Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[C:3]([NH2:6])([CH3:5])[CH3:4].Cl[C:10]([O:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1)=[O:11].C(N(C(C)C)CC)(C)C.C(=O)([O-])O.[Na+]>ClCCl>[F:1][C:2]([F:8])([F:7])[C:3]([NH:6][C:10](=[O:11])[O:12][C:13]1[CH:14]=[CH:15][C:16]([N+:19]([O-:21])=[O:20])=[CH:17][CH:18]=1)([CH3:5])[CH3:4]
Reactant: CC(C)(N)C(F)(F)F
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(NC(=O)Oc1ccc([N+](=O)[O-])cc1)C(F)(F)F
Temperature: -15 °C
Reaction time: 2 h
Yield: 26.1 %

Procedure:
To a solution of 0.35 g (2.75 mmol) of 1,1,1-trifluoro-2-methylpropan-2-ylamine (CAS 812-18-0) in 20 ml of dichloromethane, cooled to −15° C., is added dropwise 1.00 g (4.96 mmol) of 4-nitrophenyl chloroformate (CAS 7693-46-1) dissolved in 15 ml of dichloromethane, while maintaining the temperature at −15° C. 0.48 ml (2.75 mmol) of diisopropylethylamine in 10 ml of dichloromethane is then added, still at −15° C. Stirring is continued at −15° C. for 2 hours, and the temperature of the mixture is then allowed to return to 0° C. over 1 hour. 20 ml of saturated aqueous sodium hydrogen carbonate solution are then added. The organic phase is separated out by settling and dried over sodium sulfate, and the solvent is partially evaporated off under reduced pressure to a volume of about 8 ml. This solution is chromatographed on a column of 40 g of silica gel, eluting with a mixture of 20% cyclohexane in dichloromethane, to give 0.21 g of 4-nitrophenyl 1,1,1-trifluoro-2-methylpropan-2-ylcarbamate in the form of a white solid.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([CH2:14][O:15][CH3:16])[O:7][C@H:6]1[N:17]1[CH:25]=[N:24][C:23]2[C:18]1=[N:19][C:20]([Cl:27])=[N:21][C:22]=2Cl)(=[O:3])[CH3:2].[NH2:28][N:29]1[CH2:33][CH2:32][CH2:31][C@H:30]1COC.C(N(CC)CC)C.[O:44]1CCO[CH2:46][CH2:45]1>ClCCl>[C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([CH2:14][O:15][CH3:16])[O:7][C@@H:6]1[N:17]1[C:18]2[N:19]=[C:20]([Cl:27])[N:21]=[C:22]([NH:28][N:29]3[CH2:33][CH2:32][CH2:31][CH:30]3[O:44][CH2:45][CH3:46])[C:23]=2[N:24]=[CH:25]1)(=[O:3])[CH3:2]
Reactant: C1COCCO1
Reactant: COC[C@H]1O[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: COC[C@@H]1CCCN1N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC1CCCN1Nc1nc(Cl)nc2c1ncn2[C@H]1O[C@H](COC)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Reaction time: 20 h
Yield: 18 %

Procedure:
9-(2',3'-Di-O-acetyl-5'-O-methyl-β-D-ribofuranosyl)-2,6-dichloro-9H-purine (1.3 g, 3.1 mmol), (S)-N-amino-2-(methoxymethyl)pyrrolidine (0.81 g, 6.2 mmol) and triethylamine (0.63 g, 6.2 mmol) were dissolved in dioxan. After stirring for 20 h the reaction mixture was diluted with dichloromethane (150 ml) and washed with water (2×75 ml). The organic phase was dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by flash chromatography eluting with a mixture of dichloromethane and 10% ammonia in ethanol (97:3) to afford (S)-2',3'-di-O-acetyl-2-chloro-5'-O-methyl-N-[2-(methylmethoxy)-1-pyrrolidinyl]adenosine (0.28 g, 18%) as a foam. 1H-NMR (400 MHz, CDCl3) δ1.70-2.10 (4H, m, pyrrolidine C--H), 2.05 (3H, s, --OCOCH3), 2.18 (3H, S, --OCOCH3), 2.85 (1H, m, pyrrolidine C--H), 3.10 (1H, br, pyrrolidine C--H), 3.22 (3H, s, --OCH3), 3.35-3.70 (8H, m, H-5'a and H-5'b, --OCH3, pyrrolidine, --CH2 --), 4.32 (1H, s, H-4'), 5.55 (1H, d, H-3'), 5.75 (1H, t, H-3'), 6.32 (1H, d, H-1'), 8.17 (1H, s, H-8). HPLC retention time 15.57 min. (gradient elution over 25 min.; 20-80% acetonitrile/0.1% TFA in water).
Reaction SMILES: C(OC(=O)[NH:5][CH2:6][C@@H:7]1[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([O:24][CH3:25])[N:22]=3)[N:17]=[CH:16][CH:15]=2)[CH2:8]1)C.C(=O)([O-])[O-].[K+].[K+]>CO.O>[CH3:25][O:24][C:21]1[N:22]=[C:23]2[C:18](=[CH:19][CH:20]=1)[N:17]=[CH:16][CH:15]=[C:14]2[CH2:13][CH2:12][N:9]1[CH2:10][CH2:11][C@@H:7]([CH2:6][NH2:5])[CH2:8]1
Reactant: CCOC(=O)NC[C@@H]1CCN(CCc2ccnc3ccc(OC)nc23)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: COc1ccc2nccc(CCN3CC[C@@H](CN)C3)c2n1
Reaction time: 18 h
Yield: 98.6 %

Procedure:
To a stirred solution of ethyl[((3S)-1-{2-[6-(methyloxy)-1,5-naphthyridin-4-yl]ethyl}-3-pyrrolidinyl)methyl]carbamate (0.80 g, 2.09 mmole) in MeOH (30 mL) and H2O (15 mL) at RT was added potassium carbonate (1.44 g, 10.5 mmole). After 18 h, the reaction contents were concentrated under reduced pressure and filtered through celite (EtOH) to give the title compound (0.59 g, 99%) as a light brown oil: LC-MS (ES) m/e 289 (M+H)+.
Reaction SMILES: [CH:1](O)=[O:2].C(OC(=O)C)(=O)C.[NH:11]1[C:19]2[C:14](=[C:15]([N:20]3[CH2:25][CH2:24][N:23]([C:26](=[O:36])[C@H:27]([NH2:35])[CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=4)[CH2:22][CH2:21]3)[CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12]1.N1(C2C=CC=C3C=2C=CN3)CCNCC1.C(OC(N[C@H](CC1C=CC=CN=1)C(O)=O)=O)(C)(C)C>C1COCC1.C(OCC)(=O)C>[NH:11]1[C:19]2[C:14](=[C:15]([N:20]3[CH2:25][CH2:24][N:23]([C:26](=[O:36])[C@H:27]([NH:35][CH:1]=[O:2])[CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=4)[CH2:22][CH2:21]3)[CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12]1
Reactant: O=CO
Reactant: N[C@H](Cc1ccccn1)C(=O)N1CCN(c2cccc3[nH]ccc23)CC1
Agent: CC(C)(C)OC(=O)N[C@H](Cc1ccccn1)C(=O)O
Agent: c1cc(N2CCNCC2)c2cc[nH]c2c1
Solvent: CCOC(C)=O
Solvent: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: O=CN[C@H](Cc1ccccn1)C(=O)N1CCN(c2cccc3[nH]ccc23)CC1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
A mixture of formic acid (0.9 mL; 24 mmol) and acetic anhydride (1.8 mL; 19.5 mmol) was stirred at 60° C. for 4 hours, then cooled to ambient temperature. The resulting mixed anhydride was added to a −10° C. solution of (1R)-2-[4-(1H-indol-4-yl)piperazin-1-yl]-2-oxo-1-(pyridin-2-ylmethyl)ethylamine (prepared in two steps from 4-piperazin-1-yl-1H-indole and (2R)-2-[(tert-butoxycarbonyl)amino]-3-pyridin-2-ylpropanoic acid according to the procedures outlined in examples 1 and 2) (1.07 g.; 3.0 mmol) in THF (30 mL). The mixture was allowed to warm to ambient temperature over 3 hours, diluted with ethyl acetate, and washed with saturated aqueous Na2CO3. The organic layer was dried over MgSO4, filtered, and the solvent removed in vacuo. The crude residue was purified by flash chromatography to afford the title compound as a beige solid foam (720 mg.; 64%). MS EI M+.@ m/z 377; 1H NMR, 400 MHz, DMSO-d6.
Reaction SMILES: [O:1]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([NH2:19])=O)=[C:11]([C:20](=[O:34])[NH:21][CH:22]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[CH2:23][CH:24]([CH3:26])[CH3:25])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.O>O1CCOCC1>[CH3:25][CH:24]([CH3:26])[CH2:23][CH:22]([NH:21][C:20](=[O:34])[C:11]1[CH:10]=[C:9]([CH2:8][O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:14]=[CH:13][C:12]=1[CH2:15][CH2:16][C:17]#[N:19])[C:27]1[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=1
Reactant: CC(C)CC(NC(=O)c1cc(COc2ccccc2)ccc1CCC(N)=O)c1ccc(F)cc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: O
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: CC(C)CC(NC(=O)c1cc(COc2ccccc2)ccc1CCC#N)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 82.2 %

Procedure:
To a suspension of the compound prepared in Example 15 (119 mg) in dioxane (2 ml) were added pyridine (0.1 ml) and trifluoromethanesulfonic acid anhydride (54 μl) at 0° C. under an atmosphere of argon. The mixture was stirred at room temperature for 10 minutes. To the reaction mixture was added water and the mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride subsequently, dried over anhydrous magnesium sulfate and concentrated. The residue was washed with n-hexane:ethyl acetate to give the title compound (94 mg) having the following physical data.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.Br[CH2:16][CH2:17][O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C.C(OCC)(=O)C>[Si:19]([O:18][CH2:17][CH2:16][N:12]1[CH:13]=[C:9]([B:4]2[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]2)[CH:10]=[N:11]1)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC1(C)OB(c2cnn(CCO[Si](C)(C)C(C)(C)C)c2)OC1(C)C

Procedure:
A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.05 g, 0.2 mmol), (2-bromoethoxy)(tert-butyl)dimethylsilane (61 uL, 0.28 mmol, Aldrich, Cat. No. 428426), and cesium carbonate (250 mg, 0.77 mmol) in acetonitrile (1 mL) was stirred at 90° C. overnight. After cooling it was diluted with ethyl acetate. Then the organic solution was washed with water, brine; dried over Na2SO4. After filtration the filtrate was concentrated to yield 74 mg of product which was directly used in the next step reaction without further purification.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]#[N:11])=[CH:2]1.[CH2:12]([O:14][C:15](=[O:23])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18](I)[CH:17]=1)[CH3:13].C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CS(C)=O.[Cu](I)I>[CH2:12]([O:14][C:15](=[O:23])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]([C:10]#[N:11])=[CH:2]2)[CH:17]=1)[CH3:13]
Reactant: CCOC(=O)c1cccc(I)c1
Reactant: N#Cc1c[nH]c2ccccc12
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cccc(-n2cc(C#N)c3ccccc32)c1
Temperature: 75 °C
Reaction time: 72 h
Yield: 66.5 %

Procedure:
To a solution of 1H-indole-3-carbonitrile (0.28 g) in dimethyl sulfoxide (3 mL) were added 3-iodobenzoic acid ethyl ester (0.61 g), cesium carbonate (0.65 g), copper iodide (0.038 g) and N,N-dimethyl grycine (0.041 g), this mixture was stirred at 75° C. for 3 days. To this reaction mixture was added ethyl acetate, the insoluble material was removed by filtration and this filtrate was concentrated under reduced pressure. To this residue was added water, the precipitated solid was collected by filtration, and washed with water and n-hexane, and dried under reduced pressure at 40° C. to give the title compound (0.38 g).
Reaction SMILES: CN([CH:4]=[O:5])C.[CH2:6]([N:13](/C=C/C)C(=O)C)[C:7]1[CH:12]=CC=[CH:9][CH:8]=1.[C:20]([Cl:23])(Cl)=O>>[Cl:23][C:20]1[C:9]([CH:4]=[O:5])=[CH:8][C:7]([CH3:12])=[CH:6][N:13]=1
Reactant: O=C(Cl)Cl
Reactant: C/C=C/N(Cc1ccccc1)C(C)=O
Reactant: CN(C)C=O
Product: Cc1cnc(Cl)c(C=O)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
DMF (2.86 mL, 37.0 mmol) was added slowly over 2 minutes to an ice-cold solution of N-benzyl-N—((E)-propenyl)-acetamide (1.0 g, 5.3 mmol) and phosgene (20% in toluene; 18.3 mL, 37.0 mmol). After stirring for 30 minutes at 0° C., the ice bath was removed, and the reaction was stirred at room temperature for 2 hours, and then heated to 75° C. for 4.5 hours. The mixture was poured over ice and extracted with CH2Cl2. The organic layer was dried over MgSO4, filtered, and concentrated, and the residue was purified by silica gel chromatography (0-50% EtOAc in hexanes) to give the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[CH:4]=1)#[CH:2].[Br:10][C:11]1[CH:12]=[N:13][CH:14]=[C:15](Br)[CH:16]=1>C(N(CC)CC)C.C(OCC)(=O)C.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Br:10][C:11]1[CH:12]=[N:13][CH:14]=[C:15]([C:2]#[C:1][C:3]2[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[CH:4]=2)[CH:16]=1
Reactant: C#Cc1cccc(F)c1
Reactant: Brc1cncc(Br)c1
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Fc1cccc(C#Cc2cncc(Br)c2)c1
Temperature: 70 °C
Yield: 27.5 %

Procedure:
Add 1-ethynyl-3-fluorobenzene (250 mg, 2.11 mmol) to a mixture of 3,5-dibromopyridine (500 mg, 2.11 mmol) in triethylamine (4 mL) containing bis(triphenylphosphine)palladium (II) dichloride (28 mg, 0.04 mmol) and copper (I) iodide (15 mg, 0.08 mmol) and heat at 70° C. for 2 h. Cool to room temperature, dilute with ethyl acetate and an aqueous solution of ammonium chloride and separate the resulting layers. Wash the organic layer with an aqueous saturated solution of sodium chloride, dry (magnesium sulfate), filter and concentrate. Purify by silica gel chromatography, eluting with 0.5% ethanol in 50:50 dichloromethane:hexanes to give the title compound (160 mg, 28%).
Reaction SMILES: CN.[OH2:3].Cl.Cl[C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12](Cl)=[O:13])[CH:7]=1>C1(C)C=CC=CC=1>[N:9]1[CH:10]=[CH:11][CH:6]=[CH:7][C:8]=1[C:12]([OH:13])=[O:3]
Reactant: O
Reactant: O=C(Cl)c1cc(Cl)ccn1
Agent: CN
Agent: Cl
Solvent: Cc1ccccc1
Product: O=C(O)c1ccccn1
Temperature: -5 °C

Procedure:
A reaction vessel is laden with methylamine as a 40% aqueous solution (117 kg, 1507 mol of methylamine). Water (97.5 kg) is added and the solution is cooled to −5° C. A solution of the crude 4-chloropyridine-2-carbonyl chloride hydrochloride (approx. 330 kg, including toluene, obtained from 60 kg of 2-picolinic acid by the process detailed in stage 1/method 1a) in toluene is added to such a degree that the temperature of the reaction mixture does not exceed 30° C. After stirring further at 20° C. for 1 h, the insoluble constituents are filtered out of the reaction mixture. After the phases have been separated, the organic phase is washed with water (90 kg). For better phase separation, 5 kg of sodium chloride are added. The majority of the toluene is distilled out of the organic phase under reduced pressure (final vacuum 40 mbar at jacket temperature 95° C.). The crude 4-chloro-N-methylpyridine-2-carboxamide is thus obtained as an orange- to dark brown-colored oil and is used in the next stage without further purification.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:9]([CH2:11]Br)=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[NH2:13][C:14]([NH2:16])=[S:15]>C(O)C>[OH:1][N:2]=[C:3]([C:9]1[N:13]=[C:14]([NH2:16])[S:15][CH:11]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: NC(N)=S
Reactant: CCOC(=O)C(=NO)C(=O)CBr
Solvent: CCO
Product: CCOC(=O)C(=NO)c1csc(N)n1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A mixture of ethyl 2-hydroxyimino-4-bromoacetoacetate (a mixture of syn and anti isomers) (2.4 g) and thiourea (0.76 g) in ethanol (15 ml) was stirred for 1 hour at 60° C. Ethanol was distilled off under reduced pressure and water was added to the residue. The resultant mixture was adjusted to pH 1.0 and washed with ethyl acetate. The aqueous layer was adjusted to pH 4.5 with triethylamine and extracted with ethyl acetate. The extract was washed with water and a saturated sodium chloride aqueous solution and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was subjected to column chromatography on silica gel using a mixture of ethyl acetate and benzene (1:3) as developing solvent. The eluates containing syn isomer were collected and concentrated to give ethyl 2-hydroxyimino-2-(2-amino-1,3-thiazol-4-yl)acetate (syn isomer) (0.3 g).
Reaction SMILES: Cl[C:2]1[C:10](C)=[C:9](Cl)[C:8]([N+:13]([O-])=O)=[CH:7][C:3]=1C(O)=O.[O-]S(S([O-])=O)=O.[Na+].[Na+].Cl.[C:25](=[O:28])([O-])[O-:26].[Na+].[Na+]>COCCO.O>[CH:3]1[C:2]([C:25]([OH:26])=[O:28])=[CH:10][CH:9]=[C:8]([NH2:13])[CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1c(Cl)c(C(=O)O)cc([N+](=O)[O-])c1Cl
Agent: Cl
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: COCCO
Solvent: O
Product: Nc1ccc(C(=O)O)cc1
Temperature: 25 °C

Procedure:
55 g of 2,4-dichloro-3-methyl-5-nitrobenzoic acid and 141.6 g of Na2S2O4 are boiled in a mixture of 440 ml of glycol monomethyl ether and 440 ml of water for 3 hours. 620 ml of 1/2-concentrated HCl are added to the still warm solution and the mixture is then boiled up once more. After cooling to room temperature, the mixture is poured into 1.5 l of water and brought to pH 5 with sodium carbonate. 24.6 g of aminobenzoic acid are obtained. Melting point: 202°-3°.
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]([C:20]3[S:21][CH:22]=[CH:23][N:24]=3)=[O:19])[CH2:14][CH2:13]2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:8]1[CH2:9][CH:10]([N:12]2[CH2:13][CH2:14][N:15]([C:18]([C:20]3[S:21][CH:22]=[CH:23][N:24]=3)=[O:19])[CH2:16][CH2:17]2)[CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CC(N2CCN(C(=O)c3nccs3)CC2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1nccs1)N1CCN(C2CNC2)CC1
Reaction time: 3.5 h

Procedure:
To a solution of compound 7c in CH2Cl2 (100 mL) was added TFA (30 mL). The reaction was stirred for 3.5 h and the solvent was evaporated in vacuo. The residue was purified by reverse phase preparative HPLC to give compound 5e (5.15 g). MS m/z (M+H+) 253.1.
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12][C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)=[C:8]([N+:20]([O-])=O)[CH:7]=1.[NH4+].[Cl-]>[Fe]>[NH2:20][C:8]1[CH:7]=[C:6]([O:5][CH2:4][C:3]2[CH:23]=[C:24]([F:27])[CH:25]=[CH:26][C:2]=2[F:1])[CH:11]=[CH:10][C:9]=1[S:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1
Reactant: O=[N+]([O-])c1cc(OCc2cc(F)ccc2F)ccc1Sc1ccc(O)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Product: Nc1cc(OCc2cc(F)ccc2F)ccc1Sc1ccc(O)cc1
Yield: 86.1 %

Procedure:
The product from Example 86c (1.70 g, 4.2 mmol) was reacted with Fe and NH4Cl as described in Example 10E to give the title compound (1.3 g, 84%).
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[C:11]([O:15][C:16]([NH:18][C@H:19]1[CH2:23][C@@H:22]([C:24]([O:26][CH3:27])=[O:25])[CH:21]=[CH:20]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].[C:28]([Si:32]([O:35][CH2:36][CH2:37]I)([CH3:34])[CH3:33])([CH3:31])([CH3:30])[CH3:29].Cl>C1COCC1.O>[C:11]([O:15][C:16]([NH:18][C@H:19]1[CH2:23][C@@:22]([CH2:37][CH2:36][O:35][Si:32]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:34])[CH3:33])([C:24]([O:26][CH3:27])=[O:25])[CH:21]=[CH:20]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: COC(=O)[C@H]1C=C[C@@H](NC(=O)OC(C)(C)C)C1
Reactant: CC(C)(C)[Si](C)(C)OCCI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)[C@@]1(CCO[Si](C)(C)C(C)(C)C)C=C[C@@H](NC(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of LiHMDS in THF (72.9 mL of a 1 M solution, 72.9 mmol, 2.2 eq) at −78° C. under Ar was added a solution of (1R,4S)-methyl 4-((t-butoxycarbonyl)amino)cyclopent-2-enecarboxylate (prepared according to the procedure of US 20050101628 A1 (see page 31, column 1, Procedure B, step B)), 8.00 g, 33.2 mmol, 1 eq) in THF (40 mL) dropwise over 1 hr. After stirring for 30 min, a solution of t-butyl(2-iodoethoxy)dimethylsilane (13.29 g, 46.4 mmol, 1.4 eq) in THF (20 mL) was added. The solution was kept at −78° C. for 15 min, then gradually warmed to 0° C. over 2 hrs, and kept at 0° C. for 1 hr. 1 N HCl and water were added, the solution extracted with DCM, the organics combined, dried over MgSO4, and concentrated. Purification by chromatography (400 g column) eluting with 5 to 20% EtOAc/heptane afforded the title compound of Step A. 1H NMR (CHLOROFORM-d) δ: 5.76-5.85 (m, 2H), 4.90 (d, J=9.0 Hz, 1H), 4.72-4.82 (m, 1H), 3.69 (s, 3H), 3.57-3.64 (m, 2H), 2.24 (dd, J=13.9, 8.0 Hz, 1H), 2.14 (dd, J=14.1, 3.5 Hz, 2H), 1.71-1.82 (m, 1H), 1.40-1.50 (m, 9H), 0.84-0.90 (m, 9H), 0.03 (s, 6H). ESI-MS (m/z): Calculated for C20H37NO5Si: 422.2 (M+23). found: 422.2.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[CH:7][C:8]2[C:12]([OH:13])=[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[S:10][C:9]=2[N:20]=1)([CH3:4])[CH3:3].[C:21]([O-])(=[O:23])[CH3:22].[Na+]>C(OC(=O)C)(=O)C>[C:21]([O:13][C:12]1[C:8]2[CH:7]=[CH:6][C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])=[N:20][C:9]=2[S:10][C:11]=1[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)(=[O:23])[CH3:22]
Reactant: CC(C)(C)c1ccc2c(O)c(-c3ccccc3)sc2n1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Oc1c(-c2ccccc2)sc2nc(C(C)(C)C)ccc12
Yield: 91.6 %

Procedure:
A solution of 1.42 g (5 mmol) of 6-(1,1-dimethylethyl)-3-hydroxy-2-phenyl-7-azabenzo[b]thiophene and 1.42 g sodium acetate in 20 mL of acetic anhydride was heated at reflux for 1 hour. The solution was concentrated and the residue was partitioned between ether and water. The ether layer was washed with sodium bicarbonate solution and brine, dried and concentrated. The residue was crystallized from ether-hexane to afford 1.49 g (91%) of fine white needles, m.p. 128°-9° C.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.Cl.[O:22]1[C:26]2([CH2:30][CH2:29][NH:28][CH2:27]2)[CH2:25][CH:24]([OH:31])[CH2:23]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([N:28]3[CH2:29][CH2:30][C:26]4([O:22][CH2:23][CH:24]([OH:31])[CH2:25]4)[CH2:27]3)=[O:14])[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Reactant: OC1COC2(CCNC2)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1)N1CCC2(CC(O)CO2)C1

Procedure:
In analogy to the procedure described in Example 47 b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b)) was reacted with 1-oxa-7-azaspiro[4.4]nonan-3-ol hydrochloride in the presence of TBTU and DIEA to obtain the title compound as yellow oil; MS (EI): m/e=410.5 [MH+].
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]2[N:3]1[CH:29]1[CH2:37][CH2:36][C:35]2[NH:34][N:33]=[CH:32][C:31]=2[CH2:30]1.[H-].[Na+].CN(C)C(=O)C.[CH3:46][C:47]1([CH3:50])[CH2:49][O:48]1>O.C(OCC)(=O)C>[OH:48][C:47]([CH3:50])([CH3:49])[CH2:46][N:34]1[C:35]2[CH2:36][CH2:37][CH:29]([N:3]3[C:2](=[O:1])[C:7]([CH2:8][C:9]4[CH:10]=[CH:11][C:12]([C:15]5[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=5)=[CH:13][CH:14]=4)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]4[N:26]=[CH:27][N:28]=[C:4]34)[CH2:30][C:31]=2[CH:32]=[N:33]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCc3[nH]ncc3C2)c2ncnn12
Reactant: CC1(C)CO1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCc3c(cnn3CC(C)(C)O)C2)c2ncnn12
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 8 %

Procedure:
A mixture of 4′-{[5-oxo-7-propyl-4-(4,5,6,7-tetrahydro-1H-indazol-5-yl)-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.36 g), sodium hydride (0.044 g) and N,N-dimethylacetamide (3 mL) was stirred at 0° C. for 5 min and then at room temperature for 20 min. 2,2-Dimethyloxirane (0.65 mL) was added, and the mixture was stirred at 120° C. for 1.5 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.035 g, 8%).