Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C@@H:4]([N:11]2[CH2:16][C:15]([CH3:18])([CH3:17])[O:14][CH:13](O)[C:12]2=[O:20])[CH2:3][CH2:2]1.[Br-].C1([PH+](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:41][C:42]1[CH:43]=[C:44]([CH:47]=[CH:48][C:49]=1[N:50]1[CH:54]=[C:53]([CH3:55])[N:52]=[CH:51]1)[CH:45]=O>>[O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C@@H:4]([N:11]2[CH2:16][C:15]([CH3:18])([CH3:17])[O:14]/[C:13](=[CH:45]\[C:44]3[CH:47]=[CH:48][C:49]([N:50]4[CH:54]=[C:53]([CH3:55])[N:52]=[CH:51]4)=[C:42]([F:41])[CH:43]=3)/[C:12]2=[O:20])[CH2:3][CH2:2]1
Reactant: CC1(C)CN([C@H]2CCOc3ccccc32)C(=O)C(O)O1
Reactant: Cc1cn(-c2ccc(C=O)cc2F)cn1
Agent: [Br-]
Agent: c1ccc([PH+](c2ccccc2)c2ccccc2)cc1
Product: Cc1cn(-c2ccc(/C=C3\OC(C)(C)CN([C@H]4CCOc5ccccc54)C3=O)cc2F)cn1

Procedure:
25.4 mg of the title compound was obtained from 4-[(S)-chroman-4-yl]-2-hydroxy-6,6-dimethylmorpholin-3-one, triphenylphosphonium bromide, and 3-fluoro-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde in the same manner as in Example 12.
Reaction SMILES: [NH:1]1[C:5]2=[C:6]([NH:10][C:11](=[O:13])[CH3:12])[N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.[Cl:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:16]=1[C:17](Cl)=[O:18]>>[Cl:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:16]=1[C:17]([C:3]1[C:4]2[C:5](=[C:6]([NH:10][C:11](=[O:13])[CH3:12])[N:7]=[CH:8][CH:9]=2)[NH:1][CH:2]=1)=[O:18]
Reactant: O=C(Cl)c1c(F)cccc1Cl
Reactant: CC(=O)Nc1nccc2cc[nH]c12
Product: CC(=O)Nc1nccc2c(C(=O)c3c(F)cccc3Cl)c[nH]c12

Procedure:
N-[3-(2-Chloro-6-fluorobenzoyl)-1H-pyrrolo[2,3-c]pyridin-7-yl]acetamide was prepared analogously using N-(1H-pyrrolo[2,3-c]pyridin-7-yl) acetamide and 2-chloro-6-fluoro benzoyl chloride (Compound No. 8).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:9]=[CH:8][C:7](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:6][CH:5]=1.[C:23]([C:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]=1)#[CH:24]>CCCCCCC>[C:25]1([C:23]#[C:24][C:7]2[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:21])[F:22])=[CH:9][CH:8]=2)[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]=1
Reactant: Cc1ccc(S(=O)(=O)Oc2ccc(OC(F)(F)F)cc2)cc1
Reactant: C#CC1=CCCCC1
Solvent: CCCCCCC
Product: FC(F)(F)Oc1ccc(C#CC2=CCCCC2)cc1

Procedure:
This product was prepared from toluene-4-sulfonic acid 4-trifluoromethoxy-phenyl ester and 1-ethynyl-cyclohexene following the general procedure for the Sonogashira cross-coupling process described above. Chromatography eluent: heptane; yield (110 mg, 83%); 1H NMR δ (CDCl3): 7.41 (d, J=8.38 Hz, 2H), 7.21 (d, J=8.37 Hz, 2H), 6.28 (m, 1H), 2.17 (dm, 4H), 1.63 (dm, 4H); LCMS m/z: 266.
Reaction SMILES: CO[C:3](=[O:26])[C@H:4]([CH2:24][OH:25])[NH:5][C:6](=[O:23])[C@H:7]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].O.[NH2:28][NH2:29]>CO>[C:12]([O:11][C:9]([NH:8][C@H:7]([C:6]([NH:5][C@H:4]([C:3]([NH:28][NH2:29])=[O:26])[CH2:24][OH:25])=[O:23])[CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:10])([CH3:13])([CH3:15])[CH3:14]
Reactant: COC(=O)[C@H](CO)NC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Reactant: NN
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CO)C(=O)NN
Temperature: 25 °C
Reaction time: 15 h

Procedure:
18.3 g of tert-butyloxycarbonyl-L-phenylalanyl-L-serine methyl ester were dissolved in 50 ml of methyl alcohol, and to this solution 7.5 ml of 80% hydrazine mono hydrate were added. The mixture was stirred for 15 hours at room temperature and then the reaction mixture was concentrated under reduced pressure to give a solid substance. The solid substance was allowed to re-crystallization with ethyl alcohol and thereby tert-butyloxycarbonyl-L-phenylalanyl-L-serine hydrazide was obtained.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([OH:12])=O.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[NH:23]1[C:27]2=[N:28][CH:29]=[CH:30][CH:31]=[C:26]2[C:25](C(OCC)=O)=[N:24]1.N1C2=NC=CC=C2C(C(OC(C)C)=O)=N1>C1COCC1>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([C:25]1[C:26]2[C:27](=[N:28][CH:29]=[CH:30][CH:31]=2)[NH:23][N:24]=1)=[O:12]
Reactant: O=C(O)Cc1cccc(F)c1F
Reactant: CCOC(=O)c1n[nH]c2ncccc12
Agent: CC(C)OC(=O)c1n[nH]c2ncccc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(Cc1cccc(F)c1F)c1n[nH]c2ncccc12
Yield: 91 %

Procedure:
To a solution of 2,3-difluorophenylacetic acid (236 mg, 1.4 mmol) in THF at OC was added 3.85 mL (3.85 mmol) of a solution of lithium bis-trimethylsilylamide in THF. The resulting solution was then added to solution of a 2:1 mixture of ethyl 1H-pyrazolo[3,4-b]pyridine-3-carboxylate and isopropyl 1H-pyrazolo[3,4-b]pyridine-3-carboxylate (104 mg, 0.55 mmol) in THF. The resulting mixture was heated at 75C for 3 hours. The reaction progress was monitored by TLC and HPLC and quenched with saturated NH4Cl, diluted with EtOAc and washed with saturated NaHCO3 and brine. The organic layer was dried over MgSO4 and concentrated to give 137 mg (91% yield) of 2-(2,3-difluorophenyl)-1-(1H-pyrazolo[3,4-b]pyridin-3-yl)ethanone. LC-MS Rt=3.3 min ES+ (274.0) ES− (272.1).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH:7]([C:18](=[O:20])[NH2:19])[C:8]1[C:9]2[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:10]=2[S:11][CH:12]=1)([CH3:6])=[O:5])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH:28]=[CH:29][C:30]1[CH:35]=[CH:34][C:33]([F:36])=[C:32]([F:37])[CH:31]=1.C(OCC)(=O)C>CC(N(C)C)=O.[Cu](I)I.O>[CH2:1]([O:3][P:4]([CH:7]([C:8]1[C:9]2[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:10]=2[S:11][CH:12]=1)[C:18](=[O:20])[NH:19][CH:28]=[CH:29][C:30]1[CH:35]=[CH:34][C:33]([F:36])=[C:32]([F:37])[CH:31]=1)([CH3:6])=[O:5])[CH3:2]
Reactant: Fc1ccc(C=CBr)cc1F
Reactant: CCOP(C)(=O)C(C(N)=O)c1csc2ccc(Cl)cc12
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CCOP(C)(=O)C(C(=O)NC=Cc1ccc(F)c(F)c1)c1csc2ccc(Cl)cc12
Temperature: 25 °C

Procedure:
[Carbamoyl-(5-chloro-benzo[b]thiophen-3-yl)-methyl]-methyl-phosphinic acid ethyl ester (60.0 g, 181 mmol) was placed in a reactor under nitrogen, followed by addition of cesium carbonate (35.3 g, 108 mmol) and copper iodide (6.90 g, 36.2 mmol) and the resulting mixture was stirred at ambient temperature. DMA (123 g) and N,N′-dimethylethylenediame (6.36 g, 72.1 mmol) (with the addition flask washed with DMA (30 g)) were added and the resulting mixture heated to 70-75° C. with about 30-60 minutes, over which time a thin blue suspension was observed to form. To the resulting mixture was then added 4-(2-bromo-vinyl)-1,2-difluoro-benzene (47.6 g, 217 mmol) over about 10-30 minutes (with the addition flask washed with DMA (30 g)), then stirred for 5 to 7 hours at 75-85° C., with the progress of the reaction monitored by HPLC. When the reaction was deemed complete, the reaction mixture was cooled to 60-78° C., ethyl acetate (345 g) was added followed by addition of water (303 g), and the mixture stirred for 10-30 minutes. The resulting phases were separated. To the organic phase was added a solution of NaCl (30 g in 270 g H2O), followed by stirring for 10-30 min at a temperature of 55-65° C. The resulting phases were separated, to the organic phase was added again a solution of NaCl (30 g in 270 g H2O), followed by stirring for 10-30 min at a temperature of 55-65° C. The resulting phases were separated and treated a third time with addition of a solution of NaCl (30 g in 270 g H2O), followed by stirring for 10-30 min at a temperature of 55-65° C. The resulting phases were separated, the organic phase heated to distill off 107-139 g of solvent (at 50-65° C.). To the resulting residue, cyclohexane (280 g) was added over 20-40 minutes and the resulting mixture cooled to 10-15° C., then stirred at this temperature for 2-3 hours, over which time a thick suspension was observed to form. The resulting suspension was filtered, the filtercake washed with a mixture of cyclohexane (135 g) and ethyl acetate (45 g), then dried at 55-60° C., under vacuum to yield the title compound as a solid.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2=[CH:13][N:14]=[C:15]([O:17][CH3:18])[CH:16]=[C:11]2[C:10]([CH:19]=[O:20])=[C:9]1[CH:21]([CH3:23])[CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O-:24]Cl=O.[Na+]>CC(O)(C)C.CC(=CC)C.O>[CH2:1]([N:8]1[C:12]2=[CH:13][N:14]=[C:15]([O:17][CH3:18])[CH:16]=[C:11]2[C:10]([C:19]([OH:24])=[O:20])=[C:9]1[CH:21]([CH3:23])[CH3:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [O-][Cl+][O-]
Reactant: COc1cc2c(C=O)c(C(C)C)n(Cc3ccccc3)c2cn1
Agent: CC=C(C)C
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: COc1cc2c(C(=O)O)c(C(C)C)n(Cc3ccccc3)c2cn1
Temperature: 25 °C

Procedure:
To a solution of 1-benzyl-2-isopropyl-5-methoxy-1H-pyrrolo[2,3-c]pyridine-3-carbaldehyde (Compound 7, 20 mg, 0.065 mmol) in t-BuOH (1.5 ml) and 2-methyl-2-butene (1 ml) was added a solution of NaH2PO4 (94 mg, 0.78 mmol) and NaClO2 (80%, 73 mg, 0.65 mmol) in H2O (1.5 ml). The mixture was stirred at room temperature and additional 2-methyl-2-butene and a solution of NaH2PO4 and NaClO2 in H2O were added at the above ratio every 6-16 h until the progress of the reaction was satisfactory. The reaction mixture was extracted with EtOAc (×3) and the combined organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by preparative thin layer chromatography (PTLC) on silica gel (50% EtOAc-hexanes) to yield the title compound.
Reaction SMILES: [N:1]([CH2:4][C:5]1[C:6]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[N:7][CH:8]=[CH:9][CH:10]=1)=[N+]=[N-]>CO.[Pd]>[N:11]1([C:6]2[C:5]([CH2:4][NH2:1])=[CH:10][CH:9]=[CH:8][N:7]=2)[CH2:12][CH2:13][O:14][CH2:15][CH2:16]1
Reactant: [N-]=[N+]=NCc1cccnc1N1CCOCC1
Agent: [Pd]
Solvent: CO
Product: NCc1cccnc1N1CCOCC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 76.9 %

Procedure:
To a solution of the product from Example 115A (0.62 g) in methanol (10 ml) was added Pd/C (0.06 g) under N2 atmosphere. The reaction mixture was stirred at room temperature under H2 atmosphere. After 6 h, the reaction mixture was filtered through celite and concentrated to yield 0.42 g (78%) of product. MS (ESI+) m/z 194 (M+H)+;
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.C(Cl)Cl.[C-:15]#[N:16].[Na+].O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CCCCCC>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([C:15]#[N:16])=[O:8])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: [C-]#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: CCCCCC
Solvent: ClCCl
Product: COc1ccc(C(=O)C#N)cc1
Temperature: 2.5 °C
Reaction time: 4 h

Procedure:
A mixture of p-methoxybenzoyl chloride (11.9 grams; 0.07 mole) and tetrabutylammonium bromide (0.10 gram) in 60 mls. of methylene dichloride is cooled to 0°-5° C. and a solution of sodium cyanide (3.63 grams; 0.074 mole) in 8 mls. of water is added thereto at 0-5° C. Upon completion of the addition of the sodium cyanide the reaction mixture is stirred at 0-5° C. for an additional period of about 11/4 hours and filtered. The filtrate is dried over magnesium sulfate, filtered to separate the magnesium sulfate and evaporated under vacuum to obtain an oil which solidifies. The solid is dissolved in hot hexane and the hexane solution is treated with activated carbon and filtered to separate the carbon. The filtrate is cooled to room temperature and later filtered to recover 6.2 grams of the desired product which melts at 51°-53° C.
Reaction SMILES: [C:1]([O:9][CH2:10][CH2:11][N:12]([CH3:14])[CH3:13])(=[O:8])/[CH:2]=[CH:3]/[C:4]([O:6][CH3:7])=[O:5].[CH3:15][I:16]>C(OCC)C>[I-:16].[CH3:7][O:6][C:4](=[O:5])/[CH:3]=[CH:2]/[C:1]([O:9][CH2:10][CH2:11][N+:12]([CH3:15])([CH3:14])[CH3:13])=[O:8]
Reactant: CI
Reactant: COC(=O)/C=C/C(=O)OCCN(C)C
Solvent: CCOCC
Product: COC(=O)/C=C/C(=O)OCC[N+](C)(C)C
Product: [I-]
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2-(dimethylamino)ethyl methyl fumarate 19 (760 mg, 3.7 mmol) in diethyl ether (20 ml) was added methyl iodide (246 μl, 3.9 mmol). The mixture was stirred at room temperature for 18 hours where a precipitate slowly formed. The mixture was filtered, washed with diethyl ether and dried in a vacuum oven at 55° C. for 18 hours to give (E)-2-((4-methoxy-4-oxobut-2-enoyl)oxy)-N,N,N-trimethylethanaminium iodide, a white solid (1.15 g, 90%).
Reaction SMILES: [C:1]([O:9][C:10]1([CH2:23][C:24]2[CH:29]=[C:28](OC)[C:27](OC)=[C:26]([O:34][CH3:35])[CH:25]=2)[C:18]2[C:13](=[CH:14][CH:15]=[C:16](C)[CH:17]=2)[N:12]([CH2:20][CH3:21])[C:11]1=[O:22])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1C2C(=CC=C([Cl:54])C=2)N(CC)C1=O)(=O)C1C=CC=CC=1.COC1C=C(C=CC=1)CCl>>[C:1]([O:9][C:10]1([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:34][CH3:35])[CH:25]=2)[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([Cl:54])[CH:17]=2)[N:12]([CH2:20][CH3:21])[C:11]1=[O:22])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN1C(=O)C(Cc2cc(OC)c(OC)c(OC)c2)(OC(=O)c2ccccc2)c2cc(C)ccc21
Reactant: CCN1C(=O)C(OC(=O)c2ccccc2)c2cc(Cl)ccc21
Agent: COc1cccc(CCl)c1
Product: CCN1C(=O)C(Cc2cccc(OC)c2)(OC(=O)c2ccccc2)c2cc(Cl)ccc21

Procedure:
This compound was made in an analogous fashion to 1-ethyl-5-methyl-2-oxo-3-(3,4,5-trimethoxybenzyl)indolin-3-yl benzoate using 5-chloro-1-ethyl-2-oxoindolin-3-yl benzoate and 3-methoxy benzyl chloride (purchased from Fisher Scientific). 1H NMR δ 8.06 (d, 2H), 7.61 (t, 1H), 7.46 (t, 2H), 7.25 (dd, 1H), 7.09 (t, 1H), 7.02 (d, 1H), 6.76 (dd, 1H), 6.64 (m, 2H), 6.52 (s, 1H), 3.72 (m, 4H), 3.57 (m, 2H), 3.27 (d, 1H), 1.04 (t, 3H). Calculated mass for C25H22NClO4, 435.12. Observed 458.1 (M+Na).
Reaction SMILES: C(C(O)=O)(F)(F)F.[Cl:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([S:19]([NH:22][C@H:23]3[CH2:28][CH2:27][CH2:26][CH2:25][C@H:24]3[C:29]([O:31]C(C)(C)C)=[O:30])(=[O:21])=[O:20])=[CH:16][CH:17]=2)[C:12]([NH:36][C:37]([NH2:39])=[NH:38])=[N:11][CH:10]=1>C(Cl)Cl>[ClH:8].[Cl:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([S:19]([NH:22][C@H:23]3[CH2:28][CH2:27][CH2:26][CH2:25][C@H:24]3[C:29]([OH:31])=[O:30])(=[O:20])=[O:21])=[CH:16][CH:17]=2)[C:12]([NH:36][C:37]([NH2:39])=[NH:38])=[N:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCC[C@@H]1NS(=O)(=O)c1ccc2c(Cl)cnc(NC(=N)N)c2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cl
Product: N=C(N)Nc1ncc(Cl)c2ccc(S(=O)(=O)N[C@H]3CCCC[C@H]3C(=O)O)cc12
Temperature: 23 °C
Reaction time: 6 h
Yield: 35714.3 %

Procedure:
CF3CO2H (3.0 mL) was added to a stirred solution of t-butyl (±)-cis-2-{[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl]amino}cyclohexanecarboxylate (66 mg, 0.14 mmol) in CH2Cl2 (3.0 mL) and the mixture was stirred at 23° C. for 6 h. The solvents were evaporated in vacuo, azeotroping CH2Cl2 (×3). The residue was dissolved in EtOAc and a solution of HCl in Et2O (200 μL, 1.0 M) was added which gave a precipitate. The white solid was collected by filtration and dried to give (±)-cis-2-{[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl]amino}cyclohexanecarboxylic acid hydrochloride (35 mg, 0.069 25 mmol).
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([NH:26][CH:27]([CH2:31][OH:32])[C:28](O)=[O:29])(=[O:25])=[O:24])=[CH:19][CH:18]=1>>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([S:23]([NH:26][CH:27]([CH2:31][O:32][CH:6]2[CH2:5][CH2:4][CH2:3][CH2:2][O:1]2)[C:28]([NH:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[O:29])(=[O:24])=[O:25])=[CH:21][CH:22]=1
Reactant: COC(=O)CCCN
Reactant: C1=COCCC1
Reactant: O=C(O)C(CO)NS(=O)(=O)c1ccc(Cl)cc1
Agent: Cl
Product: COC(=O)CCCNC(=O)C(COC1CCCCO1)NS(=O)(=O)c1ccc(Cl)cc1

Procedure:
The procedure described in Example 1 was repeated, except that dihydropyran (1.37 ml) and methyl 4-aminobutanate hydrochloride (1.69 g) were successively reacted with (RS)-2-(4-chlorobenzenesulfonylamino)-3-hydroxypropanoic acid (2.80 g) to obtain (RS)-2-(4-chlorobenzenesulfonylamino)-N-(3-methoxycarbonylpropyl)-3-(tetrahydropyran-2-yloxy)propanamide (3.12 g).
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[F:14])[C:8]([OH:10])=[O:9])(=[O:4])=[O:3].C([O-])(O)=O.[Na+].[F:20][C:21]([F:25])([F:24])[CH2:22][NH2:23].[ClH:26]>O>[Cl:26][C:11]1[CH:12]=[C:13]([F:14])[C:5]([S:2]([NH:23][CH2:22][C:21]([F:25])([F:24])[F:20])(=[O:4])=[O:3])=[CH:6][C:7]=1[C:8]([OH:10])=[O:9]
Reactant: NCC(F)(F)F
Reactant: O=C(O)c1ccc(F)c(S(=O)(=O)Cl)c1
Reactant: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: O=C(O)c1cc(S(=O)(=O)NCC(F)(F)F)c(F)cc1Cl
Yield: 83 %

Procedure:
4.997 g (18.3 mmol) 3-chlorosulfonyl-4-fluorobenzoic acid, 2.90 g (27.5 mmol) NaHCO3 were dissolved in 50 mL water. 1.45 mL (18.3 mmol) trifluoroethylamine was added dropwise to solution. Solution was acidified to pH=1 with concentrated HCl and product was extracted into ethyl acetate. Dried over MgSO4 and concentrated. 5.27 g recovered (83% yield). Crude product was used in subsequent step without further purification. 1H NMR (300 MHz, DMSO-d6) δ 9.22-9.37 (dt, 1H, J=6.44, 30.24 Hz), 7.80-7.92 (dd, 1H, J=9.91, 25.78 Hz), 4.04-4.16 (m, 1H), 3.77-3.90 (m, 1H).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:6](Cl)=[O:7].C(N(CC)CC)C.[CH:25]([O:28][C:29]([N:31]1[CH2:37][CH2:36][CH2:35][CH:34]([NH:38][C:39]2[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=2)[C:33]2[CH:45]=[C:46]([CH3:53])[C:47]([C:49]([F:52])([F:51])[F:50])=[CH:48][C:32]1=2)=[O:30])([CH3:27])[CH3:26]>C(Cl)(Cl)Cl.C(Cl)Cl>[CH:25]([O:28][C:29]([N:31]1[CH2:37][CH2:36][CH2:35][CH:34]([N:38]([C:6](=[O:7])[C:5]2[CH:4]=[C:3]([C:2]([F:17])([F:16])[F:1])[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=2)[C:39]2[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=2)[C:33]2[CH:45]=[C:46]([CH3:53])[C:47]([C:49]([F:51])([F:52])[F:50])=[CH:48][C:32]1=2)=[O:30])([CH3:27])[CH3:26]
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: Cc1cc2c(cc1C(F)(F)F)N(C(=O)OC(C)C)CCCC2Nc1cccnc1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1cc2c(cc1C(F)(F)F)N(C(=O)OC(C)C)CCCC2N(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cccnc1
Yield: 50.7 %

Procedure:
Add 3,5-bis(trifluoromethyl)-benzoyl chloride (0.220 mL, 1.22 mmol) and triethylamine (0.180 mL, 1.29 mmol) over a 24 h period to a solution of 7-methyl-5-(pyridin-3-ylamino)-8-trifluoromethyl-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylic acid isopropyl ester (114 mg, 0.280 mmol) in chloroform (1.9 mL) at 70° C. Allow the reaction to cool, dilute with methylene chloride (20 mL) and wash sequentially with 10% HCl, saturated aqueous sodium bicarbonate, water, and then brine. Dry (MgSO4), concentrate, and purify via column chromatography (silica gel; 20% to 40% EtOAc:hexanes) to give 92 mg (51%) of the title compound as a white solid APCI MS m/z 648 [M+H]+.
Reaction SMILES: O[CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.[Cr](Cl)([O-])(=O)=[O:17].[NH+:21]1C=CC=[CH:23][CH:22]=1>ClCCl>[OH:17][CH2:23][CH2:22][NH:21][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Reactant: O=[Cr](=O)([O-])Cl
Reactant: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(CNCCO)CC1
Reaction time: 2 h
Yield: 81.4 %

Procedure:
tert-Butyl 4-(hydroxymethyl)piperidine-1-carboxylate (4.3 g) was dissolved in dichloromethane (50 ml) and pyridinium chlorochromate (6.46 g) was added. The reaction was stirred for 2 hours and filtered through a thin bed of silica eluting with ethyl acetate/hexane (⅓). The resulting aldehyde was dissolved in ethanol (20 mL) and ethanolamine (2.44 g) was added along with 10% palladium (Pd) on Carbon (100 mg). The reaction mixture was hydrogenated at 2.5 bar for 24 hours, filtered and concentrated. The residue was dissolved in methanol and passed through a SCX cartridge eluting with methanol. The product was eluted with 7N ammonia in methanol to afford the sub-titled compound (4.2 g) as an oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][C:6]1[C:15]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=2[C:9](=[O:16])[NH:8][N:7]=1.[CH:20]([C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1)=[O:21].C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.COCCOC.O.C(O)C>[O:16]=[C:9]1[C:10]2[CH2:11][CH2:12][CH2:13][CH2:14][C:15]=2[C:6]([CH2:5][C:4]2[CH:3]=[C:2]([C:26]3[CH:25]=[CH:24][CH:23]=[C:22]([CH:20]=[O:21])[CH:27]=3)[CH:19]=[CH:18][CH:17]=2)=[N:7][NH:8]1
Reactant: O=Cc1cccc(B(O)O)c1
Reactant: O=c1[nH]nc(Cc2cccc(Br)c2)c2c1CCCC2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Solvent: CCO
Product: O=Cc1cccc(-c2cccc(Cc3n[nH]c(=O)c4c3CCCC4)c2)c1
Temperature: 70 °C

Procedure:
A suspension of EXAMPLE 90 (500 mg, 1.57 mmol), 3-formylphenylboronic acid (352 mg, 2.35 mmol), dichlorobis(triphenylphosphine)palladium(II) (112 mg, 0.16 mmol) and sodium carbonate (2M solution, 3.13 mmol, 1.6 mL) in a 7/3/3 mixture of 1,2-dimethoxyethane/water/ethanol (23 mL) was purged with nitrogen, and heated at 70° C. for 16 hours. After cooling to room temperature, the reaction mixture was concentrated on a rotary evaporator. The crude solid was separated by HPLC (Zorbax® C-18 ODS packing material [Agilent Technologies, Santa Clara, Calif.], 0.1% trifluoroacetic acid/CH3CN/H2O) to provide the title compound. MS (DCI/NH3) m/z 345 (M+H)+.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:25])[CH2:13][CH:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[C:11]2[C:6](=[CH:7][C:8]([OH:24])=[CH:9][CH:10]=2)[O:5]1.Cl[CH2:27][C:28]#[N:29].CCOCC>CN(C)C=O>[C:28]([CH2:27][O:24][C:8]1[CH:7]=[C:6]2[C:11]([CH:12]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:21])([F:23])[F:22])[CH:15]=3)[CH2:13][C:4]([CH3:25])([CH3:3])[O:5]2)=[CH:10][CH:9]=1)#[N:29]
Reactant: CC1(C)CC(c2cccc(C(F)(F)F)c2)c2ccc(O)cc2O1
Reactant: N#CCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC1(C)CC(c2cccc(C(F)(F)F)c2)c2ccc(OCC#N)cc2O1
Temperature: 60 °C

Procedure:
Sodium hydride (0.93 g, 80% dispersion in oil) was added to a solution of 2,2-dimethyl-4-(3-trifluoromethylphenyl)chroman-7-ol (containing 1 mole of carbon tetrachloride of crystallisation) (7.5 g) in dimethylformamide (25 ml). Chloroacetonitrile (1.76 g) was added and the mixture heated at 60° C. for 3 hours. The solvent was removed under reduced pressure and the resulting oil was poured into water. The aqueous solution was extracted with ether and the etheeal extracts were dried (MgSO4) and evaporated under reduced pressure to yield an oil. Chromatography on alumina with ether--petrol (40°-60° C.), 1:3 as eluate gave the title compound which crystallised on standing.
Reaction SMILES: [OH:1][C:2]1([C:26]2[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=2)[C:11]2[C:6](=[CH:7][C:8]([O:12][CH2:13][O:14][CH3:15])=[CH:9][CH:10]=2)[O:5][CH2:4][CH:3]1[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][O:24][CH3:25])=[CH:18][CH:17]=1.[Cl:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38]Cl.C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1>CN(C)C=O.O>[OH:1][C:2]1([C:26]2[CH:27]=[CH:28][C:29]([O:32][CH2:38][CH2:37][O:36][CH2:35][CH2:34][Cl:33])=[CH:30][CH:31]=2)[C:11]2[C:6](=[CH:7][C:8]([O:12][CH2:13][O:14][CH3:15])=[CH:9][CH:10]=2)[O:5][CH2:4][CH:3]1[C:16]1[CH:17]=[CH:18][C:19]([O:22][CH2:23][O:24][CH3:25])=[CH:20][CH:21]=1
Reactant: ClCCOCCCl
Reactant: COCOc1ccc(C2COc3cc(OCOC)ccc3C2(O)c2ccc(O)cc2)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COCOc1ccc(C2COc3cc(OCOC)ccc3C2(O)c2ccc(OCCOCCCl)cc2)cc1
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 93.1 %

Procedure:
4-Hydroxy-4-(4-hydroxyphenyl)-7-(methoxymethoxy)-3-[4-(methoxymethoxy)phenyl]chroman (770 mg, 1.4 mmol), bis-(2-chloroethyl)ether (810 mg, 5.7 mmol), potassium carbonate (782 mg, 5.7 mmol) and 18-crown-6(132 mg, 0.49 mmol) were dissolved in dry N,N-dimethylformamide (10 mL) under argon atmosphere, which was then stirred at 100° C. for 2.5 hours. The reaction solution was cooled down to normal temperature, water was added thereto, and the mixture was extracted with ethyl acetate. The organic extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to flash column chromatography (n-hexane:ethyl acetate=2:1) to give the title compound (0.71 g, yield 35%) as a red oil.