (60%), 6.3 mmol], DIPEA (2 ml, 11.6 mmol), and HATU (1030 mg, 2.72 mmol) were mixed in DMF (50 ml), the resulting reaction mixture was stirred at room temperature for 44 h until the reaction finished (monitored by TLC). The reaction mixture was then partitioned between DCM and water (100 ml each, the water phase was extracted with DCM (100 ml). The combined organic phase was washed with water, sat. aqueous sodium bicarbonate, and brine, dried over sodium sulphate, filtered, and concentrated to yield the crude product. Then the crude product was firstly purified by column chromatography on silica gel (DCM:MeOH=100:1) and re-purified by preparative TLC (DCM:MeOH=40:1) to afford the desired product (150 mg, 46.9%) as a off white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][N:17]([C:20]4[N:25]=[CH:24][N:23]=[C:22]([C:26](O)=[O:27])[CH:21]=4)[CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:29]=1.[NH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[C:31]1([NH:30][C:26]([C:22]2[CH:21]=[C:20]([N:17]3[CH2:16][CH2:15][CH:14]([N:10]4[CH2:9][CH2:8][C:7]5[CH:29]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=5[NH:12][C:11]4=[O:13])[CH2:19][CH2:18]3)[N:25]=[CH:24][N:23]=2)=[O:27])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: Nc1ccccc1
Reactant: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)O)ncn3)CC1)C(=O)N2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)Nc4ccccc4)ncn3)CC1)C(=O)N2

Procedure:
120.0 mg (0.30 mmol) 6-[4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-pyrimidine-4-carboxylic acid, 30 μL (0.33 mmol) aniline, 120.0 mg (0.37 mmol) TBTU and 100 μL (0.71 mmol) triethylamine in 2 mL DMF were stirred overnight at RT. The mixture was filtered through a syringe filter and purified by preparative HPLC. The product fractions were combined and lyophilised.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:42])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([CH2:28]OS(C)(=O)=O)[CH:25]=[C:24]([Br:34])[CH:23]=2)[C:10]=1[CH2:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH3:2].C1COCC1.[CH3:48]COC(C)=O.C[C:55]#[N:56]>CNC>[CH2:1]([O:3][C:4](=[O:42])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([CH2:28][N:56]([CH3:55])[CH3:48])[CH:25]=[C:24]([Br:34])[CH:23]=2)[C:10]=1[CH2:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH3:2]
Reactant: CC#N
Reactant: CCOC(C)=O
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(Br)cc(COS(C)(=O)=O)c2)c1CCC(=O)OCC
Agent: CNC
Solvent: C1CCOC1
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(Br)cc(CN(C)C)c2)c1CCC(=O)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
The a solution of 4-[3-[6-(3-Bromo-5-methanesulfonyloxymethyl-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (2.5 g, 3.72 mmol) in MeCN (40 mL), N,N-dimethylamine 2M/THF (3.72 mL, 7.44 mmol) was added, and stirred at room temperature overnight. The solvent was removed under reduced pressure. Flash column chromatography (50% EtOAc/Hex) provided a light yellow oil (1.47 g, 64% yield). 1H NMR (CDCl3): δ 7.08 (t, 1H), 7.03 (s, 1H), 6.93 (s, 1H), 6.79 (s, 1H), 6.77 (d, 1H), 6.68 (d, 1H), 4.17-4.06 (m, 4H), 3.99 (dd, 2H), 3.92 (dd, 2H), 3.34 (s, 2H), 2.97 (dd, 2H), 2.63 (dd, 2H), 2.56-2.46 (m, 4H), 2.23 (s, 6H), 2.17-0.89 (m, 16H).
Reaction SMILES: [S:1]1[C:5]2=[C:6]([C:13]([OH:15])=[O:14])[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[N:4]2[CH:3]=[CH:2]1.O[CH2:17][CH:18]1[CH2:27][CH2:26][N:25]2[CH:20]([CH2:21][CH2:22][CH2:23][CH2:24]2)[CH2:19]1>>[S:1]1[C:5]2=[C:6]([C:13]([O:15][CH2:17][CH:18]3[CH2:27][CH2:26][N:25]4[CH:20]([CH2:21][CH2:22][CH2:23][CH2:24]4)[CH2:19]3)=[O:14])[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[N:4]2[CH:3]=[CH:2]1
Reactant: OCC1CCN2CCCCC2C1
Reactant: O=C(O)c1c2ccccc2n2ccsc12
Product: O=C(OCC1CCN2CCCCC2C1)c1c2ccccc2n2ccsc12

Procedure:
Thiazolo[3,2-a]indole-9-carboxylic acid (D16) was converted to its acid chloride and reacted with eq-2-hydroxymethylquinolizidine using a procedure analogous to that described in Example 10 to afford the title compound as a white solid mp 129°-131° C. (ether).
Reaction SMILES: [F:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[C:9](=O)([O-])[O-].[K+].[K+].CI.CN(C=O)C>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[CH:6][N:7]=1
Reactant: O=C([O-])[O-]
Reactant: Oc1ccc(F)nc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: COc1ccc(F)nc1
Temperature: 45 °C
Reaction time: 2.5 h
Yield: 92.6 %

Procedure:
To a 20 mL microwave vial, 6-fluoropyridin-3-ol (Alfa Aesar, 1.04 g, 9.18 mmol), potassium carbonate (1.90 g, 13.8 mmol) and methyl iodide (Aldrich, 0.689 mL, 11.0 mmol) were mixed into DMF (6 mL). The brown mixture was stirred at 45° C. for 2.5 h. The mixture was diluted with water and the aqueous phase was extracted with EtOAc (3×20 mL). The combined organic phases were washed with saturated aqueous sodium chloride (30 mL). The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo to afford 2-fluoro-5-methoxypyridine (1.08 g, 92% yield) as a light brown oil. This material was used in the next reaction without further purification. 1H NMR (400 MHz, CDCl3) δ ppm 7.79-7.85 (m, 1H) 7.33 (td, J=6.02, 3.23 Hz, 1H) 6.86 (dd, J=8.90, 3.42 Hz, 1H) 3.85 (s, 3H). m/z (ESI, positive ion): 128.1 (M+H)+.
Reaction SMILES: [C:1]([OH:5])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.Cl.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[C:22]([C:27](Cl)=[O:28])[C:23]([CH3:26])=[N:24][CH:25]=2)=[CH:16][CH:15]=1.CC(C)([O-])C.[K+]>C(Cl)Cl>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[C:22]([C:27]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:28])[C:23]([CH3:26])=[N:24][CH:25]=2)=[CH:16][CH:15]=1
Reactant: Cc1ncc(-c2ccc(Cl)cc2)cc1C(=O)Cl
Reactant: CC(C)(C)O
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ncc(-c2ccc(Cl)cc2)cc1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 20.9 %

Procedure:
Tert-butanol (1.08 g) and dry pyridine (1.31 g) in dry methylene dichloride (20 ml) were added dropwise to the product (2 g) of Stage 1 in dry methylene dichloride (40 ml). After stirring at room temperature for 2 hours, potassium tert-butoxide (1 g) was added and stirring was continued for a further hour. The mixture was washed twice with water, dried and filtered through a bed of activated charcoal and silica. Concentration of the filtrate gave the title product (0.42 g), m.p. 70°-72°.
Reaction SMILES: [OH:1][CH:2]([C:34]([CH3:38])([CH3:37])[CH2:35][OH:36])[C:3]([NH:5][CH2:6][CH2:7][C:8]([O:10][CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:33])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]/[CH:23]=[CH:24]\[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[O:9])=[O:4].[C:39](Cl)(=O)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>>[CH2:39]([O:36][CH2:35][C:34]([CH3:37])([CH3:38])[CH:2]([OH:1])[C:3]([NH:5][CH2:6][CH2:7][C:8]([O:10][CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:33])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]/[CH:23]=[CH:24]\[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[O:9])=[O:4])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)NCCCOC(=O)CCNC(=O)C(O)C(C)(C)CO
Product: CCCCCCCC/C=C\CCCCCCCC(=O)NCCCOC(=O)CCNC(=O)C(O)C(C)(C)COCc1ccccc1
Yield: 50.6 %

Procedure:
3-(N-Oleoylamino]propyl 3-[N-(2,4-dihydroxy-3,3-dimethyl-1-oxobutyl)amino]propionate (540 mg) and 140 mg of benzoyl chloride were reacted in the same manner as in Example 36 to obtain 318 mg of the title compound (yield: 51%).
Reaction SMILES: [BrH:1].N[C:3]1[CH:12]=[C:11]2[C:6]([C:7]([C:14]([F:17])([F:16])[F:15])=[CH:8][C:9](=[O:13])[O:10]2)=[CH:5][CH:4]=1.N([O-])=O.[Na+]>O>[Br:1][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([C:14]([F:17])([F:16])[F:15])=[CH:8][C:9](=[O:13])[O:10]2)=[CH:5][CH:4]=1
Reactant: Br
Reactant: Nc1ccc2c(C(F)(F)F)cc(=O)oc2c1
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=c1cc(C(F)(F)F)c2ccc(Br)cc2o1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58.2 %

Procedure:
To a solution of 48% HBr (4.5 g, 26.7 mmol) (3 mL) containing 7-amino-4-trifluoromethylcoumarin (Aldrich) (2.0 g, 8.8 mmol) at -10° C. was added NaNO2 (670 mg in 1 mL of H2O) then Cu powder 35 mg was added. The reaction mixture was stirred at r.t. for 30 min., then heated to 100° C. for 30 min. The reaction mixture was cooled to 0° C. and H2O (25 mL) was added. The mixture was extracted with EtOAc (400 mL) and the combined organic phase was washed with brine (200 mL) dried over MgSO4 and evaporated. The crude solid was purified by chromatography on silica gel using hexane:EtOAc 8:2 as eluent, to give 1.5 g (58%) of the title compound as a white solid.
Reaction SMILES: [S:1]1(=[O:12])(=[O:11])[C:5]2[CH:6]=[C:7]([NH2:10])[CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1.N1C=CC=CC=1.Cl[C:20]([O:22][CH2:23][C:24]([Cl:27])([Cl:26])[Cl:25])=[O:21].O>O1CCCC1>[O:12]=[S:1]1(=[O:11])[C:5]2[CH:6]=[C:7]([NH:10][C:20](=[O:21])[O:22][CH2:23][C:24]([Cl:27])([Cl:26])[Cl:25])[CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: Nc1ccc2c(c1)S(=O)(=O)C=C2
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: O
Solvent: C1CCOC1
Product: O=C(Nc1ccc2c(c1)S(=O)(=O)C=C2)OCC(Cl)(Cl)Cl

Procedure:
To a solution of 1-benzothiophen-6-amine 1,1-dioxide (1.00 g, 5.52 mmol) and pyridine (0.525 ml, 6.62 mmol) in tetrahydrofuran (18 ml) was added, under ice-cooling, 2,2,2-trichloroethyl chloroformate (0.916 ml, 6.62 mmol), and the mixture was stirred at room temperature for 1 hour and half. Water was poured to the reaction mixture, and the resulting solution was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Hexane was poured to the residue, and 1.71 g (87.1%) of the desired product as a solid was separated by filtration.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[CH:21]=[C:20]2[C:12]([C:13]3[CH:14]=[CH:15][N:16]=[CH:17][C:18]=3[N:19]2[NH:22][CH3:23])=[CH:11][CH:10]=1.[C:24](OC(=O)C)(=[O:26])[CH3:25]>N1C=CC=CC=1>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[CH:21]=[C:20]2[C:12]([C:13]3[CH:14]=[CH:15][N:16]=[CH:17][C:18]=3[N:19]2[N:22]([C:24](=[O:26])[CH3:25])[CH3:23])=[CH:11][CH:10]=1
Reactant: CC(=O)OC(C)=O
Reactant: CNn1c2cnccc2c2ccc(Cl)cc21
Solvent: O=C(O)C(F)(F)F
Solvent: c1ccncc1
Product: CC(=O)N(C)n1c2cnccc2c2ccc(Cl)cc21
Yield: 28.3 %

Procedure:
A solution of the product of example 43 (19 mg, 0.082 mmol) in pyridine (0.40 ml) was treated with acetic anhydride (0.037 ml, 0.36 mmol) in two portions over 48 h. The reaction was subsequently concentrated to dryness and the residue coevaporated with AcOH under reduced pressure. The crude product was purified as described in example 46. The pure fractions with product were combined and lyophilized to provide 9 mg of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@H:24]3[CH2:29][CH2:28][C@H:27]([CH2:30]OS(C4C=CC(C)=CC=4)(=O)=O)[CH2:26][CH2:25]3)=[N:9][C:10]=2[C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1.[CH3:42][NH2:43]>CO>[CH3:42][NH:43][CH2:30][C@H:27]1[CH2:28][CH2:29][C@H:24]([C:8]2[N:4]3[CH:5]=[CH:6][N:7]=[C:2]([NH2:1])[C:3]3=[C:10]([C:11]3[CH:12]=[CH:13][C:14]([O:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:15][CH:16]=3)[N:9]=2)[CH2:25][CH2:26]1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CC[C@H](c3nc(-c4ccc(Oc5ccccc5)cc4)c4c(N)nccn43)CC2)cc1
Reactant: CN
Solvent: CO
Product: CNC[C@H]1CC[C@H](c2nc(-c3ccc(Oc4ccccc4)cc3)c3c(N)nccn32)CC1

Procedure:
A solution of trans-toluene-4-sulfonic acid 4-[8-amino-1-(4-phenoxyphenyl)-imidazo[1,5-a]pyrazin-3-yl]-cyclohexylmethyl ester (15.0 mg, 0.0264 mmol), 2.0 M of methylamine in MeOH (0.5 mL) and MeOH (2 mL) was microwaved at 300 watt, 100° C. for 1 h. The material was concentrated and purified by a prep TLC plate, eluting with 8% (7N NH3 in MeOH) in DCM, to afford the title compound as an off-white solid. 1H NMR (400 MHz, CDCl3): δ 1.10-1.22 (m, 2H), 1.60-1.69 (m, 1H), 1.81-1.95 (m, 2H), 1.97-2.03 (m, 2H), 2.10 (d, J=11.4 Hz, 2H), 2.46 (s, 3H), 2.51 (d, J=6.6 Hz, 2H), 2.87-2.97 (m, 1H), 5.09 (br. s., 2H), 7.04-7.18 (m, 6H), 7.23 (d, J=5.1 Hz, 1H), 7.34-7.41 (m, 2H), 7.59-7.66 (m, 2H). MS (ES+): m/z 427.89 (100) [MH+]. HPLC: tR=1.89 min (polar—5 min).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Mg].[C:11]1([CH2:17][CH2:18][CH:19]=[O:20])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(OCC)C>[C:4]1([CH2:3][CH2:2][CH:19]([OH:20])[CH2:18][CH2:17][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: BrCCc1ccccc1
Reactant: O=CCCc1ccccc1
Agent: [Mg]
Solvent: CCOCC
Product: OC(CCc1ccccc1)CCc1ccccc1
Reaction time: 1 h

Procedure:
A solution of 2-(bromoethyl)benzene (1.73 g; 9.33 mmol) in diethylether (10 ml) was added to a stirred slurry of magnesium turnings (250 mg; 10.18 mmol) in 5 ml of ether. The reaction was initiated with a heat gun, and after the addition was complete the mixture was heated on an oil bath for 30 min. 3-Phenyl-1-propanal (1.25 g; 9.33 mmol) was added in 10 ml of ether, and reflux was continued for 1 hour. The reaction was cooled and quenched with saturated ammonium chloride, extracted into 2×ethyl acetate, and the combined organic portions were dried and concentrated. Chromatographic purification on a silica gel column (10% ethyl acetate in hexane) delivered 1.42 g(63%) of the diphenyl alcohol. 1H NMR (300 MHz, CDCl3): δ 1.84 (m, 4H); 2.61-2.76 (m, 4H); 3.65 (m, 1H); 7.19-7.29 (m, 10H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=1[C:5](=[NH:9])[O:6][CH2:7][CH3:8].[F:14][C:15]([F:26])([F:25])[C:16]1[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=1[C:18](Cl)=[O:19]>>[F:14][C:15]([F:25])([F:26])[C:16]1[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=1[C:18]([N:9]=[C:5]([O:6][CH2:7][CH3:8])[C:4]1[CH:10]=[CH:11][CH:12]=[CH:13][C:3]=1[O:2][CH3:1])=[O:19]
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Reactant: CCOC(=N)c1ccccc1OC
Product: CCOC(=NC(=O)c1ccccc1C(F)(F)F)c1ccccc1OC

Procedure:
starting from ethyl o-methoxybenzimidate and o-trifluoromethyl-benzoyl chloride there is obtained ethyl N-(o-trifluoromethyl-benzoyl)-o-methoxybenzimidate and therefrom with methylhydrazine there is obtained 3-(o-anisyl)-1-methyl-5-(o-trifluoromethyl-phenyl)-1H-1,2,4-triazole, m.p. 74°-78° C.;
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6]4=[C:7]([C:17](=[O:27])[C:18]([CH2:20][C:21]5[CH:22]=[N:23][CH:24]=[N:25][CH:26]=5)=[CH:19][N:5]4[C:4]=2[CH:3]=1)[CH:8]=[C:9]([OH:16])[CH:10]=3.Cl.Cl[CH2:30][C:31]1[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=1>>[Br:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6]4=[C:7]([C:17](=[O:27])[C:18]([CH2:20][C:21]5[CH:22]=[N:23][CH:24]=[N:25][CH:26]=5)=[CH:19][N:5]4[C:4]=2[CH:3]=1)[CH:8]=[C:9]([O:16][CH2:30][C:31]1[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=1)[CH:10]=3
Reactant: ClCc1cccnc1
Reactant: O=c1c(Cc2cncnc2)cn2c3c(cc(O)cc13)Sc1ccc(Br)cc1-2
Agent: Cl
Product: O=c1c(Cc2cncnc2)cn2c3c(cc(OCc4cccnc4)cc13)Sc1ccc(Br)cc1-2
Yield: 66.8 %

Procedure:
According to Example 34, the compound (109 mg) produced in Example 76 was reacted with 3-chloromethylpyridine hydrochloride (62 mg) to obtain the title compound (88 mg; 67%).
Reaction SMILES: [CH3:1][N:2]([S:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]([F:27])([F:26])[F:25])(=[O:17])=[O:16])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12](=[S:14])[NH2:13])=[CH:8]2.[C:28]([O:33][CH2:34][CH3:35])(=[O:32])[C:29]#[C:30][CH3:31].C(P(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>O1CCCC1>[CH3:1][N:2]([S:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]([F:27])([F:25])[F:26])(=[O:17])=[O:16])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:14][CH:30]([CH2:29][C:28]([O:33][CH2:34][CH3:35])=[O:32])[CH2:31][N:13]=1)=[CH:8]2
Reactant: CN(c1cccc2cc(C(N)=S)[nH]c12)S(=O)(=O)c1ccccc1C(F)(F)F
Reactant: CC#CC(=O)OCC
Agent: CCCCP(CCCC)CCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)CC1CN=C(c2cc3cccc(N(C)S(=O)(=O)c4ccccc4C(F)(F)F)c3[nH]2)S1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 57 %

Procedure:
A mixture of 7-(methyl{[2-(trifluoromethyl)phenyl]sulfonyl}amino)-1H-indole-2-carbothioamide (2.65 g), ethyl but-2-ynoate (1.5 mL), tributylphosphine (1.6 mL), toluene (30 mL) and tetrahydrofuran (20 mL) was stirred for 2.5 hr at room temperature. The reaction solution was concentrated, and the obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=2:8-4:6) to give the title compound (1.92 g, yield: 57%) as a pale-yellow oil.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=3)[C:15]([OH:17])=O)[CH2:9][CH2:8][C:6]=2[N:7]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:54]([C:57]1[CH:58]=[C:59]([CH:61]=[CH:62][CH:63]=1)[NH2:60])([CH3:56])[CH3:55]>CN(C=O)C>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=3)[C:15]([NH:60][C:59]3[CH:61]=[CH:62][CH:63]=[C:57]([CH:54]([CH3:56])[CH3:55])[CH:58]=3)=[O:17])[CH2:9][CH2:8][C:6]=2[N:7]=1
Reactant: Nc1ncc2c(n1)CCN(c1cccc(C(=O)O)c1)C2
Reactant: CC(C)c1cccc(N)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)c1cccc(NC(=O)c2cccc(N3CCc4nc(N)ncc4C3)c2)c1
Temperature: 25 °C
Reaction time: 0.05 h
Yield: 37 %

Procedure:
A mixture of 3-(2-amino-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)benzoic acid (162 mg, 0.60 mmol), N,N-diisopropylethylamine (0.523 mL, 3.0 mmol), and HBTU (250 mg, 0.66 mmol) in 6.0 mL DMF was stirred at room temperature for 3 minutes, briefly warmed to approx. 50° C. to dissolve solids, stirred an additional 10 minutes at room temperature, then 3-isopropylaniline (0.127 mL, 0.90 mmol) added and the reaction heated at 65° C. After 2 hours the mixture was partitioned between EtOAc and aqueous Na2CO3 solution, the EtOAc layer washed with H2O, brine, dried with anhydrous Na2SO4 and rotary evaporated to a solid. The solid was chromatographed eluting with EtOAc/MeOH. The resulting solid was subjected to an EtOAc/NaHCO3 work-up to remove any silica gel impurity and then recrystallized from EtOAc to give the title compound as a pale yellow-beige solid (86 mg, 37%). 1H NMR (DMSO-d6) δ: 10.09 (s, 1H), 8.13 (s, 1H), 7.64-7.66 (m, 1H), 7.58-7.63 (m, 1H), 7.50-7.53 (m, 1H), 7.32-7.40 (m, 2H), 7.18-7.29 (m, 2H), 6.96-7.01 (m, 1H), 6.41 (s, 2H), 4.29 (s, 2H), 3.65 (t, J=6.0 Hz, 2H), 2.88 (spt, J=7.0 Hz, 1H), 2.77 (t, J=5.9 Hz, 2H), 1.22 (d, J=7.0 Hz, 6H).
Reaction SMILES: C(=O)([O-])N.[Cl:5][C:6]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)=[O:7].[NH2:17][CH2:18][CH2:19][CH2:20][N:21](C(C)(C)C)C(=O)[O-]>>[ClH:5].[CH3:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][C:6](=[O:7])[NH:17][CH2:18][CH2:19][CH2:20][NH2:21])=[CH:10][CH:11]=1
Reactant: CC(C)(C)N(CCCN)C(=O)[O-]
Reactant: COc1ccc(OC(=O)Cl)cc1
Agent: NC(=O)[O-]
Product: COc1ccc(OC(=O)NCCCN)cc1
Product: Cl

Procedure:
This carbamate, m.p. 162°-165° soften at 110°, was prepared from 4-methoxyphenyl chloroformate and N-[3-aminopropyl]tert.-butylcarbamate by the procedure of Example 1.
Reaction SMILES: [CH2:1]([OH:6])[C:2]([Br:5])([Br:4])[Br:3].Cl[C:8]([O-:10])=O.C(Cl)(Cl)=O.[N-:15]=[N+:16]=[N-:17].[Na+]>>[N:15]([C:8]([O:6][CH2:1][C:2]([Br:5])([Br:4])[Br:3])=[O:10])=[N+:16]=[N-:17]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C([O-])Cl
Reactant: OCC(Br)(Br)Br
Agent: O=C(Cl)Cl
Agent: [Na+]
Product: [N-]=[N+]=NC(=O)OCC(Br)(Br)Br

Procedure:
Tribromoethanol (43.8 parts) was converted to the corresponding chloroformate by reaction with 40 parts of phosgene in the presence of a stoichiometric amount of base. The purified intermediate was reacted with an excess of sodium azide to produce the β,β,β-tribromoethyl azidoformate.
Reaction SMILES: [F:1][CH2:2][C@@H:3]1[C@@H:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[O:18][N:17]=[C:16]([CH2:19][OH:20])[CH:15]=3)=[CH:10][CH:9]=2)[O:6][C:5]([CH3:22])([CH3:21])[N:4]1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].[CH3:30][S:31](Cl)(=[O:33])=[O:32].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[F:1][CH2:2][C@@H:3]1[C@@H:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[O:18][N:17]=[C:16]([CH2:19][O:20][S:31]([CH3:30])(=[O:33])=[O:32])[CH:15]=3)=[CH:10][CH:9]=2)[O:6][C:5]([CH3:22])([CH3:21])[N:4]1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24]
Reactant: CC(C)(C)OC(=O)N1[C@H](CF)[C@@H](c2ccc(-c3cc(CO)no3)cc2)OC1(C)C
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1[C@H](CF)[C@@H](c2ccc(-c3cc(COS(C)(=O)=O)no3)cc2)OC1(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 94.3 %

Procedure:
A methylene chloride solution (20 ml) of (4S,5R)-tert-butyl 4-(fluoromethyl)-5-(4-(3-(hydroxymethyl)isoxazol-5-yl)phenyl)-2,2-dimethyloxazolidine-3-carboxylate (876 mg, 2.16 mmol) is cooled to 0° C. and methanesulfonyl chloride (250 mg, 2.16 mmol) is added followed by diisopropylethylamine (278 mg, 2.16 mmol). The reaction is stirred for one hour at 0° C. The reaction is diluted with methylene chloride (20 ml) and washed with water (2×10 ml). The organic phase is dried over sodium sulfate and concentrated to give the title compound (987 mg): m/z (Cl) 485 ([M+H]+.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[CH:3]([OH:8])[C:4]([F:7])([F:6])[F:5].S(OC)(O[CH3:15])(=O)=O.[OH-].[Na+]>>[CH:3]([O:8][CH3:15])([C:4]([F:7])([F:6])[F:5])[C:2]([F:10])([F:9])[F:1]
Reactant: OC(C(F)(F)F)C(F)(F)F
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [OH-]
Product: COC(C(F)(F)F)C(F)(F)F

Procedure:
Chain transfer agent of structure (1) may also be obtained by reaction of a fluorine containing alcohol R2OH with an alkylating agent of structure R1—L. In one example, reaction of 1,1,1,3,3,3-hexafluoro-2-propanol with dimethyl sulfate in the presence of aqueous sodium hydroxide affords a partially fluorinated ether with the structure (CF3)2CHOCH3, as disclosed in U.S. Pat. No. 3,346,448.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)[Br:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:25](=O)[C:26]1[O:30][CH:29]=[CH:28][CH:27]=1.C(N(CC)CC)C>C(Cl)Cl.C(OCC)C>[Br:2][C:1]([Br:5])=[CH:25][C:26]1[O:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=Cc1ccco1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOCC
Product: BrC(Br)=Cc1ccco1
Temperature: -60 °C
Yield: 64.1 %

Procedure:
A solution of carbon tetrabromide (241.6 g, 0.73 mol) in anhydrous DCM (1000 mL) was cooled to −20° C. under nitrogen and triphenylphosphine (191.1 g, 0.73 mol) in anhydrous DCM (1000 mL) was added drop wise. After twenty minutes of stirring, the reaction was cooled to −60° C., and then a mixture of furfural (30 mL, 0.36 mol) and triethylamine (50.5 mL, 0.36 mol) in anhydrous DCM (375 mL) were added drop wise. The mixture was brought to room temperature and diethyl ether (500 mL) was added with stirring. The reaction was filtered and filtrate was concentrated in vacuo. Column chromatography (SiO2, heptanes) yielded the title compound (58.1 g, 63%) as a brown oil: