Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH3:9])[N:5]=[C:4]([N:10]2[C@H:15]([CH3:16])[CH2:14][CH2:13][C@H:12]([C:17]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[CH2:11]2)[CH:3]=1.[C:27]([C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][C:30]=1[F:38])#[N:28].[O-]P([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.O>[C:27]([C:29]1[CH:34]=[CH:33][C:32]([C:2]2[N:7]=[C:6]([NH:8][CH3:9])[N:5]=[C:4]([N:10]3[C@H:15]([CH3:16])[CH2:14][CH2:13][C@H:12]([C:17]([NH:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[O:18])[CH2:11]3)[CH:3]=2)=[CH:31][C:30]=1[F:38])#[N:28]
Reactant: CNc1nc(Cl)cc(N2C[C@@H](C(=O)NCc3ccccc3)CC[C@H]2C)n1
Reactant: N#Cc1ccc(B(O)O)cc1F
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: CNc1nc(-c2ccc(C#N)c(F)c2)cc(N2C[C@@H](C(=O)NCc3ccccc3)CC[C@H]2C)n1
Temperature: 100 °C
Yield: 173.4 %

Procedure:
(3S,6R)-1-[6-Chloro-2-(methylamino)-4-pyrimidinyl]-6-methyl-N-(phenylmethyl)-3-piperidinecarboxamide (300 mg, 0.80 mmol), (4-cyano-3-fluorophenyl)boronic acid (176 mg, 1.07 mmol, 1.3 equiv), Pd2(dba)3 (56 mg, 0.061 mmol, 0.075 equiv), tricyclohexylphosphine (34.5 mg, 0.123 mmol, 0.15 equiv), and K3PO4 (296 mg, 1.39 mmol, 1.7 equiv) were charged to a 30 mL microwave vial, followed by addition of 1,4-dioxane (6 mL) and water (2 mL). The mixture was bubbled with argon for 10 minutes, and heated at 100° C. for 20 hours. A duplicate run was performed. The crude mixture of both runs were combined and filtered through celite, and the filtrate was concentrated in vacuo. The residue was partitioned between EtOAc (50 mL) and brine (15 mL). The organic was dried over Na2SO4, filtered and conc in vacuo. Purification by silica gel column chromatography using gradient elution of 1% EtOAc in CHCl3 to 100% EtOAc gave the title compound (636 mg) as a foam. LC-MS (ES) m/z=459 [M+H]+.
Reaction SMILES: [CH2:1]([N:3](CC)CC)[CH3:2].C(N)C.Cl[C:12]1[N:20]2[CH:21]([C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)[CH2:22][O:23][C:18]3=[C:19]2[C:14](=[C:15]([F:37])[CH:16]=[C:17]3[C:30]2[C:31]([CH3:36])=[N:32][O:33][C:34]=2[CH3:35])[N:13]=1>CN1CCCC1=O.CO>[CH3:36][C:31]1[C:30]([C:17]2[C:18]3[O:23][CH2:22][CH:21]([C:24]4[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=4)[N:20]4[C:12]([NH:3][CH2:1][CH3:2])=[N:13][C:14]([C:19]=34)=[C:15]([F:37])[CH:16]=2)=[C:34]([CH3:35])[O:33][N:32]=1
Reactant: CCN(CC)CC
Reactant: Cc1noc(C)c1-c1cc(F)c2nc(Cl)n3c2c1OCC3c1cccnc1
Agent: CCN
Solvent: CN1CCCC1=O
Solvent: CO
Product: CCNc1nc2c(F)cc(-c3c(C)noc3C)c3c2n1C(c1cccnc1)CO3
Temperature: 150 °C
Yield: 19.1 %

Procedure:
Triethylamine (16 μL, 0.12 mmol) and ethylamine (0.2 mL, 3 mmol) were added to 2-chloro-7-(3,5-dimethylisoxazol-4-yl)-9-fluoro-4-pyridin-3-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine (15 mg, 0.040 mmol) in N-methylpyrrolidinone (0.41 mL) and the mixture was heated in a microwave at 150° C. for 20 min. The mixture was diluted with methanol and purified by preparative LCMS using pH 10 buffer to afford the title compound (3.0 mg, 19%). LCMS calc. for C21H21FN5O2 (M+H)+: m/z=394.2. found: 394.1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:10](=[O:11])[O:9][CH2:8][C:5]2=[N:6][CH:7]=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1>>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:8][C:5]2[N:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=2[C:10]([OH:9])=[O:11])=[CH:15][CH:14]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: O=C1OCc2ncc(F)cc21
Product: O=C(O)c1cc(F)cnc1COc1ccc(Cl)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 18 from 3-fluorofuro[3,4-b]pyridin-5(7H)-one (step 4) and 4-chlorophenol:
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[N:11]([CH3:13])[C:10]1[S:14][C:15]([C:17]([O:19]C)=[O:18])=[CH:16][C:9]2=1>>[Cl:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[N:11]([CH3:13])[C:10]1[S:14][C:15]([C:17]([OH:19])=[O:18])=[CH:16][C:9]2=1
Reactant: COC(=O)c1cc2c3cccc(Cl)c3n(C)c2s1
Agent: [K+]
Agent: [OH-]
Product: Cn1c2sc(C(=O)O)cc2c2cccc(Cl)c21
Yield: 98.9 %

Procedure:
Prepared from KOH (4.73 g), (50) (5.9 g) after reflux overnight yielding (57) 5.54 g (99.3%). M.p. 233°-234° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7](Br)[CH:6]=1.[NH4+].[OH-].[CH3:15][N:16](C=O)C>[C-]#N.[C-]#N.[Zn+2]>[CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:15]#[N:16])[CH:6]=1
Reactant: CN(C)C=O
Reactant: COC(=O)Cc1cccc(Br)c1
Agent: [C-]#N
Agent: [NH4+]
Agent: [OH-]
Product: COC(=O)Cc1cccc(C#N)c1
Temperature: 80 °C

Procedure:
Nitrogen was bubbled through a mixture of (3-bromo-phenyl)-acetic Acid methyl ester (22.85 g, 99.78 mmol), Zn(CN)2 (7.25 g, 61.75 mmol), and DMF (100 mL) for about 5 minutes followed by addition of tetrakistriphenylphosphine(0) palladium (4.60 g, 3.98 mmol). The mixture was heated for 3 h at 80° C. and was cooled to room temperature. Aqueous 2N NH4OH was added and the product was extracted into EtOAc (3×). The organic solution was washed with 2N NH4OH (2×) followed by brine (2×). The organic solution was dried (MgSO4), filtered, and concentrated in vacuo. Purification by flash chromatography (6:1 hexanes:EtOAc) provided the title compound as an oil (15.19 g). 1H NMR (400 MHz, CDCl3) δ 7.57-7.41 (m, 4H), 3.706 (s, 3H), 3.703 (s, 2H).
Reaction SMILES: Br[CH2:2][C:3]1[C:8](I)=[CH:7][N:6]=[C:5]([Cl:10])[CH:4]=1.[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([CH:22]=[CH2:23])=[C:16]([NH:18][C:19](=[O:21])[CH3:20])[CH:17]=1.C(N1C2C=CC=CC=2C=CC2N=C(Cl)C(F)=CC=2C1)(=O)C>>[C:19]([N:18]1[C:16]2[CH:17]=[C:12]([Cl:11])[CH:13]=[CH:14][C:15]=2[CH:22]=[CH:23][C:8]2[CH:7]=[N:6][C:5]([Cl:10])=[CH:4][C:3]=2[CH2:2]1)(=[O:21])[CH3:20]
Reactant: C=Cc1ccc(Cl)cc1NC(C)=O
Reactant: Clc1cc(CBr)c(I)cn1
Agent: CC(=O)N1Cc2cc(F)c(Cl)nc2C=Cc2ccccc21
Product: CC(=O)N1Cc2cc(Cl)ncc2C=Cc2ccc(Cl)cc21

Procedure:
The title compound was prepared from 25D and 6C in two steps by a route analogous to that used for the preparation of 1D. HPLC Rt=2.809 min; LCMS Found: (M+H)+=319.
Reaction SMILES: [F:1][C:2]1([F:8])[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:16][CH2:17][Cl:18]>CC(C)=O>[Cl:18][CH2:17][CH2:16][N:5]1[CH2:6][CH2:7][C:2]([F:8])([F:1])[CH2:3][CH2:4]1
Reactant: ClCCBr
Reactant: FC1(F)CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: FC1(F)CCN(CCCl)CC1
Temperature: 50 °C
Reaction time: 8 h
Yield: 16.1 %

Procedure:
To a solution of 4,4-difluoropiperidine (1.00 g, 6.35 mmol) in acetone (15 mL), were added potassium carbonate (2.19 g, 15.9 mmol) and 1-bromo-2-chloroethane (635 μL, 7.62 mmol) and the mixture was stirred for 8 h at 50° C. Insoluble materials were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc/hexane=0/100→30/70) to obtain title compound (188 mg, 16%) as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]([CH3:10])([CH3:9])[CH3:8])[N:5]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[C:3]=1[C:21]#[N:22].[OH-:23].[Na+]>C(O)C>[NH2:1][C:2]1[N:6]([C:7]([CH3:9])([CH3:10])[CH3:8])[N:5]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[C:3]=1[C:21]([NH2:22])=[O:23]
Reactant: [OH-]
Reactant: CC(C)(C)n1nc(-c2ccc(C(F)(F)F)cc2)c(C#N)c1N
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)n1nc(-c2ccc(C(F)(F)F)cc2)c(C(N)=O)c1N

Procedure:
To a solution of 5-amino-1-tert-butyl-4-cyano-3-(4'-trifluoromethylphenyl)pyrazole (308 mg, 1.0 mmol) in ethanol (15 ml) was added 10M sodium hydroxide (3 ml) and the mixture heated at reflux for 72 h. On cooling, ethanol was removed under reduced pressure and water (50 ml) added. The resulting precipitate was collected by filtration, and washed with water (2×25 ml), to give the title compound (200 mg) as a colorless solid after recrystallisation from ethyl acetate m.p. 210-211°. δH (CDCl3) 1.67 (9H, s), 5.16 (2H, br s), 5.69 (2H, br s), and 7.71 (4H, s).
Reaction SMILES: [N:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[NH:4][CH2:3][CH2:2]2.[NH:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[C:15]1[O:19][C:18](S)=[N:17][N:16]=1.C(O)CCCC>C(Cl)(Cl)Cl>[N:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[N:4]([C:18]1[O:19][C:15]([C:11]3[NH:10][CH:14]=[CH:13][CH:12]=3)=[N:16][N:17]=1)[CH2:3][CH2:2]2
Reactant: C1CN2CCC(CC2)N1
Reactant: Sc1nnc(-c2ccc[nH]2)o1
Solvent: ClC(Cl)Cl
Solvent: CCCCCO
Product: c1c[nH]c(-c2nnc(N3CCN4CCC3CC4)o2)c1
Reaction time: 15 h

Procedure:
A mixture of 1,4-diazabicyclo[3.2.2]nonane (3.02 g, 23.9 mmol), 5-(1H-pyrrol-2-yl)-1,3,4-oxadiazole-2-thiol (Compound B) (5.0 g, 20.9 mmol) and 1-pentanol (50 ml) was stirred for 15 h. The mixture was solved in chloroform and was filtered through celite. The mixture was purified three times by silica gel chromatography, using chloroform, methanol and aqueous ammonia (89:10:1). The product was dried and evaporated. Yield 382 mg (6%). LC-ESI-HRMS of [M+H]+ shows 260.15096 Da. Calc. 260.15059 Da, dev. 1.4 ppm.
Reaction SMILES: [F:1][C:2]1[C:3]([N:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:16][CH2:15]2)=[C:4]([C:7]([F:13])=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)[CH2:5]Cl.B.[Na].Cl>CS(C)=O>[CH2:23]([O:22][C:20]([N:17]1[CH2:18][CH2:19][N:14]([C:3]2[C:2]([F:1])=[CH:9][C:8]([N+:10]([O-:12])=[O:11])=[C:7]([F:13])[C:4]=2[CH3:5])[CH2:15][CH2:16]1)=[O:21])[CH3:24]
Reactant: CCOC(=O)N1CCN(c2c(F)cc([N+](=O)[O-])c(F)c2CCl)CC1
Agent: B
Agent: Cl
Agent: [Na]
Solvent: CS(C)=O
Product: CCOC(=O)N1CCN(c2c(F)cc([N+](=O)[O-])c(F)c2C)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 96.8 %

Procedure:
To a solution of 3,6-difluoro-2-(4-ethoxycarbonyl-1-piperazinyl)-5-nitrobenzyl chloride (8.1 g) in dimethylsulfoxide (90 ml) is added gradually sodium boron hydride (1.8 g) at below 30° C. The mixture is stirred at the same temperature for one hour, and the reaction mixture is pored into ice water, and then acidified with conc. hydrochloric acid and extracted with diethyl ether. The solvent is distilled off to give 2-(4-ethoxycarbonyl-1-piperazinyl)-3,6-difluoro-5-nitrotoluene (7.1 g).
Reaction SMILES: [F:1][C:2]([F:42])([C:38]([F:41])([F:40])[F:39])[CH2:3][CH2:4][CH2:5][S:6][CH2:7][C@@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C@@H:18]1[CH2:35][C:34]2[CH:33]=[C:32]([OH:36])[CH:31]=[CH:30][C:29]=2[C@@H:28]2[C@@H:19]1[C@H:20]1[C@@:24]([CH2:26][CH2:27]2)([CH3:25])[C@@H:23]([OH:37])[CH2:22][CH2:21]1.C(OC(=O)C)(=O)C.B1([O-])OO1.[OH2:54].[OH2:55].O.O.[Na+]>>[F:42][C:2]([F:1])([C:38]([F:39])([F:40])[F:41])[CH2:3][CH2:4][CH2:5][S:6]([CH2:7][C@@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C@@H:18]1[CH2:35][C:34]2[CH:33]=[C:32]([OH:36])[CH:31]=[CH:30][C:29]=2[C@@H:28]2[C@@H:19]1[C@H:20]1[C@@:24]([CH2:26][CH2:27]2)([CH3:25])[C@@H:23]([OH:37])[CH2:22][CH2:21]1)(=[O:55])=[O:54]
Reactant: O
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCN4CCC[C@H]4CSCCCC(F)(F)C(F)(F)F)[C@H]3[C@@H]1CC[C@@H]2O
Agent: [Na+]
Agent: [O-]B1OO1
Solvent: CC(=O)OC(C)=O
Product: C[C@]12CC[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCN4CCC[C@H]4CS(=O)(=O)CCCC(F)(F)C(F)(F)F)[C@H]3[C@@H]1CC[C@@H]2O

Procedure:
Under the conditions of Example 3, 76 mg of 7α-{5-[(2S)-2-(4,4,5,5,5-pentafluoropentylthiomethyl)-pyrrolidin-1-yl]-pentyl}-estra-1,3,5(10)-triene-3,17β-diol (Example 26f) is acetylated with acetic anhydride, and the crude product is oxidized, as described in Example 4, with sodium perborate tetrahydrate, worked up and chromatographed. 31 mg of the title compound is obtained as oil. [α]D22=30.6° (c=0.515 in methanol).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[F:7][CH2:8][CH2:9]I.[Br:11][C:12]1[CH:13]=[C:14]([C:18]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)=[CH2:19])[CH:15]=[CH:16][CH:17]=1.ClCCl>CN(C)C=O.C1CCCCC1.C(OCC)(=O)C.O>[Br:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([C:20]2[CH:21]=[CH:22][C:23]([O:26][CH2:9][CH2:8][F:7])=[CH:24][CH:25]=2)=[CH2:19])[CH:13]=1
Reactant: C=C(c1ccc(O)cc1)c1cccc(Br)c1
Reactant: FCCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: C1CCCCC1
Product: C=C(c1ccc(OCCF)cc1)c1cccc(Br)c1
Temperature: 55 °C
Reaction time: 8 h
Yield: 54.7 %

Procedure:
Cesium carbonate (2.18 g, 6.67 mmol, 1.2 eq) and 1-fluoro-2-iodoethane (1.1 g, 6.4 mmol, 1.2 eq) were added to a solution of 4-[1-(3-bromo-phenyl)-vinyl]-phenol (1.5 g, 5.3 mmol, 1.0 eq) in dry N,N-dimethylformamide (15 mL). The mixture was stirred overnight at 55° C.; dichloromethane (100 mL) and water (50 mL) were then added. The organic phase was washed with water (3×) and dried over sodium sulfate. Evaporation of solvent gave crude ether that was purified by flash chromatography (eluent: cyclohexane/ethyl acetate=9:1 then) to give 931 mg (yield 54%) of desired product as yellow oil.
Reaction SMILES: [CH2:1]([N:3]1[C:10](=[O:11])[CH:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:8][C@H:4]1[C:5]([OH:7])=O)[CH3:2].C(N1CCOCC1)C.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[Cl:49][C:50]1[CH:55]=[C:54]([F:56])[CH:53]=[CH:52][C:51]=1[CH2:57][NH2:58].C(=O)([O-])O.[Na+]>ClCCl.CN(C)C=O>[Cl:49][C:50]1[CH:55]=[C:54]([F:56])[CH:53]=[CH:52][C:51]=1[CH2:57][NH:58][C:5](=[O:7])[C@@H:4]1[CH2:8][CH:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10](=[O:11])[N:3]1[CH2:1][CH3:2]
Reactant: CCN1C(=O)C(Cc2ccccc2)C[C@H]1C(=O)O
Reactant: NCc1ccc(F)cc1Cl
Agent: CCN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCN1C(=O)C(Cc2ccccc2)C[C@H]1C(=O)NCc1ccc(F)cc1Cl
Reaction time: 0.17 h
Yield: 11.4 %

Procedure:
Crude 1-ethyl-5-oxo-4-(phenylmethyl)-proline (0.052 g, 0.09 mmol, prepared as described below) was suspended in a mixture of dichloromethane (0.5 ml) and dimethylformamide (0.5 ml) and to this was added N-ethyl morpholine (0.034 ml, 0.27 mmol) causing most of the material to dissolve. 1-Hydroxybenzotriazole (0.016 g, 0.12 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.022 g, 0.12 mmol) were then added and the mixture was stirred for 10 minutes before adding [(2-chloro-4-fluorophenyl)methyl]amine (0.019 g, 0.12 mmol). The mixture was then left to stand at room temperature overnight. Saturated aqueous sodium hydrogen carbonate (˜2 ml) was added to the mixture and stirred for 10 minutes. The organic layer was isolated by filtering through a phase separator and then washed with 2M aqueous hydrogen chloride. The organic layer was separated again and evaporated to give a yellow oil which was purified by mass-directed automated HPLC to give pure N-[(2-chloro-4-fluorophenyl)methyl]-1-ethyl-5-oxo-4-(phenylmethyl)-prolinamide (0.004 g) as a colourless oil. LC/MS [M+H]+=389, retention time=2.90 minutes.
Reaction SMILES: C[Si](C)(C)CC[O:5][C:6](=[O:29])[CH2:7][C@@H:8]([CH3:28])[CH2:9][C:10]([N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([Cl:21])[CH:19]=2)[CH:14]=[C:13]1[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:11].FC(F)(F)C(O)=O.O.C(OCC)(=O)C>C(Cl)Cl>[Cl:21][C:18]1[CH:19]=[C:20]2[C:15]([CH:14]=[C:13]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[N:12]2[C:10](=[O:11])[CH2:9][C@H:8]([CH3:28])[CH2:7][C:6]([OH:29])=[O:5])=[CH:16][CH:17]=1
Reactant: CCCCCCc1cc2ccc(Cl)cc2n1C(=O)C[C@H](C)CC(=O)OCC[Si](C)(C)C
Solvent: CCOC(C)=O
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCc1cc2ccc(Cl)cc2n1C(=O)C[C@H](C)CC(=O)O
Reaction time: 72 h

Procedure:
To the cold solution of 5-(6-Chloro-2-hexyl-indol-1-yl)-3-(S)-methyl-5-oxo-pentanoic acid 2-trimethylsilanyl-ethyl ester in methylene chloride was added trifluoro acetic acid and was stirred for three days. The reaction mixture was then treated with water and ethyl acetate. The product was purified by column chromatography.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[C:6]1([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C1(C)C=CC=CC=1.O1CCCC1>[Cl:1][CH2:2][C:3]([N:12]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4]
Reactant: O=C(Cl)CCl
Reactant: c1ccc(Nc2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=C(CCl)N(c1ccccc1)c1ccccc1
Temperature: 100 °C
Yield: 75.5 %

Procedure:
Chloroacetyl chloride (0.32 ml, 4.02 mmol) was dissolved in a mixed solvent of toluene (6 ml) and tetrahydrofuran (2 ml). The solution was added with diphenylamine (690 mg, 4.08 mmol) at room temperature, and the heated at 100° C. for 80 minutes. The solvent was evaporated under reduced pressure, and the solid precipitated was suspended and washed in ethyl ether. The solid was collected by filtration and dried under reduced pressure to obtain the title compound as colorless solid (746 mg, yield: 75%).
Reaction SMILES: [F:1][C:2]1[C:3]([O:22][CH3:23])=[C:4]([CH:8]([CH3:21])[CH2:9][C:10]([OH:20])([C:16]([F:19])([F:18])[F:17])[C:11](OCC)=[O:12])[CH:5]=[CH:6][CH:7]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C.O>C(OCC)C>[F:1][C:2]1[C:3]([O:22][CH3:23])=[C:4]([C@H:8]([CH3:21])[CH2:9][C@:10]([OH:20])([C:16]([F:19])([F:18])[F:17])[CH:11]=[O:12])[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(O)(CC(C)c1cccc(F)c1OC)C(F)(F)F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Solvent: CCOC(C)=O
Product: COc1c(F)cccc1[C@H](C)C[C@@](O)(C=O)C(F)(F)F
Reaction time: 1.5 h
Yield: 41.5 %

Procedure:
1.56 g (5.7 mmol) of 1,1′-bi-2-naphthol are admixed with 5.7 ml (2.85 mmol) of a 0.5 M titanium tetraisopropoxide solution in toluene and the red solution is stirred for 2 hours at room temperature. 9.5 g (57.2 mmol) of 2-fluoro-6-(1-methyleneethyl)anisole and 12.5 ml (95 mmol) of ethyl trifluoropyruvate are added and the mixture is heated at 140° C. for 18 hours. After cooling it is immediately purified by column chromatography on silica gel (hexane/ethyl acetate 0-5%) to give 8.9 g of ethyl 4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)pent-4-enoate. 8.9 g (26.5 mmol) of ethyl 4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)pent-4-enoate are dissolved in 200 ml of methanol and 2 ml of acetic acid, and 890 mg of palladium on carbon (10%) are added. The suspension is shaken for 1.5 hours under a hydrogen atmosphere under atmospheric pressure until the hydrogen uptake is 560 ml. The mixture is filtered through Celite, the filter bed being rinsed thoroughly with ethyl acetate. Removal of the solvent gives 8.6 g of ethyl 4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)pentanoate. 8.6 g (25.4 mmol) of ethyl 4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)-pentanoate in 350 ml of diethyl ether are cooled to −30° C. and over 15 minutes 1.7 g (44.7 mmol) of lithium aluminum hydride in solid form are added in portions. The mixture is stirred for 1.5 hours, in the course of which the temperature climbs to −15° C., followed by dropwise addition in succession of ethyl acetate and water and by a further hour of stirring until a readily filterable precipitate has formed. The suspension is filtered through Celite, the filter bed being thoroughly rinsed with ethyl acetate. The phases of the filtrate are separated and extraction is carried out again with ethyl acetate. The extracts are washed with saturated sodium chloride solution and dried over sodium sulphate and the solvent is removed in vacuo. Separation by column chromatography on silica gel (hexane/diisopropyl ether 0-15%) yields 3.1 g of (2R*,4R*)-4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)pentanal
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6](=[O:8])[N:5]([CH2:9][CH2:10][CH2:11][CH3:12])[C:4](=[O:13])[CH:3]=1.[N:14]([O-])=[O:15].[Na+]>C(O)(=O)C>[N:14]([C:3]1[C:4](=[O:13])[N:5]([CH2:9][CH2:10][CH2:11][CH3:12])[C:6](=[O:8])[NH:7][C:2]=1[NH2:1])=[O:15]
Reactant: O=N[O-]
Reactant: CCCCn1c(=O)cc(N)[nH]c1=O
Agent: [Na+]
Solvent: CC(=O)O
Product: CCCCn1c(=O)[nH]c(N)c(N=O)c1=O
Temperature: 70 °C

Procedure:
A mixture of 6-amino-3-butyl-1,3-dihydropyrimidine-2,4-dione (4.0 g, 21.8 mmol) and aqueous acetic acid (120 ml) was heated at 70° C. until complete solution as attained, and the solution was cooled to 30° C. Sodium nitrite (3 g) was added in small portions while stirring, forming an orange precipitate. The reaction mixture was cooled to 0° C., and the precipitate filtered off, washed with water, and dried under reduced pressure, to provide 5-nitroso-6-amino-3-butyl-1,3-dihydropyrimidine-2,4-dione, which was used in the next reaction with no further purification.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:16]2[C:11](=[CH:12][C:13]([CH3:17])=[CH:14][CH:15]=2)[O:10][C:9](=[O:18])[CH:8]=1)(=O)=O.C([Sn](CCCC)(CCCC)[C:26]([O:28][CH2:29][CH3:30])=[CH2:27])CCC.[Cl-].[Li+]>O1CCOCC1.C(OCC)(=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:29]([O:28][C:26]([C:7]1[C:16]2[C:11](=[CH:12][C:13]([CH3:17])=[CH:14][CH:15]=2)[O:10][C:9](=[O:18])[CH:8]=1)=[CH2:27])[CH3:30]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: Cc1ccc2c(OS(=O)(=O)C(F)(F)F)cc(=O)oc2c1
Agent: [Pd]
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: C=C(OCC)c1cc(=O)oc2cc(C)ccc12
Temperature: 100 °C

Procedure:
To a solution of 7-methyl-2-oxo-2H-chromen-4-yl trifluoromethanesulfonate (prepared as described in U.S. Pat. No. 5,552,437) (2.5 g, 8.1 mmol) and tributyl(1-ethoxyvinyl)tin (2.88 mL, 8.5 mmol) in 1,4-dioxane (25 mL), lithium chloride (1.03 g, 24.3 mmol) was added. The reaction flask was then purged twice with nitrogen and tetrakis(triphenylphosphine) palladium(0) (468 mg, 0.405 mmol) was added. The reaction was then heated overnight at 100° C. After cooling, the reaction mixture was concentrated under reduced pressure and the crude residue obtained was diluted with ethyl acetate, washed with a saturated ammonium chloride aq. solution, water and brine, dried over MgSO4, filtered and concentrated. The crude residue obtained was purified by column chromatography (EtOAc/hexanes, 25:75 to 40:60) to afford the title compound. 1H NMR (400 MHz, acetone-d6): 7.76 (d, 1H), 7.22 (s, 1H), 7.19 (d, 1H), 6.35 (s, 1H), 4.64 (d, 1H), 4.61 (d, 1H), 4.04 (q, 2H), 2.47 (s, 3H), 1.40 (t, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.Cl[C:10]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:11]=1[NH2:12].[OH-].[K+].C(O)C>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:10]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:11]=2[NH2:12])=[CH:4][CH:3]=1
Reactant: Fc1ccc(S)cc1
Reactant: Nc1cc([N+](=O)[O-])ccc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1cc([N+](=O)[O-])ccc1Sc1ccc(F)cc1

Procedure:
A mixture of 29.7 g. (0.231 mole) of 4-fluorothiophenol, 41 g. (0.238 mole) of 2-chloro-5-nitroaniline and 14.9 g. (0.266 mole) of potassium hydroxide in 500 ml. of 95 percent aqueous ethanol is heated to its reflux temperature and maintained at reflux for one hour, then cooled with an ice bath. Some crude product is isolated as a solid by filtration, then the filtrate is diluted with water and extracted with four 300 ml. portions of chloroform. The combined extracts are washed with four 300 ml. portions of water and then with saturated sodium chloride solution and dried. Evaporation under vacuum provides a residue which is combined with the previously isolated crude solid product, 2-(4-fluorophenylthio)-5-nitroaniline. The solid is dissolved in 500 ml. of chloroform, then the solution is saturated with hydrogen chloride gas. The white precipitate which forms is separated by filtration, washed with chloroform and diethyl ether and dried to provide 2-(4-fluorophenylthio)-5-nitroaniline hydrochloride.