Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:17][C:18]#[N:19])=[N:4][CH:5]=[C:6]([N:8]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[N:9]2)[CH:7]=1.[H][H]>CO.[Ni]>[Cl:1][C:2]1[C:3]([CH2:17][CH2:18][NH2:19])=[N:4][CH:5]=[C:6]([N:8]2[CH:12]=[CH:11][C:10]([C:13]([F:14])([F:16])[F:15])=[N:9]2)[CH:7]=1
Reactant: [H][H]
Reactant: N#CCc1ncc(-n2ccc(C(F)(F)F)n2)cc1Cl
Agent: [Ni]
Solvent: CO
Product: NCCc1ncc(-n2ccc(C(F)(F)F)n2)cc1Cl

Procedure:
A solution of 3-chloro-5-[3-(trifluoromethyl)-1H-pyrazol-1-yl]-2-pyridineacetonitrile (i.e. the product of Step B; 5.0 g, 0.017 mol) in methanol (50 mL) was shaken in a Parr hydrogenation apparatus in the presence of Raney nickel (5.0 g) and a hydrogen pressure of 50 psi (345 kPa) at room temperature for 2 h. The mixture was filtered through a pad of Celite® diatomaceous filter aid, and the filter pad was washed with dichloromethane. The filtrate was concentrated under reduced pressure to afford the title compound (2.0 g), which was used without further purification.
Reaction SMILES: [NH2:1][C:2](=[N:4][C:5]1[S:6][CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([NH:18][NH2:19])=[O:17])[N:11]=2)[N:9]=1)[NH2:3].S(O)(O)(=O)=O.CS[C:27](=[NH:29])[NH2:28].C(OCC)(=O)C>CS(C)=O>[NH2:1][C:2](=[N:4][C:5]1[S:6][CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16](=[O:17])[NH:18][NH:19][C:27]([NH2:29])=[NH:28])[N:11]=2)[N:9]=1)[NH2:3]
Reactant: NNC(=O)c1cccc(-c2csc(N=C(N)N)n2)n1
Reactant: CSC(=N)N
Agent: O=S(=O)(O)O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: N=C(N)NNC(=O)c1cccc(-c2csc(N=C(N)N)n2)n1
Temperature: 100 °C
Reaction time: 6 h
Yield: 81.2 %

Procedure:
A mixture of 2-(diaminomethyleneamino)-4-(6-hydrazinocarbonylpyridin-2-yl)thiazole (3.0 g) and 2-methyl-2-thiopseudourea sulfate (1.8 g) in dimethylsulfoxide (30 ml) was stirred for 6 hours at 100° C., and then the mixture was cooled to ambient temperature. To the mixture was added ethyl acetate (30 ml) under stirring. The isolated precipitate was collected by filtration and the precipitate was added to a mixture of water and ethyl acetate. The mixture was adjusted to pH 10 with 4N-sodium hydroxide and precipitate was collected by filtration to give 2-(diaminomethyleneamino)-4-(6-guanidinocarbamoylpyridin-2-yl)thiazole (2.48 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:14])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8].C(=O)([O-])[O-].[Na+].[Na+].I[CH2:22][CH3:23]>C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:14])[CH2:13][CH2:12][N:11]([CH2:22][CH3:23])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CCI
Reactant: OC1(c2ccc(F)c(F)c2)CCNC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CCN1CCC(O)(c2ccc(F)c(F)c2)C1

Procedure:
Preparation according to Example 8: 3-(3,4-difluorophenyl)pyrrolidin-3-ol (0.38 g, 1.9 mmol), acetonitrile (20 mL), sodium carbonate (0.26 g, 4.75 mmol), iodoethane (0.29 g, 1.9 mmol). Refluxed 2 h. Purification by HPLC on Waters OBD C18, 5 μm (MeOH/33 mM NH3, 35:65 to 50:50). Yield: 0.26 g. The amine was converted to the fumaric acid salt and recrystallized from 2-propanol/diisopropyl ester: M.p. 157-158° C.; MS m/z (relative intensity, 70 eV) 227 (M+, 26), 212 (18), 141 (30), 127 (23), 113 (22), 71 (bp).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:34]=[CH:35][C:36]=1[OH:37])[C:5]([CH2:7][NH:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[CH:17]1[CH2:26][CH2:25][C:24]2[CH:23]=[C:22]([O:27]C(=O)C(C)(C)C)[CH:21]=[CH:20][C:19]=2[CH2:18]1)=O.Cl[CH2:39][C:40]([N:42]1[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1)=O>>[F:1][C:2]1[CH:3]=[C:4]([CH:34]=[CH:35][C:36]=1[O:37][CH2:39][CH2:40][N:42]1[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1)[CH2:5][CH2:7][NH:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[CH:17]1[CH2:26][CH2:25][C:24]2[CH:23]=[C:22]([OH:27])[CH:21]=[CH:20][C:19]=2[CH2:18]1
Reactant: O=C(CCl)N1CCCCC1
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCC(=O)c2ccc(O)c(F)c2)c1
Product: COc1ccc(C2CCc3cc(O)ccc3C2)c(NCCc2ccc(OCCN3CCCCC3)c(F)c2)c1
Yield: 10.7 %

Procedure:
Synthesized from pivalic acid 6-{2-[(3-fluoro-4-hydroxybenzoyl)methylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (20 mg) and 2-chloro-1-piperidin-1-ylethanone (13 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (2.2 mg) was obtained.
Reaction SMILES: [CH2:1]([C@H:5]1[CH2:10][N:9]([C:11]2[N:12]=[C:13]([C:16]3[C:24]4[C:19](=[N:20][CH:21]=[CH:22][CH:23]=4)[N:18](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:17]=3)[S:14][CH:15]=2)[CH2:8][CH2:7][N:6]1C(OC(C)(C)C)=O)[CH:2]([CH3:4])[CH3:3].C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([C@@H:5]1[NH:6][CH2:7][CH2:8][N:9]([C:11]2[N:12]=[C:13]([C:16]3[C:24]4[C:19](=[N:20][CH:21]=[CH:22][CH:23]=4)[NH:18][N:17]=3)[S:14][CH:15]=2)[CH2:10]1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)C[C@H]1CN(c2csc(-c3nn(C(c4ccccc4)(c4ccccc4)c4ccccc4)c4ncccc34)n2)CCN1C(=O)OC(C)(C)C
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)C[C@H]1CN(c2csc(-c3n[nH]c4ncccc34)n2)CCN1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl (2S)-2-isobutyl-4-[2-(1-tritylpyrazolo[5,4-b]pyridin-3-yl)thiazol-4-yl]piperazine-1-carboxylate (149 mg, 0.2176 mmol) and triethylsilane (101.2 mg, 139.0 μL, 0.8704 mmol) in DCM (2 mL) at 0° C. was added TFA (0.3 mL,). Then ice-bath removed and mixture stirred at room temperature for 1 h. Added more TFA (0.3 mL) and stirred for a further 1 h. Basified with minimal sat. NaHCO3 and extracted with EtOAc. Organics combined, washed with small amount of water, brine, dried (MgSO4), filtered and concentrated in vacuo. Crude product purified by flash chromatography (12 g SiO2, 0 to 6% MeOH (containing 10% ammonium hydroxide)/DCM) to leave product as a pale green solid after freeze-drying (MeCN/H2O) (18.18 mg, 24%); 1H NMR DMSO-d6 δ 0.87-0.86 (br m, 1H), 0.92 (dd, 6H), 1.31-1.20 (m, 2H), 1.85-1.76 (m, 1H), 2.36 (t, 1H), 2.71 (td, 1H), 2.87-2.78 (m, 2H), 3.00 (d, 1H), 3.80 (dd, 2H), 6.30 (s, 1H), 7.37 (dd, 1H), 8.64 (m, 2H); ES+ 343.08.
Reaction SMILES: NC(CCS(OC1C=CC=CC=1)(=O)=O)C(NC1C=CC=CC=1)=O.[N+:24]([C:27]1[CH:28]=[C:29]([S:34](Cl)(=[O:36])=[O:35])[CH:30]=[CH:31][C:32]=1[Cl:33])([O-:26])=[O:25].[C:38]1([OH:44])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>>[N+:24]([C:27]1[CH:28]=[C:29]([S:34]([O:44][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)(=[O:35])=[O:36])[CH:30]=[CH:31][C:32]=1[Cl:33])([O-:26])=[O:25]
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)ccc1Cl
Reactant: Oc1ccccc1
Agent: NC(CCS(=O)(=O)Oc1ccccc1)C(=O)Nc1ccccc1
Product: O=[N+]([O-])c1cc(S(=O)(=O)Oc2ccccc2)ccc1Cl

Procedure:
Thus, for example, 2-amino-4-phenoxysulfonyl-butyranilide can be obtained by reacting 3-nitro-4-chloro-benzene-sulfonic acid-chloride with phenol to yield 2-nitro-4-phenoxysulfonylchloro-benzene, reacting this product with ammonia to give 2-nitro-4-phenoxy-sulfonyl-aniline, acylating this compound with butyryl-chloride to form 2-nitro-4-phenoxysulfonyl-butyranilide, and by subsequently hydrogenating said product catalytically.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]3[C:17](=[CH:18][CH:19]=2)[CH:16]=[CH:15][C:14]2[CH:13]=[CH:12][C:11]([CH2:20][C:21]([CH3:23])=[O:22])=[CH:10][C:9]3=2)[CH2:3][CH2:2]1.Cl[C:25]1C=C2C(=CC=1)C1N(COCC[Si](C)(C)C)C(C3C(C#N)=CC=CC=3C#N)=NC=1C1C=CC(CC(=O)C)=CC2=1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]3[C:17](=[CH:18][CH:19]=2)[CH:16]=[CH:15][C:14]2[CH:13]=[CH:12][C:11]([CH2:20][C:21]([CH3:25])([OH:22])[CH3:23])=[CH:10][C:9]3=2)[CH2:2][CH2:3]1
Reactant: CC(=O)Cc1ccc2c(c1)c1cc(Cl)ccc1c1c2nc(-c2c(C#N)cccc2C#N)n1COCC[Si](C)(C)C
Reactant: CC(=O)Cc1ccc2ccc3ccc(OCC4CC4)cc3c2c1
Product: CC(C)(O)Cc1ccc2ccc3ccc(OCC4CC4)cc3c2c1

Procedure:
This phenanthrene was prepared as described in Step 3 of Example 135, substituting 1-[6-(cyclopropylmethoxy)-3-phenanthryl]acetone from Step 3 above for 2-(9-chloro-6-(2-oxopropyl)-1-{[2-(trimethylsilyl)ethoxy]methyl)-1H-phenanthro[9,10-d]imidazol-2-yl)isophthalonitrile. The crude product was used directly in the next reaction.
Reaction SMILES: [O-:1][C:2]#[N:3].[K+].O[CH:6]([CH2:15][CH3:16])[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)=[O:8].C(=O)(O)[O-].[Na+]>Cl.O>[CH2:15]([C:6]1[NH:3][C:2](=[O:1])[O:8][C:7]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)[CH3:16]
Reactant: N#C[O-]
Reactant: CCC(O)C(=O)c1ccccn1
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Product: CCc1[nH]c(=O)oc1-c1ccccn1
Reaction time: 1 h

Procedure:
Potassium cyanate (35.4 g, 0.44 mol) was added to a solution of 2-hydroxy-1-(2-pyridyl)butan-1-one (31 g, 0.15 mol) in 250 ml of 2N HCl diluted with 300 ml of water. After 1 hour the acidity was adjusted (pH=1) with concentrated hydrochloric acid and then allowed to stir overnight. The mixture was made basic by addition of aqueous sodium bicarbonate. The resulting gummy precipitate was chromatographed on silca gel and recrystallized twice from 50% aqueous ethanol to give the title compound, m.p. 196°-197° C. (dec.).
Reaction SMILES: C(OC([N:6]1[CH2:30][C@:29]2([C:31](=[O:35])[CH2:32][S:33][CH3:34])[C@@H:8]([CH2:9][C@H:10]3[C@H:23]4[C@@:14]([F:27])([C@:15]5([CH3:26])[C:20]([C@@H:21]([F:24])[CH2:22]4)=[CH:19][C:18](=[O:25])[CH:17]=[CH:16]5)[C@@H:13]([OH:28])[CH2:12][C@@:11]32[CH3:36])[CH2:7]1)=O)=C.[ClH:37].O1CCOCC1>C(Cl)Cl>[ClH:37].[F:27][C@@:14]12[C@:15]3([CH3:26])[C:20](=[CH:19][C:18](=[O:25])[CH:17]=[CH:16]3)[C@@H:21]([F:24])[CH2:22][C@H:23]1[C@@H:10]1[CH2:9][C@@H:8]3[C@:29]([C:31](=[O:35])[CH2:32][S:33][CH3:34])([C@@:11]1([CH3:36])[CH2:12][C@@H:13]2[OH:28])[CH2:30][NH:6][CH2:7]3
Reactant: C=COC(=O)N1C[C@@H]2C[C@H]3[C@@H]4C[C@H](F)C5=CC(=O)C=C[C@]5(C)[C@@]4(F)[C@@H](O)C[C@]3(C)[C@]2(C(=O)CSC)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CSCC(=O)[C@@]12CNC[C@@H]1C[C@H]1[C@@H]3C[C@H](F)C4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@@]12C
Temperature: 25 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
A mixture of compound 185 (122 mg, 0.234 mmol) and HCl 4M in Dioxane (2 ml, 8.00 mmol) in DCM (10 ml) is stirred at RT for 2 hours, then the solvent is evaporated and the crude is dried in vacuo for 16 hours. MeOH (15 ml) is added and the solution is stirred at 45° C. for 20 minutes. The solvent is evaporated to afford the title compound (106 mg, 93% yield).
Reaction SMILES: [C@H:1]1([C:11]([OH:13])=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[CH2:14]([O:16][C:17]([C:19]1([NH2:28])[CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20]1)=[O:18])[CH3:15].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:14]([O:16][C:17]([C:19]1([NH:28][C:11]([C@H:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4][CH2:3][CH2:2]2)=[O:13])[CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20]1)=[O:18])[CH3:15]
Reactant: O=C(O)[C@@H]1CCCc2ccccc21
Reactant: CCOC(=O)C1(N)Cc2ccccc2C1
Agent: CN(C)C(On1nnc2cccnc21)=[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: CCOC(=O)C1(NC(=O)[C@@H]2CCCc3ccccc32)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.5 %

Procedure:
To a solution of (R)-1,2,3,4-tetrahydro-naphthalene-1-carboxylic acid (300 mg, 1.7 mmol), 2-amino-indan-2-carboxylic acid ethyl ester (349 mg, 1.7 mmol), HATU (760 mg, 2.0 mmol) in anhydrous DMF (10 mL) is added DIPEA (330 μL, 2 mmol). The resulting solution is stirred at RT overnight. After the removal of DMF in vacuo, the residue is dissolved in EtOAc (100 mL) and washed with water (1×10 mL) and brine (2×10 mL). The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is purified by flash column chromatography (120 g silica gel, gradient elution: 5%-50% EtOAc in heptane) to give a pure product (67) as white solid (615 mg, 100%).
Reaction SMILES: [CH3:1][C@@H:2]([NH2:11])[C@@H:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:12](=O)(OCC)[O:13]CC.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH3:1][C@@H:2]1[C@H:3]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[O:10][C:12](=[O:13])[NH:11]1
Reactant: CCOC(=O)OCC
Reactant: C[C@@H](N)[C@@H](O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: C[C@H]1NC(=O)O[C@H]1c1ccccc1
Temperature: 160 °C
Yield: 101.8 %

Procedure:
A round bottom flask, equipped with a distillation apparatus, is charged with (1S,2R) -norephedrine (18.16 g, 99.1 mmol), diethyl carbonate (27.6 mL, 228 mmol), and potassium carbonate (28.9 g, 209 mmol), and heated at 160° C. (oil bath temperature). The distillation head temperature remained at ca 80° C. when ethanol is collected in the collection flask, which is cooled in an ice bath. When the head temperature drops to 60° C. (ca 5 hours), the oil bath is removed and the mixture is cooled to room temperature. The mixture is diluted in dichloromethane and washed with water (2X) and dried (magnesium sulfate). Concentration in vacuo affords an off-white solid (17.88 g), which is recrystallized in hexane-ethyl acetate 1:1.5, to afford the title compound as white crystals, 15.2 g; mp 120°-121° C., [α]D =171.4° (2.042% in chloroform).
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][CH2:6][CH:7]1[CH2:10][N:9]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)[CH2:8]1)=[O:4].[N-:20]=[C:21]=[O:22]>CN(C)C=O.C(Cl)(Cl)Cl.CO>[Cl:18][C:15]1[CH:14]=[C:13]([NH:20][C:21](=[O:22])[NH:1][CH2:2][C:3]([NH:5][CH2:6][CH:7]2[CH2:10][N:9]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=3)[CH2:8]2)=[O:4])[CH:12]=[CH:17][CH:16]=1
Reactant: NCC(=O)NCC1CN(Cc2ccc(Cl)c(Cl)c2)C1
Reactant: [N-]=C=O
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(CNC(=O)Nc1cccc(Cl)c1)NCC1CN(Cc2ccc(Cl)c(Cl)c2)C1
Reaction time: 8 h

Procedure:
A solution of 2-Amino-N-[1-(3,4-dichloro-benzyl)-azetidin-3-ylmethyl]-acetamide (1 M equivalent) in dimethylformamide is treated with a solution of the isocyanate (1.5 M equivalents) in dimethylformamide and left at room temperature overnight. The reaction mixture is diluted with chloroform/methanol 50:50 and applied to a SCX-3 1 g cartridge. The cartridge is washed with chloroform methanol 50:50, and the compound eluted with a solution of 10% ammonia in methanol. The solvent is evaporated to afford the title compound.
Reaction SMILES: [C:1]([C:3]12[O:19][CH:18]1[CH2:17][CH:16]([C:20]([CH3:31])=[CH:21][C:22]1[N:23]=[C:24]([CH2:27][N:28]=[N+]=[N-])[S:25][CH:26]=1)[O:15][C:14](=[O:32])[CH2:13][CH:12]([OH:33])[C:11]([CH3:35])([CH3:34])[C:10](=[O:36])[CH:9]([CH3:37])[CH:8]([OH:38])[CH:7]([CH3:39])[CH2:6][CH2:5][CH2:4]2)#[N:2].CP(C)C>O1CCCC1.C(OCC)(=O)C>[C:1]([C:3]12[O:19][CH:18]1[CH2:17][CH:16]([C:20]([CH3:31])=[CH:21][C:22]1[N:23]=[C:24]([CH2:27][NH2:28])[S:25][CH:26]=1)[O:15][C:14](=[O:32])[CH2:13][CH:12]([OH:33])[C:11]([CH3:34])([CH3:35])[C:10](=[O:36])[CH:9]([CH3:37])[CH:8]([OH:38])[CH:7]([CH3:39])[CH2:6][CH2:5][CH2:4]2)#[N:2]
Reactant: CC(=Cc1csc(CN=[N+]=[N-])n1)C1CC2OC2(C#N)CCCC(C)C(O)C(C)C(=O)C(C)(C)C(O)CC(=O)O1
Agent: CP(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(=Cc1csc(CN)n1)C1CC2OC2(C#N)CCCC(C)C(O)C(C)C(=O)C(C)(C)C(O)CC(=O)O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.7 %

Procedure:
To a stirred solution of the compound prepared in Example 5 (117 mg, 0.21 mmol) in tetrahydrofuran (2 mL) under argon was added trimethylphosphine (231 mL, 0.23 mmol, 1M in tetrahydrofuran) and the reaction was stirred at room temperature for 1 hour, then quenched with ammonium hydroxide (325 mL, 28% in water). The mixture was stirred for an additional 30 min. The volatiles were removed in vacuo and the crude material was purified (SiO2, ethyl acetate, then 1–10% MeOH/CHCl3 gradient elution). The material obtained was dissolved in ethyl acetate (20 mL) and washed twice with 20 mL portions of saturated aqueous sodium bicarbonate. The solution was dried over sodium sulfate and dried in vacuo to provide the title compound (100.5 mg, 89%) as a white solid. MS (ESI+): 534.2 (M+H)+.
Reaction SMILES: O[CH2:2][C@@H:3]([CH3:16])[CH2:4][N:5]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[O:8][CH2:7][C:6]1=[O:15].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:41]I>C(Cl)(Cl)Cl>[I:41][CH2:2][C@@H:3]([CH3:16])[CH2:4][N:5]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[O:8][CH2:7][C:6]1=[O:15]
Reactant: II
Reactant: C[C@H](CO)CN1C(=O)COc2ccccc21
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Product: C[C@H](CI)CN1C(=O)COc2ccccc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 80 %

Procedure:
A reaction flask was charged with (S)-4-(3-Hydroxy-2-methylpropyl]-4H-benzo[1,4]oxazin-3-one (2.52 g, 11.4 mmol), triphenylphosphine (6.12 g, 23.3 mmol), imidazole (1.98 g, 29.1 mmol), and iodine (8.88 g, 35.0 mmol) in CHCl3 (30 mL) and stirred at rt for 20 h. The reaction mixture was washed with saturated sodium thiosulfate, dried over Na2SO4, filtered, and concentrated. The product was purified by flash column chromatography (SiO2; n-heptane/EtOAc 3:1) to give the title compound (3.02 g, 80%). 1H NMR (CDCl3) δ 7.07-7.00 (m, 4H), 4.65-4.55 (m, 2H), 3.94 (dd, J=1.7 Hz, J=6.7 Hz, CH2), 3.23-3.14 (m, 2H), 2.18-2.07 (m, 1H), 1.05 (d, J=6.1 Hz, CH3).
Reaction SMILES: [H-].[Na+].Br[CH2:4][C:5](=[O:11])[CH2:6][C:7]([O:9][CH3:10])=[O:8].[Na].[CH2:13]([OH:22])[CH:14]=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl>C(COC)OC>[CH2:13]([O:22][CH2:4][C:5](=[O:11])[CH2:6][C:7]([O:9][CH3:10])=[O:8])/[CH:14]=[CH:15]/[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)CC(=O)CBr
Reactant: OCC=Cc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: COC(=O)CC(=O)COC/C=C/c1ccccc1
Temperature: -30 °C
Reaction time: 1 h
Yield: 24.3 %

Procedure:
4 Grams of 60% sodium hydride was suspended in 150 ml of anhydrous dimethoxyethane and the suspension was cooled to -30° C. Then, 19.4 g of methyl 4-bromoacetoacetate was added dropwise to the suspension and stirred for 1 hour. Further, at the same temperature, an anhydrous dimethoxyethane solution of sodium cinnamy alcoholate prepared from 13.4 g of cinnamyl alcohol, 4 g of 60% of sodium hydride and 75 ml of dimethoxyethane was added dropwise thereto, and the reaction mixture was refluxed for 15 hours. After the reaction mixture was cooled to a room temperature, the reaction mixture was poured into 1N-hydrochloric acid being ice-cooled, and the whole mixture was extracted with ether. The ether extract was washed with water and dried with anhydrous sodium sulfate, and the solvent was removed by evaporation. The residue was purified by means of a silica gel column chromatography (eluent: methanol:dichloromethane=1:20) to yield 6 g of methyl 4(E)-cinnamyloxyacetoacetate Refractive index: nD20 1.5402
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].[F:15][C:16]1[CH:17]=[C:18]([N:23]2[CH2:27][CH2:26][CH:25]([C:28](O)=[O:29])[C:24]2=[O:31])[CH:19]=[CH:20][C:21]=1[F:22].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:28]([CH:25]1[CH2:26][CH2:27][N:23]([C:18]2[CH:19]=[CH:20][C:21]([F:22])=[C:16]([F:15])[CH:17]=2)[C:24]1=[O:31])=[O:29]
Reactant: O=C(O)C1CCN(c2ccc(F)c(F)c2)C1=O
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)C1CCN(c2ccc(F)c(F)c2)C1=O
Yield: 25.2 %

Procedure:
This compound was prepared according to method A with 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.100 g; 0.424 mmol), 1-(3,4-difluorophenyl)-2-oxopyrrolidine-3-carboxylic acid (0.108 g; 0.445 mmol), HATU (0.166 g; 0.437 mmol) and N,N-diisopropylethylamine (0.186 mL; 1.06 mmol) in DMF (5 mL). The crude material was purified by flash chromatography on silica gel (eluent: 2 to 20% of ethyl acetate in dichloromethane) to give 0.0446 g (25%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-1-(3,4-difluorophenyl)-2-oxopyrrolidine-3-carboxamide as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][C:3]=1[F:12].[Cl:13][C:14]1[C:15]([F:22])=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH:17]=O.N1CCCCC1>CO>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[CH:17]/[C:16]3[CH:19]=[CH:20][CH:21]=[C:14]([Cl:13])[C:15]=3[F:22])/[C:7](=[O:11])[NH:8]2)=[CH:4][C:3]=1[F:12]
Reactant: O=Cc1cccc(Cl)c1F
Reactant: O=C1Cc2cc(F)c(Cl)cc2N1
Solvent: C1CCNCC1
Solvent: CO
Product: O=C1Nc2cc(Cl)c(F)cc2/C1=C/c1cccc(Cl)c1F
Temperature: 50 °C
Yield: 87 %

Procedure:
To the mixture of 6-chloro-5-fluoroindolin-2-one (Natrochem) (2.88 g, 15.5 mmol) and 3-chloro-2-fluorobenzaldehyde (3.69 g, 23.3 mmol) (Aldrich) in methanol (140 mL) was added piperidine (3.96 g, 46.6 mmol) (Aldrich) dropwise. The mixture was then heated at 50° C. for 3 h. After cooled to 4° C., the mixture was filtered and resulting precipitate was collected, dried to give E/Z-6-chloro-3-(3-chloro-2-fluoro-benzylidene)-5-fluoro-1,3-dihydro-indol-2-one as a yellow solid (Yield 4.4 g, 87%).
Reaction SMILES: [C-:1]#[N:2].[Na+].Br[CH2:5][C@H:6]([OH:13])[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].C(OCC)(=O)C>O.C(O)C>[C:1]([CH2:5][C@@H:6]([OH:13])[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])#[N:2]
Reactant: [C-]#N
Reactant: CCOC(=O)C[C@@H](O)CBr
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: CCOC(=O)C[C@H](O)CC#N
Temperature: 25 °C
Reaction time: 16 h
Yield: 59.8 %

Procedure:
To a 50 gallon reactor containing a solution of 2.2 kg (44 mol) of sodium cyanide dissolved in 40 L of demineralized water was added 7 kg (33 mol) of (S)-4-bromo-3-hydroxybutyric acid, ethyl ester (Example 3) dissolved in 8 L of ethanol. The reaction mixture was stirred for 16 hours at room temperature. Ethyl acetate (65 L) was added, the mixture agitated, and the layers were allowed to separate. The lower aqueous layer was transferred to a 50 gallon vessel containing 2.5 kg of sodium chloride and 65 L of ethyl acetate, the mixture was agitated and the layers allowed to separate, and the lower aqueous layer was cut off. The organic layers were combined and concentrated in vacuo. The residue was distilled to afford 3.1 kg of the title compound; bp 110-125° C. 0.5 mm Hg; optical rotation [α]D25 =33.1° (C=1.08, chloroform);
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1I)[OH:4].[F:14][C:15]([F:22])([F:21])[C:16]1[CH:20]=[CH:19][NH:18][N:17]=1.C([O-])([O-])=O.[K+].[K+].CN[C@@H]1CCCC[C@H]1NC>C(OCC)(=O)C.[Cu]I.C1(C)C=CC=CC=1>[F:1][C:2]([F:13])([F:12])[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:18]1[CH:19]=[CH:20][C:16]([C:15]([F:22])([F:21])[F:14])=[N:17]1)[OH:4]
Reactant: FC(F)(F)c1cc[nH]n1
Reactant: OC(c1ccccc1I)C(F)(F)F
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: OC(c1ccccc1-n1ccc(C(F)(F)F)n1)C(F)(F)F
Temperature: 130 °C
Yield: 45.1 %

Procedure:
2,2,2-Trifluoro-1-(2-iodo-phenyl)-ethanol (0.331 g, 1.1 mmol), 3-trifluoromethyl pyrazole (0.136 g, 1.0 mmol), CuI (0.019 g, 0.1 mmol), K2CO3 (0.290 g, 2.1 mmol), (1R,2R)—N,N′-dimethyl-cyclohexane-1,2-diamine (0.028 g, 0.2 mmol) and toluene (10 ml) were combined in a 20 ml pressure tube. The mixture was heated at 130° C. (oil bath temperature) for 12 h. The reaction mixture was diluted with ethyl acetate, and washed with H2O (2×20 ml), brine, and dried by sodium sulfate. Removal of solvent gave crude product which was purified by ISCO column chromatography using 5-10% ethyl acetate in hexane as solvent to give 140 mg of 2,2,2-trifluoro-1-[2-(3-trifluoro methyl-pyrazol-1-yl)-phenyl]-ethanol.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19]C)[CH:14]=3)[CH:9]=[N:10]2)=[CH:5][CH:4]=1.[Cl-].[Cl-].[Cl-].[Al+3]>>[OH:19][C:15]1[CH:14]=[C:13]([C:8]2[CH:9]=[N:10][C:11]3[C:6]([CH:7]=2)=[CH:5][CH:4]=[C:3]([OH:2])[CH:12]=3)[CH:18]=[CH:17][CH:16]=1
Reactant: COc1cccc(-c2cnc3cc(OC)ccc3c2)c1
Agent: [Al+3]
Agent: [Cl-]
Product: Oc1cccc(-c2cnc3cc(O)ccc3c2)c1
Yield: 76 %

Procedure:
The compound is prepared by reaction of 7-methoxy-3-(3-methoxyphenyl)-quinoline (108 mg, 0.40 mmol, 1 eq) with aluminum trichloride (433 mg, 3.26 mmol, 8 eq) according to method F. Purification by column chromatography with dichloromethane/methanol 95/5 as the eluent yields the desired product in a yield of 76%, 73 mg.