Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[CH:4][C:3]=1[C:7]#[N:8].C(N(CC)CC)C.Br[CH2:17][CH2:18][CH2:19]Br>O1CCOCC1>[N:5]1[N:6]2[CH2:17][CH2:18][CH2:19][NH:1][C:2]2=[C:3]([C:7]#[N:8])[CH:4]=1
Reactant: BrCCCBr
Reactant: N#Cc1cn[nH]c1N
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: N#Cc1cnn2c1NCCC2
Temperature: 95 °C
Reaction time: 120 h

Procedure:
To a solution of 5-aminopyrazole-4-carbonitrile (102 g) and triethylamine (316 ml) in 1,4-dioxane (2000 ml) was added 1,3-dibromopropane (115 ml), and the mixture was stirred at 95° C. for 5 days. The insoluble materials were removed by filtration, and the filtrate was concentrated in vacuo. To the residue was added 10% aqueous citric acid solution, and the mixture was extracted with chloroform. The extract was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was triturated with 2-propanol and dried in vacuo to give 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carbonitrile (8.0 g) as a solid.
Reaction SMILES: Cl.[NH2:2][OH:3].[Cl:4][C:5]1[CH:6]=[C:7]([C@@H:15]([CH2:26][CH:27]2[CH2:32][CH2:31][C:30](=O)[CH2:29][CH2:28]2)[C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][N:20]=2)=[O:17])[CH:8]=[CH:9][C:10]=1[S:11]([CH3:14])(=[O:13])=[O:12]>CO.N1C(C)=CC=CC=1C>[Cl:4][C:5]1[CH:6]=[C:7]([C@@H:15]([CH2:26][CH:27]2[CH2:32][CH2:31][C:30](=[N:2][OH:3])[CH2:29][CH2:28]2)[C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][N:20]=2)=[O:17])[CH:8]=[CH:9][C:10]=1[S:11]([CH3:14])(=[O:13])=[O:12]
Reactant: NO
Reactant: Cc1ccc(NC(=O)[C@H](CC2CCC(=O)CC2)c2ccc(S(C)(=O)=O)c(Cl)c2)nc1
Agent: Cl
Solvent: CO
Solvent: Cc1cccc(C)n1
Product: Cc1ccc(NC(=O)[C@H](CC2CCC(=NO)CC2)c2ccc(S(C)(=O)=O)c(Cl)c2)nc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of hydroxylamine hydrochloride (26.0 mg, 0.36 mmol) in methanol (0.7 mL) and 2,6-lutidine (0.7 mL) was treated with 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-N-(5-methyl-pyridin-2-yl)-3-(4-oxo-cyclohexyl)-propionamide (prepared as in Example 64, 105 mg, 0.23 mmol). The reaction mixture was stirred at 25° C. for 30 min and was then concentrated in vacuo to remove methanol. The resulting residue was suspended in ethyl acetate (10 mL), washed with water (1×5 mL), dried over magnesium sulfate, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 65/35 hexanes/ethyl acetate to 2/8 hexanes/ethyl acetate) afforded 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-(4-hydroxyimino-cyclohexyl)-N-(5-methyl-pyridin-2-yl)-propionamide was a white foam; [α]23589=−7.84° (c=0.37 chloroform); EI-HRMS m/e calcd for C22H26ClN3O4S (M+H)+ 464.1406, found 464.1409.
Reaction SMILES: [Mn]([O-])(=O)(=O)=O.[K+].[N+:7]([CH2:10][S:11]([C:13]1[C:18]2[O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:17]=2[CH:16]=[CH:15][CH:14]=1)=[O:12])([O-:9])=[O:8].S(S([O-])=O)([O-])(=O)=[O:27].[Na+].[Na+]>C(O)(=O)C.O>[N+:7]([CH2:10][S:11]([C:13]1[C:18]2[O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:17]=2[CH:16]=[CH:15][CH:14]=1)(=[O:27])=[O:12])([O-:9])=[O:8]
Reactant: O=S([O-])S(=O)(=O)[O-]
Reactant: O=[N+]([O-])CS(=O)c1cccc2c1oc1ccccc12
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])CS(=O)(=O)c1cccc2c1oc1ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 3% aqueous solution of potassium permanganate (83 ml, 16.2 mmol) was added to a stirred solution of 4-(nitromethylsulphinyl)dibenzofuran (3.72 g, 13.5 mmol) at 50° C. in acetic acid (100 ml). The reaction mixture was stirred for 1 hour at ambient temperature and then treated with a saturated aqueous solution of sodium metabisulphite until colourless. The reaction mixture was then diluted with water (200 ml). The solid material was removed by filtration, air dried and recrystallised from toluene/cyclohexane to give 4-(nitromethylsulphonyl)dibenzofuran as a white crystalline solid (2.95 g), m.p. 162°-165° C.; NMR (DMSOd6): 6.80 (s,2H) 7.48-8.79 (m,7H); m/e (electron impact): 291 (M+); microanalysis, found: C,53.6; H,3.0; N,4.7%; C13H9NO5S requires: C,53.6; H,3.1; N,4.8%.
Reaction SMILES: [ClH:1].Cl.[CH2:3]([N:10]([CH2:12][CH2:13][CH:14]1[O:19][CH2:18][CH2:17][N:16](CC2C=CC=CC=2)[CH2:15]1)C)C1C=CC=CC=1>O.C(O)C.[C].[Pd]>[ClH:1].[ClH:1].[CH3:3][NH:10][CH2:12][CH2:13][CH:14]1[O:19][CH2:18][CH2:17][NH:16][CH2:15]1
Reactant: CN(CCC1CN(Cc2ccccc2)CCO1)Cc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: O
Product: CNCCC1CNCCO1

Procedure:
The solvent is concentrated under reduced pressure and the residue is treated with 25% hydrochloric acid-ethanol in ethanol to give 2-[2-(N-benzyl-N-methylamino)ethyl]-4-benzylmorpholine dihydrochloride as white crystals, melting at 256°-258° C. with decomposition. The obtained hydrochloride compound (5.25 g) is subjected to catalytic reduction with 1 g of 10% palladium-carbon in 50 ml of water and 200 ml of ethanol. After absorbing the theoretical volume of the hydrogen, the catalyst is filtered off and the filtrate is concentrated under reduced pressure. The residue is treated with ethanol to give 2-(2-methylaminoethyl)morpholine dihydrochloride, melting at 179°-181° C. with decomposition.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.BrCC1[CH:50]=[C:49]([Cl:51])[CH:48]=[CH:47][C:46]=1[Cl:52]>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:50]=[C:49]([Cl:51])[CH:48]=[CH:47][C:46]=3[Cl:52])[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Reactant: Clc1ccc(Cl)c(CBr)c1
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nnn(Cc3cc(Cl)ccc3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 2-(bromomethyl)-1,4-dichlorobenzene and isolated as white solid (6.6 mg, 37%). MS (m/e): 441.4 (MH+).
Reaction SMILES: Cl.Cl.Cl.[CH3:4][C:5]1[C:9]([C:10]2[C:19]3[O:18][CH2:17][C@H:16]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=4)[N:15]4[C:26]([N:28]5[CH2:32][CH2:31][C@@H:30]([NH2:33])[CH2:29]5)=[N:27][C:13]([C:14]=34)=[CH:12][CH:11]=2)=[C:8]([CH3:34])[O:7][N:6]=1.C(N(CC)CC)C.Cl[C:43]([O:45][CH3:46])=[O:44]>C(Cl)Cl>[CH3:4][C:5]1[C:9]([C:10]2[C:19]3[O:18][CH2:17][C@H:16]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=4)[N:15]4[C:26]([N:28]5[CH2:32][CH2:31][C@@H:30]([NH:33][C:43](=[O:44])[O:45][CH3:46])[CH2:29]5)=[N:27][C:13]([C:14]=34)=[CH:12][CH:11]=2)=[C:8]([CH3:34])[O:7][N:6]=1
Reactant: Cc1noc(C)c1-c1ccc2nc(N3CC[C@@H](N)C3)n3c2c1OC[C@@H]3c1ccccn1
Reactant: COC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)N[C@@H]1CCN(c2nc3ccc(-c4c(C)noc4C)c4c3n2[C@@H](c2ccccn2)CO4)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.4 %

Procedure:
(3R)-1-[(4S)-7-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]pyrrolidin-3-amine trihydrochloride (35 mg, 0.068 mmol) was stirred in methylene chloride (1.0 mL) with triethylamine (47 μL, 0.34 mmol), followed by addition of methyl chloroformate (10 μL, 0.14 mmol). The mixture was stirred at room temperature for 30 min and concentrated. Purification by preparative LCMS using pH 10 buffer gave the title compound (24 mg, 75%). LCMS calc. for C25H27N6O4 (M+H)+: m/z=475.2. found: 475.3. 1H NMR (300 MHz, CD3OD) δ 8.58 (d, J=4.8 Hz, 1H), 7.69 (td, J=7.8, 1.8 Hz, 1H), 7.32 (dd, J=7.1, 5.3 Hz, 1H), 7.05 (d, J=8.1 Hz, 2H), 6.89 (d, J=8.1 Hz, 2H), 6.59 (d, J=7.9 Hz, 1H), 6.03 (s, 1H), 4.55 (dd, J=11.5, 2.8 Hz, 2H), 4.29-4.09 (m, 1H), 4.00-3.71 (m, 2H), 3.63-3.50 (m, 3H), 3.40 (dd, J=9.8, 4.6 Hz, 1H), 2.23 (s, 3H), 2.23-2.11 (m, 1H), 2.08 (s, 3H), 1.98-1.83 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:14])=[N:4][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:6]=1[CH3:7].Br[CH2:16][CH2:17][N:18]1[C:22](=[O:23])[C:21]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]2[C:19]1=[O:28].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:14][C:3]1[C:2]([NH:1][CH2:16][CH2:17][N:18]2[C:22](=[O:23])[C:21]3=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]3[C:19]2=[O:28])=[C:6]([CH3:7])[N:5]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:4]=1
Reactant: Cc1nn(-c2ccccc2)c(C)c1N
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1nn(-c2ccccc2)c(C)c1NCCN1C(=O)c2ccccc2C1=O

Procedure:
A mixture of 38.1 g. 4-amino-3,5-dimethyl-1-phenylpyrazole, 77.5 g. N-(2-bromoethyl)-phthalimide and 42 g. potassium carbonate in 600 ml. acetonitrile is boiled for 15 hours, with stirring. After cooling, insoluble material is filtered off with suction and the filtrate is evaporated. The residue is stirred with methylene chloride and suction filtered and the filtrate is purified on a silica gel column using, as elution agents, first methylene chloride and then methylene chloride-ethyl acetate (6:4 v/v). There are obtained 41 g. (56% of theory) of a brownish oil.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[NH:6]1[CH2:12][CH2:11][CH2:10][C@H:7]1[CH2:8][OH:9].C([O-])(=O)C.[Na+]>CC(C)=O.O>[Cl:1][CH2:2][C:3]([N:6]1[CH2:12][CH2:11][CH2:10][C@H:7]1[CH2:8][OH:9])=[O:4]
Reactant: OC[C@@H]1CCCN1
Reactant: O=C(Cl)CCl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: O=C(CCl)N1CCC[C@H]1CO
Reaction time: 2 h

Procedure:
A solution of chloroacetyl chloride, 27.7 g (0.247 mol), in 66.5 ml of acetone is added dropwise with stirring to a solution of 25 g (0.247 mol) of L-prolinol and 40.4 g (0.493 mol) of sodium acetate in a mixture of 400 ml of acetone and 200 ml of water at 0°-5° C. The mixture is stirred and allowed to reach room temperature over two hours, the solvent is evaporated in vacuo and the residue is suspended in 300 ml chloroform and washed with water, 2×300 ml. The chloroform layer is separated, dried over sodium sulfate, evaporated in vacuo and the residue is purified by chromatography using silica gel and eluting with dichloromethane-methanol (98:2) to give (S)-1-(chloroacetyl)-2-pyrrolidinemethanol, 34.1 g; [α]D25 -62.2° (c 1.00, methanol).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:26][CH2:25][C@@:24]2([CH3:27])[C@H:11]([CH2:12][CH2:13][C@@H:14]3[C@@H:23]2[CH2:22][CH2:21][C@@:19]2([CH3:20])[C@:15]3([OH:33])[CH2:16][CH2:17][C@@H:18]2[C:28]2[CH:32]=[CH:31][O:30][CH:29]=2)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:34]I.O>O1CCCC1>[Si:1]([O:8][C@H:9]1[CH2:26][CH2:25][C@@:24]2([CH3:27])[C@H:11]([CH2:12][CH2:13][C@@H:14]3[C@@H:23]2[CH2:22][CH2:21][C@@:19]2([CH3:20])[C@:15]3([O:33][CH3:34])[CH2:16][CH2:17][C@@H:18]2[C:28]2[CH:32]=[CH:31][O:30][CH:29]=2)[CH2:10]1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@@]2(C)[C@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](c4ccoc4)CC[C@]32O)C1
Reactant: CI
Solvent: C1CCOC1
Solvent: O
Product: CO[C@]12CC[C@H](c3ccoc3)[C@@]1(C)CC[C@H]1[C@H]2CC[C@@H]2C[C@@H](O[Si](C)(C)C(C)(C)C)CC[C@@]21C
Temperature: 70 °C

Procedure:
To a solution of 10 g of 17β-(3-furyl)-5β-androstane-3β,14β-diol (II-a: Ref. comp.) (Minato H. and Nagasaki T., J. Chem. Soc.(C), 1966, 377)in 80 ml of dimethylformamide, 18 g of imidazole and 20.0 g of t-butyldimethylsilyl chloride were added at 0° C. After 12 hrs the mixture was poured into water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and evaporated to dryness under reduced pressure and 15 g of crude 3β-tert-butyldimethylsilyloxy-17β-(3-furyl)-5β-androstan-14β-ol were obtained. A suspension of this protected alcohol and 1.3 g of KH in 75 ml of tetrahydrofuran was heated at 70° C. for an hr; then 2.7 g of methyl iodide were added. After 30' the mixture was poured into water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and evaporated to dryness under reduced pressure to give 12 g of 3β-tert-butyldimethylsilyloxy-14β-methoxy-17β-(3-furyl)-5β-androstane as a white amorphous solid.
Reaction SMILES: [C:1]([C@@H:3]1[CH2:8][C@H:7]2[C@H:5]([CH2:6]2)[N:4]1[C:9](=[O:33])[C@@H:10]([NH:22]C(=O)OCC1C=CC=CC=1)[C:11]12[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:19][C:13]([OH:21])([CH2:14]3)[CH2:12]1)[CH2:18]2)#[N:2]>C(#N)C.[Pd]>[CH2:8]1[C@@H:3]([C:1]#[N:2])[N:4]([C:9]([C@@H:10]([NH2:22])[C:11]23[CH2:12][C:13]4([OH:21])[CH2:19][CH:17]([CH2:16][CH:15]([CH2:14]4)[CH2:20]2)[CH2:18]3)=[O:33])[C@@H:5]2[C@H:7]1[CH2:6]2
Reactant: N#C[C@@H]1C[C@@H]2C[C@@H]2N1C(=O)[C@@H](NC(=O)OCc1ccccc1)C12CC3CC(CC(O)(C3)C1)C2
Agent: [Pd]
Solvent: CC#N
Product: N#C[C@@H]1C[C@@H]2C[C@@H]2N1C(=O)[C@@H](N)C12CC3CC(CC(O)(C3)C1)C2

Procedure:
To a solution of benzyl N-[(1S)-2-[(1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl]-1-(3-hydroxyadamantan-1-yl)-2-oxo-ethyl]carbamate (10 gm) (formula-IX) in acetonitrile, 5% Pd/C (50% wet, 1 gm) was added. Hydrogen gas was bubbled through the reaction mass for 4 hrs at 20-25° C. After the starting material was completely converted, the reaction mass was filtered and the filtrate evaporated to yield SAXAGLIPTIN free base of formula-I as a foamy solid. To the solid ethyl acetate (5 ml), 20 micro liters of water and n-hexane (20 ml) were added; the mixture stirred at 0-5° C. and filtered the white solid formed to yield 7.06 gm (95%) of SAXAGLIPTIN MONO HYDRATE. HPLC Purity: 99.7% (A) and the content of the impurity cyclic amidine: 0.07% (A), M.P: 105-108° C., H1NMR (300 MHz, Methanol-d4): 0.83-1.06 (m, 2H), 1.36-1.7 (m, 12H), 1.79-1.88 (ddd, 1H), 2.19 (m, 2H), 2.23 (dd, 1H), 2.46-2.56 (ddd, 1H), 3.49 (s, 1H), 3.72-3.77 (ddd, 1H), 4.96-5.01 (dd, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([OH:10])=[O:9])[CH:3]=1.[CH3:11][Si](C=[N+]=[N-])(C)C>C(OCC)(=O)C.CO>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([O:10][CH3:11])=[O:9])[CH:3]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)c1cc(Br)ccn1
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1cc(Br)ccn1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 72 %

Procedure:
To a solution of 4-bromopyridine-2-carboxylic acid (0.5 g, 2.5 mmol, Apollo Scientific) in a mixture of ethyl acetate (15 mL) and methanol (1.5 mL), was added dropwise a solution of trimethylsilyldiazomethane (3.7 mL, 2 M in diethyl ether, 7.4 mmol), at about 0° C. After the addition was complete the temperature was raised to rt and the mixture stirred for about another 1.5 h at rt. The resulting mixture was concentrated in vacuo and diethyl ether (25 mL) was added to the residue. The resulting mixture was filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, diethyl ether/hexanes 1:1) to give methyl 4-bromopyridine-2-carboxylate (0.39 g, 1.8 mmol, 73%) as a pale yellow solid: 1H-NMR (CDCl3, Bruker 400 MHz) δ 4.03 (3H, s), 7.67 (1H, dd, J=5.0, 1.6 Hz), 8.31 (1H, d, J=1.6 Hz), 8.57 (1H, d, J=5.0 Hz).
Reaction SMILES: [H-].[Na+].[CH3:3][CH2:4][O:5][C:6]([CH2:8]P(OCC)(OCC)=O)=[O:7].[CH:17](=O)/[CH:18]=[CH:19]/[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].O>O1CCCC1>[C:6]([O:5][CH2:4][CH3:3])(=[O:7])/[CH:8]=[CH:17]/[CH:18]=[CH:19]/[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCC/C=C/C=O
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCC/C=C/C=C/C(=O)OCC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (60% wt., 3.11 g) was suspended in dry tetrahydrofuran (200 ml) and cooled to 0° C. O,O-Diethyl ethoxycarbonylmethyl phosphonate (15.43 ml) was added dropwise. The reaction mixture was stirred at 0° C. for 30 min and cooled to −78° C. after which (E)-dec-2-enal (11.90 ml) was added dropwise. Stirring was continued at this temperature for 2 h, after which the mixture was warmed to room temperature. The reaction mixture was poured into water, and the aqueous phase was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over sodium sulfate, and the solvent was evaporated. The crude product was purified by column chromatography.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]([CH:13]([OH:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9]1)=O)(C)(C)C.I[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1OC>>[O:20]([CH:13]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[CH:10]1[CH2:11][CH2:12][NH:8][CH2:9]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(O)c2ccccc2)C1
Reactant: COc1ccccc1I
Product: c1ccc(OC(c2ccccc2)C2CCNC2)cc1

Procedure:
Following the procedure of Example 2, and, in Preparation 3, substituting the RS/SR mixture of enantiomers with the SS/RR mixture of enantiomers of 3-(hydroxyphenylmethyl)-pyrrolidine-1-carboxylic acid t-butyl ester (47.5 mg, 170 μmol), and substituting 2-iodoanisole with the appropriate aryl iodide, the SS/RR mixture of enantiomers (16-2) of the title compound was prepared (12.4 mg) as a TFA salt. MS m/z: [M+H]+ calcd for C17H19NO, 254.15. Found 254.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10](=O)[CH3:11])=[CH:4][CH:3]=1.[NH2:19]/[C:20](/[CH3:26])=[CH:21]\[C:22]([O:24][CH3:25])=[O:23].C(O)C>C(O)(=O)C>[CH3:26][C:20]1[NH:19][C:10]([CH3:11])=[C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[C:21]=1[C:22]([O:24][CH3:25])=[O:23]
Reactant: CC(=O)C(=Cc1ccc(F)cc1)c1ccccc1
Reactant: COC(=O)/C=C(/C)N
Solvent: CC(=O)O
Solvent: CCO
Product: COC(=O)C1=C(C)NC(C)=C(c2ccccc2)C1c1ccc(F)cc1
Yield: 111.1 %

Procedure:
24.0 g (0.1 mol) of 1-(4-fluorophenyl)-2-phenylbuten-3-one, 23 g (0.2 mol) of methyl 3-amino-crotonate and 6 ml (0.1 mol) of glacial acetic acid are heated under reflux overnight in 1 50 m of ethanol, heated under reflux for 18 h after addition of 11.5 g (0.1 mol) of methyl 3-aminocrotonate and 3ml of glacial acetic acid and heated under reflux for 18 h once more after repeated addition of 11.5 g (0.1 mol) of methyl 3-aminocrotonate and 3 ml of glacial acetic acid. The solvent is removed in vacuo, 80 ml of methanol are added to the residue, undissolved material is filtered off with suction, the methanolic solution is concentrated in vacuo and excess aminocrotonate is distilled off from the residue at 73° C.-90° C./18 mbar and subsequently at 60° C.-70° C. 0.2 mbar. 37.5 g of crude product are obtained as a brittle fused mass.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[CH:3]([OH:5])[CH3:4].[H-].[Li+].F[C:11]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=[CH:13][N:12]=1>C1COCC1>[N+:17]([C:16]1[C:11]([O:5][CH:3]([CH3:4])[C:2]([F:7])([F:6])[F:1])=[N:12][CH:13]=[CH:14][CH:15]=1)([O-:19])=[O:18]
Reactant: O=[N+]([O-])c1cccnc1F
Reactant: CC(O)C(F)(F)F
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(Oc1ncccc1[N+](=O)[O-])C(F)(F)F
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
1,1,1-Trifluoro-2-propanol (3.2 g) was dissolved in THF (4.0 ml) and cooled to 0° C. Then LiH MDS (1M in THF; 28.3 ml) was added dropwise. The reaction mixture was stirred at 0° C. for 20 minutes. A solution of 2-fluoro-3-nitro-pyridine (4.0 g) in THF (1 ml) was added and the mixture was stirred overnight. It was quenched by addition of saturated NH4Cl solution and extracted with dichloromethane. The organic layer was dried and concentrated in vacuo.
Reaction SMILES: C([O:3][CH2:4][CH2:5][O:6][NH:7][C:8]([C:10]1[N:18]([CH2:19][C:20]#[C:21][CH2:22][O:23]C2CCCCO2)[C:17]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[C:11]=1[NH:30][C:31]1[CH:36]=[CH:35][C:34]([I:37])=[CH:33][C:32]=1[F:38])=[O:9])=C.Cl.O1CCOCC1>CO>[OH:3][CH2:4][CH2:5][O:6][NH:7][C:8]([C:10]1[N:18]([CH2:19][C:20]#[C:21][CH2:22][OH:23])[C:17]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[C:11]=1[NH:30][C:31]1[CH:36]=[CH:35][C:34]([I:37])=[CH:33][C:32]=1[F:38])=[O:9]
Reactant: C=COCCONC(=O)c1c(Nc2ccc(I)cc2F)c2cnccc2n1CC#CCOC1CCCCO1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: O=C(NOCCO)c1c(Nc2ccc(I)cc2F)c2cnccc2n1CC#CCO
Temperature: 25 °C
Yield: 35.9 %

Procedure:
To a stirred solution of 3-(2-fluoro-4-iodo-phenylamino)-1-[4-(tetrahydro-pyran-2-yloxy)-but-2-ynyl]-1-H-pyrrolo[3,2-c]pyridine-2-carboxylic acid (2-vinyloxy-ethoxy)-amide (47.0 mg, 0.075 mmol) in anhydrous MeOH (3.0 mL) under N2 was added 4 M HCl in dioxane (0.10 mL, 0.40 mmol, 5.5 eq), and the reaction mixture was stirred at room temperature. After 3 h the solvent was removed in vacuo and the residue was redissolved in acetonitrile (2.0 mL) and loaded onto Phenomenex Strata-X cartridge (5 g). The cartridge was washed with water (10 mL) and methanol (15 ml). The desired product was then eluted using 2M ammonia in MeOH. Trituration from DCM-hexane afforded the title compound as a yellow solid (14.1 mg, 36.3%). 1H-NMR (400 MHz, DMSO-d6) δ ppm 11.66 (broad s, 1H), 8.58 (s, 1H), 8.36 (d, J=5.86 Hz, 1H), 7.70 (d, J=6.8 Hz, 1H), 7.63 (m, 1H), 7.55 (dd, J=11.03, 1.6 Hz, 1H), 7.26-7.17 (m, 1H), 6.23 (t, J=8.8 Hz, 1H), 5.35 (s, 2H), 5.18 (t, J=5.96 Hz, 1H), 4.80-4.74 (m, 1H), 4.02 (d, J=4.25 Hz, 2H), 3.85 (t, J=4.76 Hz, 2H), 3.60-3.48 (m, 2H); LC-MS (method D): [M+H]+=525.1, RT=1.59 min.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[S:19][C:20]([C:24]([O:26]CC)=[O:25])=[C:21]([CH3:23])[N:22]=3)=[CH:14][CH:13]=2)=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].[OH-].[Li+].CO>ClCCl>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[S:19][C:20]([C:24]([OH:26])=[O:25])=[C:21]([CH3:23])[N:22]=3)=[CH:14][CH:13]=2)=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCOC(=O)c1sc(-c2ccc(NC(=O)c3nc(Cl)c(CC)[nH]3)cc2)nc1C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: CCc1[nH]c(C(=O)Nc2ccc(-c3nc(C)c(C(=O)O)s3)cc2)nc1Cl
Yield: 76.8 %

Procedure:
The same operation as in Example (90g) was performed using ethyl 2-(4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}phenyl)-4-methyl-1,3-thiazole-5-carboxylate obtained in Example (94c) (96 mg, 0.23 mmol), 2 N lithium hydroxide (2 mL, 4 mmol), methanol (5 mL) and dichloromethane (3 mL). Purification by reverse phase chromatography (elution solvent: THF/water=0/1, 1/1, 4/1) gave 69 mg of the title compound as a light brown solid (77%).
Reaction SMILES: [I-].CC(OC([N:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[CH2:14][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=O)(C)C.[H-].[Na+].[I:36][C:37]1[CH:38]=[C:39]2[C:43](=[CH:44][CH:45]=1)[NH:42][C:41](=[O:46])[C:40]2=O.CC(C)=O>CN(C=O)C>[I:36][C:37]1[CH:38]=[C:39]2[C:43](=[CH:44][CH:45]=1)[NH:42][C:41](=[O:46])/[C:40]/2=[CH:14]\[C:10]1[NH:9][CH:13]=[CH:12][CH:11]=1
Reactant: CC(C)(C)OC(=O)n1cccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1Nc2ccc(I)cc2C1=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: O=C1Nc2ccc(I)cc2/C1=C/c1ccc[nH]1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a solution of [[1-[[(1,1-dimethylethyl)oxy]carbonyl]-1H-pyrrol-2-yl]methyl]triphenylphosphonium iodide (2.3 g, 4.0 mmol) (prepared according to the procedure of: V. H. Rawal et. al., J. Org. Chem. 1987, 52(1), 19-28) in 36 mL DMF at 0° C. under argon, was added slowly NaH (0.13 g, 5.4 mmol). The mixture was stirred at 0° C. for 45 min. The solution was then allowed to warm to room temperature and 5-iodoisatin (1.0 g, 3.66 mmol) was added. The solution was heated at reflux for 15 h, at which time acetone (1 mL) was added and the solvent mixture was evaporated. The residue was then purified via flash column chromatography (25% EtOAc/hex) to yield (Z)-1,3-dihydro-5-iodo-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 1.05 g, 83%).