Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][CH:7]([CH2:9][CH2:10][CH2:11][CH:12]([CH2:14][CH2:15][CH2:16][C:17]([OH:21])([CH:19]=[CH2:20])[CH3:18])[CH3:13])[CH3:8])[CH3:3].[CH3:22][C:23]1[C:24]([OH:32])=[C:25]([CH3:31])[C:26]([CH3:30])=[C:27]([CH:29]=1)O.FC(F)(F)C(O)=O.O>CCCCCC>[CH3:31][C:25]1[C:24]([OH:32])=[C:23]([CH3:22])[C:29]2[CH2:20][CH2:19][C@:17]([CH2:16][CH2:15][CH2:14][C@@H:12]([CH2:11][CH2:10][CH2:9][C@@H:7]([CH2:6][CH2:5][CH2:4][CH:2]([CH3:1])[CH3:3])[CH3:8])[CH3:13])([CH3:18])[O:21][C:27]=2[C:26]=1[CH3:30]
Reactant: Cc1cc(O)c(C)c(C)c1O
Reactant: C=CC(C)(O)CCCC(C)CCCC(C)CCCC(C)C
Solvent: O
Solvent: CCCCCC
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(C)c2c(c(C)c1O)CC[C@@](C)(CCC[C@H](C)CCC[C@H](C)CCCC(C)C)O2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.9 %

Procedure:
Isophytol (98%, 25.5 g.) was added, dropwise, over three hours to a mixture of trimethylhydroquinone (14.5 g.), trifluoroacetic acid (65 ml.) and water (10 ml.). The product was diluted with hexane (200 ml.), washed with methanol-water (1:1, v:v)(3×100 ml.) and saturated aqueous sodium bicarbonate solution (100 ml.). A 1% by weight solution of potassium hydroxide in methanol (100 ml.) was added and the mixture was stirred at room temperature for 30 minutes. Then 2N aqueous hydrochloric acid (100 ml.) was added, the organic phase was separated, washed with saturated aqueous sodium bicarbonate solution (100 ml.) and methanol-water (1:1, v:v) (100 ml.). The hexane was removed by concentrating on a rotary evaporator and the resulting oil was flashdistilled to give α-tocopherol (29.6 g.; bp 220° C./0.1 mm.). Purity by area % glc was 100%.
Reaction SMILES: I[C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[N:8]=2)[CH:6]=1.C([Mg]Cl)(C)C.[Li+].[Cl-].[Sn:34](Cl)([CH2:43][CH2:44][CH2:45][CH3:46])([CH2:39][CH2:40][CH2:41][CH3:42])[CH2:35][CH2:36][CH2:37][CH3:38]>C1COCC1>[CH2:43]([Sn:34]([CH2:35][CH2:36][CH2:37][CH3:38])([CH2:39][CH2:40][CH2:41][CH3:42])[C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[N:8]=2)[CH:6]=1)[CH2:44][CH2:45][CH3:46]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)cc(-n3cnc(I)c3)n2)cc1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cn(-c2cc(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)n2)cn1
Temperature: 23 °C
Reaction time: 14 h

Procedure:
To a solution of 2-(4-iodo-imidazol-1-yl)-4-trifluoromethyl-6-(4-trifluoromethylphenyl)-pyridine (example E.23) (4.83 g, 10 mmol) in THF (50 mL) at 0° C. was quickly added added i-PrMgCl.LiCl (1 M in THF, 11 mL, 11 mmol) and the mixture was stirred at 0° C. for 15 min. Then Bu3SnCl (3.25 mL, 12 mmol) was added, the cooling bath was removed and the mixture was stirred at 23° C. for 14 h. Poured into sat. NH4Cl-sol., extracted with EtOAc, washed with brine and dried over Na2SO4. Removal of the solvent in vacuum left a brown oil, which was purified by quick silica gel column chromatography with heptane/EtOAc 4:1 gave a yellow oil (4.42 g, 62%, ca. 90% pure). MS (ISP) 647.3 [(M+H)+].
Reaction SMILES: [OH-].[Na+].C1COCC1.[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:31][NH:32][C:33]2[CH:38]=[CH:37][C:36]([C:39]3[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][C:40]=3[Cl:46])=[CH:35][CH:34]=2)=[C:13]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([NH:23][CH2:24][CH2:25][C:26]([O:28]CC)=[O:27])=[O:22])=[N:19][CH:20]=2)[CH:14]=1>CO>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:31][NH:32][C:33]2[CH:38]=[CH:37][C:36]([C:39]3[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][C:40]=3[Cl:46])=[CH:35][CH:34]=2)=[C:13]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([NH:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[O:22])=[N:19][CH:20]=2)[CH:14]=1
Reactant: CCOC(=O)CCNC(=O)c1ccc(-c2cc(Cl)ccc2CNc2ccc(-c3ccc(Cl)cc3Cl)cc2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)CCNC(=O)c1ccc(-c2cc(Cl)ccc2CNc2ccc(-c3ccc(Cl)cc3Cl)cc2)cn1
Temperature: 25 °C

Procedure:
A 3M aqueous solution of NaOH (7.5 mL, 22.6 mmol) was added to a THF (40 mL) and MeOH (20 mL) solution of ethyl 3-(5-(5-chloro-2-(((2′,4′-dichloro-[1,1′-biphenyl]-4-yl)amino)methyl)phenyl)picolinamido)propanoate (6.6 g, 11.3 mmol) and the resulting homogeneous mixture was stirred at room temperature. After 16 h the resulting mixture was concentrated in vacuo, suspended in water, and acidified with 2 M HCl. The resulting precipitate was filtered off and dried in vacuo to yield the title compound.
Reaction SMILES: C1([O:7][C:8](=O)[NH:9][CH2:10][CH:11]2[CH2:16][CH2:15][C:14]([N:23]([CH3:25])[CH3:24])([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)C=CC=CC=1.[F:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][CH:32]=[C:31]2[CH:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>O1CCOCC1>[CH3:24][N:23]([CH3:25])[C:14]1([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:15][CH2:16][CH:11]([CH2:10][NH:9][C:8]([N:40]2[CH2:41][CH2:42][CH:37]([C:31]3[C:30]4[C:34](=[CH:35][CH:36]=[C:28]([F:27])[CH:29]=4)[NH:33][CH:32]=3)[CH2:38][CH2:39]2)=[O:7])[CH2:12][CH2:13]1
Reactant: Fc1ccc2[nH]cc(C3CCNCC3)c2c1
Reactant: CN(C)C1(c2ccccc2)CCC(CNC(=O)Oc2ccccc2)CC1
Solvent: C1COCCO1
Product: CN(C)C1(c2ccccc2)CCC(CNC(=O)N2CCC(c3c[nH]c4ccc(F)cc34)CC2)CC1
Yield: 22.9 %

Procedure:
The diastereoisomer mixture of (4-dimethylamino-4-phenylcyclohexylmethyl)-carbamic acid phenyl ester (387.7 mg, 1.1 mmole) was added to a solution of 5-fluoro-3-piperidine-4-yl-1H-indole (240.1 mg, 1.1 mmole) in dioxane (11 ml). The solution was boiled under reflux for 16 hours. The solution was worked up by distilling off the solvent in vacuo. The residue contained, apart from phenol, also the two diastereoisomers of 4-(5-fluoro-1H-indol-3-yl)piperidine-1-carboxylic acid-(4-dimethylamino-4-phenylcyclohexylmethyl)-amide. The diastereoisomers were separated and purified by flash chromatography on silica gel (25 g). Methanol/EE (1:1, 900 ml) was used as eluent. The non-polar diastereoisomer (150 mg, m.p. 95°-98° C., 29%) and the polar diastereoisomer of 4-(5-fluoro-1H-indol-3-yl)piperidine-1-carboxylic acid-(4-dimethylamino-4-phenylcyclohexylmethyl)-amide (120 mg, m.p. 206°-208° C., 23%) were thereby obtained in pure form.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=3)[C:17]([OH:19])=O)[C:11](=[O:23])[N:10]([CH2:24][C:25]([NH:27][C:28]([CH3:40])([C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=3)[CH3:29])=[O:26])[N:9]=2)=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.C[CH2:52][N:53]=[C:54]=NCCCN(C)C.Cl.Cl.CNC.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=3)[C:17]([N:53]([CH3:54])[CH3:52])=[O:19])[C:11](=[O:23])[N:10]([CH2:24][C:25]([NH:27][C:28]([CH3:40])([C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:37])([F:39])[F:38])[CH:31]=3)[CH3:29])=[O:26])[N:9]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(NC(=O)Cn1nc(-c2ccc(Cl)cc2)n(Cc2cccc(C(=O)O)c2)c1=O)c1cccc(C(F)(F)F)c1
Reactant: CCN=C=NCCCN(C)C
Agent: CNC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)c1cccc(Cn2c(-c3ccc(Cl)cc3)nn(CC(=O)NC(C)(C)c3cccc(C(F)(F)F)c3)c2=O)c1
Reaction time: 0.17 h

Procedure:
30 mg (0.052 mmol) of 3-(3-(4-chlorophenyl)-1-[2-(1-methyl-1-[3-(trifluoromethyl)phenyl]ethylamino)-2-oxoethyl]-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-ylmethyl)-benzoic acid (Example 471) are placed in 0.5 ml of DMF and treated with 9.2 mg (0.068 mmol) of HOBt and 13.0 mg (0.068 mmol) of EDC hydrochloride. After 10 mins' stirring, 6.0 mg (0.073 mmol) of dimethylamine hydrochloride and 10.2 mg (0.079 mmol) of N,N-diisopropylethylamine are added and the mixture is stirred overnight at RT. Without further workup, the crude product is purified directly by preparative HPLC [Method 10]. 29.8 mg (95% of theory) of the target compound are thus obtained.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10](Br)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:13]1(B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[F-].[Cs+]>CN(C)C=O.O.C(OCC)(=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:7][O:6][C:4]([C:3]1[CH:8]=[CH:9][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:11][C:2]=1[F:1])=[O:5]
Reactant: COC(=O)c1ccc(Br)cc1F
Reactant: OB(O)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(-c2ccccc2)cc1F
Temperature: 80 °C

Procedure:
Combine methyl 2-fluoro-4-bromobenzoate (1.25 g, 5.36 mmol), phenylboronic acid (1.30 g, 10.72 mmol) and CsF (2.02 g, 13.40 mmol) in dimethylformamide (25 mL) and water (3.0 mL) with stirring. Place the hetereogeneous reaction mixture open to the air in an oil bath maintained at 80° C. After 5 minutes of heating, add Pd(OAc)2 (120 mg, 0.536 mmol) in one portion and stir until reaction turns black. Cool reaction to room temperature, dilute with ethyl acetate and filter through a short plug of celite with additional ethyl acetate. Wash organics with water, dry over magnesium sulfate, filter and evaporate. Purification by flash column chromatography yields 3-fluorobiphenyl-4-carboxylic acid methyl ester as a solid. Dissolve the purified ester in tetrahydrofuran (0.25M) and add an equal volume of 1M sodium hydroxide. Stir vigorously at room temperature for 15 hours. Upon completion, acidify the reaction with conc. HCl and extract with ethyl acetate. Evaporation of the solvent yields 965 mg (84%) of the title compound. MS (m/e): 214.9 (M−).
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8]O)=[CH:4][CH:3]=1.CCN(S(F)(F)[F:16])CC>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][F:16])=[CH:6][N:7]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: OCc1ccc(Br)nc1
Solvent: ClCCl
Product: FCc1ccc(Br)nc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred solution of (6-bromopyridin-3-yl)methanol (1.00 g, 5.32 mmol) in dichloromethane (25 mL) at 0° C. was added DAST (0.70 mL, 5.32 mmol) and the resulting solution was stirred at 0° C. for one hour. The mixture was washed with a saturated sodium bicarbonate solution and concentrated. Flash column separation using a 0-10% ethyl acetate/hexane gradient gave FF1 (0.37 g, 37%). LRMS (ES) (M+H)+: observed=190.0/192.0, calculated=190.0/192.0.
Reaction SMILES: [F:1][C:2]1[C:3]([C:18](=O)[C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)=[C:4]([NH:9][C:10]([NH:12][CH2:13][C:14]([F:17])([F:16])[F:15])=[O:11])[CH:5]=[CH:6][C:7]=1[F:8].F[C:28]1C(F)=CC=C2[C:29]=1C(C1C=CC(F)=CC=1)(O)N(CC(F)(F)F)C(=O)N2.C(N(CC)CC)C.S(Cl)(Cl)=O.C([Mg]Br)C>C1COCC1>[CH2:28]([C:18]1([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[C:3]2[C:4](=[CH:5][CH:6]=[C:7]([F:8])[C:2]=2[F:1])[NH:9][C:10](=[O:11])[N:12]1[CH2:13][C:14]([F:17])([F:16])[F:15])[CH3:29]
Reactant: O=C1Nc2ccc(F)c(F)c2C(O)(c2ccc(F)cc2)N1CC(F)(F)F
Reactant: O=C(NCC(F)(F)F)Nc1ccc(F)c(F)c1C(=O)c1ccc(F)cc1
Agent: CC[Mg]Br
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCC1(c2ccc(F)cc2)c2c(ccc(F)c2F)NC(=O)N1CC(F)(F)F
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 1.5 g (3.987 mmol) N-[3,4-difluoro-2-(4-fluorobenzoyl)phenyl]-N′-(2,2,2-trifluoroethyl)urea (open form) and 5,6-difluoro-4-(4-fluorophenyl)-4-hydroxy-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one (closed form) in 8 ml THF was added 2.0 mL (19.933 mmol) triethylamine. After 1 h at 80° C., the reaction mixture was cooled to −78° C. To this solution was added 0.498 mL (4.186 mmol) thionyl chloride. After 30 minutes at −78° C., 5 mL (12.358 mmol) ethylmagnesium bromide (3.0M solution in diethyl ether) was added dropwise. After 1 h at −78° C., the reaction mixture was quenched with saturated NH4Cl and warmed to room temperature. The reaction mixture was extracted three times with EtOAc and washed with brine. The organic layer was dried over NaSO4, filtered and concentrated in vacuo. Purification by flash chromatography (1×14 cm silica gel, linear gradient 0-50% EtOAc:hexane) afforded 4-ethyl-5,6-difluoro-4-(4-fluorophenyl)-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one. Chiral Separation (ChiralPak AD column, 5 cm×50 cm, 20μ, 10-40% ethanol/hexane, modifier: DEA 1 mL/L, 60 mins) afforded 350 mg of the second isomer.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:27])=[CH:4][C:5]([F:26])=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:21])=[C:15](F)[C:16]=3[C:18]#[CH:19])[C:11](=[O:22])[C:10]([C:23]([OH:25])=[O:24])=[CH:9]2)[CH:7]=1.[CH3:28][NH2:29]>N1C=CC=CC=1>[NH2:1][C:2]1[C:3]([F:27])=[CH:4][C:5]([F:26])=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:21])=[C:15]([NH:29][CH3:28])[C:16]=3[C:18]#[CH:19])[C:11](=[O:22])[C:10]([C:23]([OH:25])=[O:24])=[CH:9]2)[CH:7]=1
Reactant: CN
Reactant: C#Cc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(-c3cc(N)c(F)cc3F)c12
Solvent: c1ccncc1
Product: C#Cc1c(NC)c(F)cc2c(=O)c(C(=O)O)cn(-c3cc(N)c(F)cc3F)c12
Temperature: 25 °C
Reaction time: 5 h

Procedure:
1-(5-Amino-2,4-difluorophenyl)-8-ethynyl-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (40 mg) was dissolved in pyridine (0.3 ml), and a 40% methylamine solution (1 ml) was added to this solution, followed by stirring at room temperature for 5 hours. The solvent was distilled off under reduced pressure, and diethyl ether was added to the residue. Solids were collected by filtration to obtain the title compound (30 mg) as a brown powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=[O:11])=[C:4]([CH3:27])[CH:3]=1.[Cl:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][C:30]=1[C:38]([O:40][CH2:41][CH3:42])=[O:39].N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH2:41]([O:40][C:38](=[O:39])[C:30]1[CH:31]=[C:32]([O:26][C:23]2[CH:22]=[CH:21][C:20]([CH:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=3[CH3:27])[CH2:9][C:10]([C:12]3[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=3)=[O:11])=[CH:25][CH:24]=2)[CH:33]=[CH:34][C:29]=1[Cl:28])[CH3:42]
Reactant: CCOC(=O)c1cc(B(O)O)ccc1Cl
Reactant: Cc1cc(Cl)ccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)c1cc(Oc2ccc(C(CC(=O)c3ccc(=O)n(C)c3)c3ccc(Cl)cc3C)cc2)ccc1Cl

Procedure:
In analogy to example 222, step 1, 5-[3-(4-chloro-2-methyl-phenyl)-3-(4-hydroxy-phenyl)-propionyl]-1-methyl-1H-pyridin-2-one (example 346, step 1) was reacted with 4-chloro-3-ethoxycarbonylphenylboronic acid in dichloromethane in the presence of copper(II) acetate, pyridine and air to give the title compound as a colourless solid, MS (ESI+): m/z=564.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:25]=[CH:24][C:3]=1[CH2:4][N:5]([CH2:10][CH:11]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:6][CH2:7][CH2:8][OH:9].O[C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][CH:40]=1)[CH:36]=[O:37].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:27]([C:28]([F:29])([F:30])[F:31])=[CH:26][CH:25]=[CH:24][C:3]=1[CH2:4][N:5]([CH2:10][CH:11]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH2:6][CH2:7][CH2:8][O:9][C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][CH:40]=1)[CH:36]=[O:37]
Reactant: O=Cc1cccc(O)c1
Reactant: OCCCN(Cc1cccc(C(F)(F)F)c1Cl)CC(c1ccccc1)c1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: O=Cc1cccc(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(c2ccccc2)c2ccccc2)c1

Procedure:
To a solution of 3-[(2-Chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propan-1-ol (0.500 g, 1.12 mmol) in toluene (4 ml) at ambient temperature was added 3-Hydroxy-benzaldehyde (0.213 g, 1.74 mmol) under Argon with stirring. The mixture was treated with polymer bound PPh3 (0.594 g, 1.782 mmol). After 15 minutes of stirring, the mixture was treated with DIAD (0.273 mL, 1.387 mmol) and was stirred at ambient temperature overnight.
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26]([OH:28])=O)[CH2:10]2)=[O:8])[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1.O[N:30]=[C:31]([NH2:35])[CH2:32][CH2:33][OH:34]>>[OH:34][CH2:33][CH2:32][C:31]1[N:35]=[C:26]([CH:11]2[CH2:12][CH:13]([C:15]3[CH:16]=[CH:17][C:18]([O:21][C:22]([F:23])([F:24])[F:25])=[CH:19][CH:20]=3)[CH2:14][N:9]([C:7]([N:1]3[CH2:6][CH2:5][S:4][CH2:3][CH2:2]3)=[O:8])[CH2:10]2)[O:28][N:30]=1
Reactant: O=C(O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCSCC2)C1
Reactant: NC(CCO)=NO
Product: O=C(N1CCSCC1)N1CC(c2ccc(OC(F)(F)F)cc2)CC(c2nc(CCO)no2)C1

Procedure:
According to General Method 6A, 1.00 g (2.390 mmol) of the compound from Example 25A and 323 mg (3.107 mmol) of N′,3-dihydroxypropanimidamide were reacted Yield: 848 mg (69% of theory)
Reaction SMILES: [Cl:1][C:2]1[C:9]([C:10]([F:13])([F:12])[F:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH:14]1([NH2:17])[CH2:16][CH2:15]1>>[Cl:1][C:2]1[C:9]([C:10]([F:13])([F:12])[F:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH:17][CH:14]1[CH2:16][CH2:15]1
Reactant: O=Cc1cccc(C(F)(F)F)c1Cl
Reactant: NC1CC1
Product: FC(F)(F)c1cccc(CNC2CC2)c1Cl

Procedure:
Synthesized according to typical procedure J from 2-chloro-3-trifluoromethylbenzaldehyde and cyclopropylamine.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[NH:3][CH:2]=1.[C:13]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].CCN(C(C)C)C(C)C.C(N=C=NCCCN(C)C)C>CN(C=O)C.C(OCC)(=O)C>[C:16]([O:15][C:13]([N:20]1[CH2:25][CH2:24][N:23]([C:10]([C:8]2[CH:7]=[CH:6][C:5]3[NH:1][CH:2]=[N:3][C:4]=3[CH:9]=2)=[O:12])[CH2:22][CH2:21]1)=[O:14])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(O)c1ccc2nc[nH]c2c1
Agent: CCN=C=NCCCN(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc3[nH]cnc3c2)CC1
Temperature: 23 °C
Reaction time: 2 h
Yield: 35.7 %

Procedure:
In a 250 mL round bottom flask with a stirbar was added Benzimidazole-5-carboxylic acid (2.00 g, 12.3 mmol), Boc-piperazine (2.41 g, 13.0 mmol, 1.05 eq), and Hunig's Base (3.78 mL, 27.1 mmol, 2.2 eq) in DMF (35 mL). After 5 minutes 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (2.60 g, 13.6 mmol, 1.1 eq) was added portion wise and the dark solution stirred for 2 hr at 23° C. The reaction was diluted with Ethyl Acetate (250 mL) and partitioned between water (50 mL). The layers were separated and the organic washed with water (2×50 mL), brine (30 mL), dried (Na2SO4), and concentrated to a dark oil. The reaction was purified using Biotage MPLC system (40M column size, 0-20% Methanol/CH2Cl2 over 35 Column Volumes) giving the desired product as a beige solid (1.45 g, 4.39 mmol, 35.6%). 1H NMR (DMSO-d6, 400 MHz) δ 12.6 (s, 1H), δ 8.31 (s, 1H), δ 7.66-7.60 (m, 2H), δ 7.25 (bs, 1H), δ 3.60-3.25 (m, 8H), δ 1.40 (s, 9H); LRMS (m/z): 353 (M+Na), 331 (M+H), 275.
Reaction SMILES: O1[C:3]23[C@:16]([CH3:22])([C:17]([CH3:21])=[CH:18][C:19](=[O:20])[CH:2]12)[C@@H:15]1[C@H:6]([C@H:7]2[C@@:11]([CH2:13][CH2:14]1)([CH3:12])[C:10](=[O:23])[C@H:9]([F:24])[CH2:8]2)[C:5](=[CH2:25])[C@H:4]3[CH3:26].[ClH:27]>C(O)(=O)C>[Cl:27][C:2]1[C:19](=[O:20])[CH:18]=[C:17]([CH3:21])[C@@:16]2([CH3:22])[C:3]=1[C@H:4]([CH3:26])[C:5](=[CH2:25])[C@@H:6]1[C@@H:15]2[CH2:14][CH2:13][C@@:11]2([CH3:12])[C@H:7]1[CH2:8][C@@H:9]([F:24])[C:10]2=[O:23]
Reactant: Cl
Reactant: C=C1[C@H]2[C@@H]3C[C@@H](F)C(=O)[C@@]3(C)CC[C@@H]2[C@@]2(C)C(C)=CC(=O)C3OC32[C@@H]1C
Solvent: CC(=O)O
Product: C=C1[C@@H](C)C2=C(Cl)C(=O)C=C(C)[C@]2(C)[C@H]2CC[C@]3(C)C(=O)[C@H](F)C[C@H]3[C@H]12

Procedure:
A solution of 4,5-epoxy-16α-fluoro-1,6β-dimethyl-7-methylenandrost-1-ene-3,17-dione (359 mg) in glacial acetic acid (5 ml) is treated with gaseous hydrogen chloride for about 30 min at room temperature. The precipitate is filtered off, washed with diethylether and then chromatographed on silica gel to give pure 4-chloro-16α-fluoro-1,6β-dimethyl-7-methylen-androsta-1,4-diene-3,17-dione (245 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](O)=[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:8]=[N:9]2)=[CH:4][C:3]=1[F:18].C(=O)([O-])[O-].[K+].[K+].[CH2:25](Cl)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN(C=O)C>[CH2:25]([N:9]1[C:10]2[C:5](=[CH:4][C:3]([F:18])=[C:2]([Cl:1])[CH:11]=2)[CH:6]=[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:8]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: ClCc1ccccc1
Reactant: CCOC(=O)c1cnc2cc(Cl)c(F)cc2c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1=Cc2cc(F)c(Cl)cc2N(Cc2ccccc2)C1
Yield: 81 %

Procedure:
16.2 g of 7-chloro-3-ethoxycarbonyl-6-fluoro-4-hydroxyquinoline, 16.8 g of potassium carbonate and 150 cm3 of DMF were heated for one hour, whilst stirring, in a round-bottomed flask equipped with a reflux condenser. 27.5 cm3 of benzyl chloride were added and the heating and stirring were maintained until the pH of the medium was neutral, which required about 2 hours. The major part of the solvent was removed by distillation in vacuo (15 mm Hg) at 100° C. The residue was taken up in 300 cm3 of water. The mixture was extracted with 3×100 cm3 of chloroform. The combined organic extracts were washed with water, dried (MgSO4) and evaporated to dryness. The residue was recrystallised from methylcellosolve. 17.5 g (81%) of 1-benzyl-7-chloro-3-ethoxycarbonyl-6-fluoroquinoline, m.p. 211°-212° C., were obtained.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH:17]([CH2:18][OH:19])[CH2:16][C:15]3[C:10](=[CH:11][C:12](Br)=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:21]2[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]2)[N:3]=1.[CH3:28][NH:29][C:30]([C:32]1[CH:37]=[CH:36][C:35](B2OC(C)(C)C(C)(C)O2)=[CH:34][N:33]=1)=[O:31]>>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH:17]([CH2:18][OH:19])[CH2:16][C:15]3[C:10](=[CH:11][C:12]([C:35]4[CH:36]=[CH:37][C:32]([C:30]([NH:29][CH3:28])=[O:31])=[N:33][CH:34]=4)=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:21]2[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]2)[N:3]=1
Reactant: CNC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CN1CCN(c2cc(N3Cc4cc(Br)ccc4CC3CO)nc(N)n2)CC1
Product: CNC(=O)c1ccc(-c2ccc3c(c2)CN(c2cc(N4CCN(C)CC4)nc(N)n2)C(CO)C3)cn1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 49A starting from {2-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-7-bromo-1,2,3,4-tetrahydroisoquinolin-3-yl}methanol and N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-carboxamide (Frontier, Cat. No. M10074). LCMS (M+H)+: m/z=489.2.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=2[C:21]#[N:22])=[CH:4][C:5](=[O:13])[N:6]([CH:8]([CH3:12])[C:9]([OH:11])=O)[CH:7]=1.[NH2:23][C:24]1[CH:36]=[CH:35][C:27]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[CH:26][CH:25]=1>>[Cl:1][C:2]1[C:3]([C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=2[C:21]#[N:22])=[CH:4][C:5](=[O:13])[N:6]([CH:8]([CH3:12])[C:9]([NH:23][C:24]2[CH:36]=[CH:35][C:27]([C:28]([O:30][C:31]([CH3:32])([CH3:33])[CH3:34])=[O:29])=[CH:26][CH:25]=2)=[O:11])[CH:7]=1
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Reactant: CC(C(=O)O)n1cc(Cl)c(-c2cc(Cl)ccc2C#N)cc1=O
Product: CC(C(=O)Nc1ccc(C(=O)OC(C)(C)C)cc1)n1cc(Cl)c(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
135 mg (purity 93%, 0.37 mmol) of 2-[5-chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]propanoic acid (racemate) and 1.2 eq. of tert-butyl 4-aminobenzoate were reacted according to General Method 5A. Yield: 281 mg (purity 58%, 85% of theory)