Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]2[C:8]([O:30][CH3:31])=[N:9][N:10]([C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:4]=2[CH:3]=1.[CH3:32][O:33][CH2:34][C@@H:35]([NH:42][C:43]([NH2:45])=[O:44])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=C(OC)C=CC=2OC)=C(C(C)C)C=1)C.O1CCOCC1>[CH3:32][O:33][CH2:34][C@@H:35]([NH:42][C:43]([NH:45][C:2]1[N:7]=[CH:6][C:5]2[C:8]([O:30][CH3:31])=[N:9][N:10]([C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:4]=2[CH:3]=1)=[O:44])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: COC[C@@H](NC(N)=O)c1ccccc1
Reactant: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)ncc12
Agent: COc1ccc(OC)c(P(C2CCCCC2)C2CCCCC2)c1-c1c(C(C)C)cc(C(C)C)cc1C(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: COC[C@@H](NC(=O)Nc1cc2c(cn1)c(OC)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1)c1ccccc1
Temperature: 100 °C
Reaction time: 6 h

Procedure:
6-Chloro-3-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridine (Example 40, Step 1; 151 mg, 0.355 mmol), (S)-1-(2-methoxy-1-phenylethyl)urea (Intermediate 16B; 108 mg, 0.556 mmol), BrettPhos pre-catalyst (17.6 mg, 0.022 mmol), and cesium carbonate (337 mg, 1.034 mmol) were taken up in 1,4-dioxane (3.5 mL) in a 5 mL microwave vial. The vial was evacuated and back-filled with N2 (×3) and the reaction stirred at 100° C. for 6 h. Room temperature was attained, the reaction mixture was filtered through Celite, eluting with MeOH, and the filtrate was concentrated in vacuo. Purification of the residue by flash chromatography (6-50% EtOAc-hexanes) gave (S)-1-(2-methoxy-1-phenylethyl)-3-(3-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)urea. MS ESI calc'd. For C36H33N5O3 [M+1]+ 584. found 584.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[C:7]([O:27][CH3:28])=[C:8]([C:13]([CH2:16][S:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[OH:26])(=[O:19])=[O:18])=[CH:14][CH:15]=2)[C:9]([O:11][CH3:12])=[O:10])=[CH:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl.Br[CH2:37][CH2:38][N:39]([CH2:42][CH3:43])[CH2:40][CH3:41].O>CN(C=O)C.C(Cl)Cl>[CH2:38]([N:39]([CH2:42][CH3:43])[CH2:40][CH2:41][O:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[S:17]([CH2:16][C:13]1[C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([O:27][CH3:28])[C:6]([C:3]2[CH:4]=[CH:5][O:1][CH:2]=2)=[CH:15][CH:14]=1)(=[O:19])=[O:18])[CH3:37]
Reactant: COC(=O)c1c(CS(=O)(=O)c2ccccc2O)ccc(-c2ccoc2)c1OC
Reactant: CCN(CC)CCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: CCN(CC)CCOc1ccccc1S(=O)(=O)Cc1ccc(-c2ccoc2)c(OC)c1C(=O)OC
Yield: 100 %

Procedure:
A solution of methyl 3-(furan-3-yl)-6-(2-hydroxybenzenesulphonylmethyl)-2-methoxybenzoate (Intermediate 137, 0.081 g), cesium carbonate (0.144 g) and N-(2-bromoethyl)-N,N,-diethylamine hydrochloride (0.058 g) in DMF (5 ml) was stirred at room temperature. On completion of the reaction, water and DCM were added and the organic layer was separated, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica eluting with a mixture of methanol and DCM (1:19) to give methyl 6-[2-(2-diethylaminoethoxy)benzenesulphonylmethyl]-3-(furan-3-yl)-2-methoxybenzoate (0.101 g) as a colourless oil.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][CH:11]([CH2:14][OH:15])[CH2:12][OH:13])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:16](I)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33].O1CCCC1>CN(C)C=O.O>[CH2:3]([O:10][CH:11]([CH2:12][O:13][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH3:16])[CH2:14][OH:15])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: OCC(CO)OCc1ccccc1
Reactant: CCCCCCCCCCCCCCCCCCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCCOCC(CO)OCc1ccccc1

Procedure:
To a suspension of about 26.07 g of washed about 50% sodium hydride in about 1000 ml of dimethylformamide was added about 90 g of 2-(benzyloxy)-1,3-propanediol with stirring under argon. An about 187.88 g portion of octadecyl iodide and about 150 ml of tetrahydrofuran were added and the thick mixture was stirred with a glass rod, and then with magnetic stirring for about 3 hours. Water was then added and the mixture was extracted with ether. The ether extract was washed with brine, dried and filtered through a pad of florisil. The solvent was removed and the residue chromatographed on florisil, eluting first with petroleum ether, then with about 10% ether in petroleum ether and finally eluting the product with about 30% ether in petroleum ether, giving about 73.3 g of the desired title compound as a waxy solid.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH2:20][CH3:21])[CH2:11][C:12]([OH:19])([C:15]([F:18])([F:17])[F:16])[CH2:13][OH:14])=[C:6]([O:22][CH3:23])[CH:5]=1)([CH3:3])[CH3:2].C(C1C=CC(C(C)C(C)C(O)(C(F)(F)F)CO)=C(OC)C=1)(C)C.CS(C)=O.[NH4+].[Cl-]>ClCCl.C(N(CC)CC)C>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH2:20][CH3:21])[CH2:11][C:12]([OH:19])([C:15]([F:17])([F:16])[F:18])[CH:13]=[O:14])=[C:6]([O:22][CH3:23])[CH:5]=1)([CH3:2])[CH3:3]
Reactant: CCC(CC(O)(CO)C(F)(F)F)c1ccc(C(C)C)cc1OC
Agent: COc1cc(C(C)C)ccc1C(C)C(C)C(O)(CO)C(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(CC(O)(C=O)C(F)(F)F)c1ccc(C(C)C)cc1OC
Temperature: 25 °C

Procedure:
The above-described mixture of 4-(4-isopropyl-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)hexan-1-ol and 4-(4-isopropyl-2-methoxyphenyl)-2-hydroxy-3-methyl-2-(trifluoromethyl)pentan-1-ol (5.35 g, 16 mmol) is dissolved in dichloromethane (164 ml). Following addition of dimethyl sulphoxide (54.8 ml) and triethylamine (11.1 ml) the SO3/pyridine complex (6.37 g, 40 mmol) is added in portions over the course of 40 minutes. After four-hour stirring at room temperature, the batch is poured onto a mixture of saturated NH4Cl solution and ice. The mixture is extracted twice with diethyl ether (250 ml each time) and the combined extracts are washed twice with brine (50 ml each time). Following removal of the solvent by evaporation, the residue is chromatographed on silica gel (eluent: hexane/diethyl ether). This isolates 3.05 g (57%) of a mixture of the two aldehydes, 4-(4-isopropyl-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)-hexanal and 4-(4-isopropyl-2-methoxyphenyl)-2-hydroxy-3-methyl-2-(trifluoromethyl)pentanal.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](=O)[N:14]=[CH:15][NH:16]2)=[CH:11][C:10]=1[F:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:23])=O>>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([Cl:23])=[N:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[F:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1nc[nH]c2cc(OCc3ccccc3)c(F)cc12
Reactant: O=P(Cl)(Cl)Cl
Product: Fc1cc2c(Cl)ncnc2cc1OCc1ccccc1
Yield: 71 %

Procedure:
7-(Benzyloxy)-6-fluoroquinazolin-4(1H)-one (2.00 g, 7.41 mmol) was taken up in phosphorus oxychloride (20 ml) and the reaction heated at reflux for 90 minutes. The reaction was cooled, azeotroped with toluene (2×50 ml) and taken up in dichloromethane (5 ml) The organic phase was washed with saturated aqueous sodium hydrogen carbonate solution and then dried over magnesium sulphate. Solvent evaporation in vacuo followed by drying of the solid in vacuo yielded 7-(benzyloxy)-4-chloro-6-fluoroquinazoline (1.50 g, 71% yield) as a pale yellow solid:
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH3:9])=[O:7].[NH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>C1C=CC=CC=1>[N:10]1([CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH3:9])=[O:7])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: C1CCNCC1
Reactant: COC(=O)CCCCI
Solvent: c1ccccc1
Product: COC(=O)CCCCN1CCCCC1

Procedure:
30.0 g. (0.124 mole) of methyl δ-iodovalerate and 42.5 g. (0.50 mole) of piperidine were dissolved in 250 ml. of benzene and heated at 60° C. for 3 hours with stirring. A colorless solid began to appear shortly after the materials were combined. The solid was removed by suction filtration, and the benzene evaporated to give methyl δ-piperidinovalerate which distilled as 23.5 g. (95%) of colorless liquid, b.p. 122°-24° C. (12.5 mm.).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[NH:15][C:14]1=[O:22])C1C=CC=CC=1.Cl>CS(C)=O.CO>[NH:8]1[CH2:9][CH2:10][CH2:11][CH2:12][C:13]2([C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[NH:15][C:14]2=[O:22])[CH2:1]1
Reactant: O=C1Nc2ccccc2C1CCCCNCc1ccccc1
Agent: Cl
Solvent: CO
Solvent: CS(C)=O
Product: O=C1Nc2ccccc2C12CCCCNC2
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
3-(4-(Benzylamino)-butyl)-indolin-2-one. Conc hydrochloric acid (90 mL) was added to a solution of the compound from the previous step in DMSO (38 mL) and MeOH (8 mL). After stirring for 30 min at 0° C. and 30 min at room temperature the mixture was poured onto ice followed by extractive work-up. The title compound was obtained as a crude orange oil (16.2 g).
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:27])[N:19]([CH2:23][C:24](O)=O)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[C:9]([Cl:28])=[N:8]2)=[C:4]([C:31]([F:34])([F:33])[F:32])[CH:3]=1.[CH3:35][N:36]1C[CH2:39][CH2:38][C@H:37]1CO>>[Cl:28][C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[C:12](/[CH:16]=[C:17]3/[C:18](=[O:27])[N:19]([CH2:23][C@@H:24]4[CH2:39][CH2:38][CH2:37][N:36]4[CH3:35])[C:20](=[O:22])[S:21]/3)[CH:11]=2)[N:7]([CH2:6][C:5]2[CH:29]=[CH:30][C:2]([Cl:1])=[CH:3][C:4]=2[C:31]([F:34])([F:32])[F:33])[N:8]=1
Reactant: CN1CCC[C@H]1CO
Reactant: O=C(O)CN1C(=O)S/C(=C\c2ccc3c(c2)c(Cl)nn3Cc2ccc(Cl)cc2C(F)(F)F)C1=O
Product: CN1CCC[C@H]1CN1C(=O)S/C(=C\c2ccc3c(c2)c(Cl)nn3Cc2ccc(Cl)cc2C(F)(F)F)C1=O

Procedure:
(5Z)-5-({3-Chloro-1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}-methylidene)-3-{[(2S)-1-methylpyrrolidin-2-yl]methyl}-1,3-thiazolidine-2,4-dione was prepared from [(5Z)-5-({3-chloro-1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 287) and (2S)-(−)-1-methyl-2-pyrrolidinemethanol following General Procedure J.
Reaction SMILES: [O-]CC.[Na+].[N:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]([O:13]CC)=O.[F:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24]#[N:25])=[CH:19][CH:18]=1.Cl>C(O)C.O>[N:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]([OH:13])=[C:23]([C:24]#[N:25])[C:20]1[CH:21]=[CH:22][C:17]([F:16])=[CH:18][CH:19]=1
Reactant: N#CCc1ccc(F)cc1
Reactant: CCOC(=O)c1ccccn1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: N#CC(=C(O)c1ccccn1)c1ccc(F)cc1
Temperature: 25 °C

Procedure:
To a solution of 40.8 g (0.60 mol) of sodium ethoxide in 200 ml absolute ethanol was added a mixture of 60.5 g (0.40 mol) of ethyl picolinate and 54.1 g (0.40 mol) of 4-fluorophenylacetonitrile. The solution was refluxed 10 minutes, then cooled to ambient temperature. The solids were dissolved by the addition of 330 ml of water. Then, 50 ml 12N hydrochloric acid was added dropwise. The solid was collected by filtration, washed with water, and dried overnight (30° C. in vacuo) to give 1-(2-pyridinyl)-2-cyano-2-(4-fluorophenyl)-ethen-1-ol. This compound was dissolved in 250 ml 48% hydrobormic acid and refluxed for 17 hours. Upon cooling, aqueous ammonium hydroxide was added until the reaction mixture was basic. The aqueous solution was extracted three times with chloroform. The combined organic extracts were washed with water, dried (MgSO4), and concentrated. The resulting solid was chromatographed on silica gel with ether-petroleum ether (1:3) as eluant, and recrystallized from 2-propanol-hexane to give the title Formula (X) compound, m.p. 56.58° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[C:10]=2[CH3:16])[N:5]=[C:4]([NH:17][CH2:18][C:19](OCC)=O)[N:3]=1.[NH3:24].[OH2:25]>>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[C:10]=2[CH3:16])[N:5]=[C:4]([NH:17][C:18](=[O:25])[CH2:19][NH2:24])[N:3]=1
Reactant: N
Reactant: CCOC(=O)CNc1nc(Cl)cc(Nc2cccc(C)c2C)n1
Reactant: O
Product: Cc1cccc(Nc2cc(Cl)nc(NC(=O)CN)n2)c1C
Temperature: 120 °C

Procedure:
A suspension of ethyl 4-chloro-6-(2,3-xylidino)-2-pyrimidinylaminoacetate (500 mg) in a 10% ammonia ethanolic solution (5 ml) is heated for 20 hours at 120° C. in closed vessel. The mixture is then diluted with water (10 ml) and filtered, yielding 300 mg of the desired amide (I, 3). By the same method the amides of the following acids have been prepared:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([O:14][CH3:15])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.N1C(C)=CC=CC=1C.II.Br[CH2:27][CH2:28][CH:29]=[C:30]1[C:36]2[CH:37]=[CH:38][CH:39]=[N:40][C:35]=2[CH2:34][O:33][C:32]2[CH:41]=[CH:42][C:43]([C:45]([OH:48])([CH3:47])[CH3:46])=[CH:44][C:31]1=2>C(O)(C)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([O:14][CH3:15])[CH2:9][CH2:10][N:11]([CH2:27][CH2:28][CH:29]=[C:30]3[C:36]4[CH:37]=[CH:38][CH:39]=[N:40][C:35]=4[CH2:34][O:33][C:32]4[CH:41]=[CH:42][C:43]([C:45]([OH:48])([CH3:47])[CH3:46])=[CH:44][C:31]3=4)[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: CC(C)(O)c1ccc2c(c1)C(=CCCBr)c1cccnc1CO2
Reactant: COC1(c2ccc(Cl)cc2)CCNCC1
Agent: II
Solvent: Cc1cccc(C)n1
Solvent: CC(C)O
Product: COC1(c2ccc(Cl)cc2)CCN(CCC=C2c3cc(C(C)(C)O)ccc3OCc3ncccc32)CC1
Temperature: 80 °C
Reaction time: 20 h
Yield: 84.3 %

Procedure:
4-(4-Chloro-phenyl)-4-methoxy-piperidine (0.072 g, 0.319 mmol) was dissolved in isopropanol (5 mL) and 2,6-lutidine (0.034 g, 37 uL, 0.319 mmol) was added. Catalytic iodine was also added. The resulting suspension was warmed to 80° C. Solid 2-[5-(3-Bromo-propylidene)-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yl]-propan-2-ol (0.060 g, 0.160 mmol) was added in approximately equal portions over 2 h. Stirring was continued an additional 20 h at 80° C. The mixture was concentrated and the resulting residue purified by silica gel chromatography (ethyl acetate to 87/10/3 ethyl acetate/methanol/triethylamine gradient) to afford the title compound (70 mg, 42%).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][NH:2]1.[CH2:10]([O:12][C:13]([C:15]1([C:18]2[CH:19]=[C:20]3[C:24](=[CH:25][CH:26]=2)[N:23]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:22](=[O:34])[C:21]3=[O:35])[CH2:17][CH2:16]1)=[O:14])[CH3:11]>O1CCCC1>[C:30]([O:29][C:27]([NH:23][C:24]1[CH:25]=[CH:26][C:18]([C:15]2([C:13]([O:12][CH2:10][CH3:11])=[O:14])[CH2:16][CH2:17]2)=[CH:19][C:20]=1[C:21](=[O:35])[C:22]([N:2]1[CH2:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:1]1)=[O:34])=[O:28])([CH3:32])([CH3:31])[CH3:33]
Reactant: CCOC(=O)C1(c2ccc3c(c2)C(=O)C(=O)N3C(=O)OC(C)(C)C)CC1
Reactant: c1ccc2c(c1)CNC2
Solvent: C1CCOC1
Product: CCOC(=O)C1(c2ccc(NC(=O)OC(C)(C)C)c(C(=O)C(=O)N3Cc4ccccc4C3)c2)CC1
Temperature: 23 °C
Reaction time: 1 h
Yield: 32.3 %

Procedure:
3.2 g of isoindoline are added to 9.3 g of 5-(1-ethoxycarbonylcyclopropyl)-1-tert-butoxycarbonyl-2,3-dioxoindoline in 100 ml of tetrahydrofuran, and the mixture is subsequently stirred at 23° C. for 1 h. The mixture is evaporated to dryness in vacuo and purified by column chromatography, giving 4.0 g (32%) of ethyl 1-[4-(tert-butoxycarbonylamino)-3-(2-isoindolin-2-yl-2-oxoacetyl)phenyl]cyclopropanecarboxylate;
Reaction SMILES: [Si]([O:8][C@H:9]([C:49]1[CH:50]=[CH:51][C:52]([OH:60])=[C:53]([NH:55][S:56]([CH3:59])(=[O:58])=[O:57])[CH:54]=1)[CH2:10][NH:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([OH:32])=[C:28]([C@@H:33]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[CH2:34][CH2:35][N:36]([CH:40]([CH3:42])[CH3:41])[CH:37]([CH3:39])[CH3:38])[CH:27]=2)=[CH:16][CH:15]=1)(C(C)(C)C)(C)C.CO.CCN(CC)CC.F.F.F>O1CCCC1>[NH3:11].[CH:40]([N:36]([CH:37]([CH3:39])[CH3:38])[CH2:35][CH2:34][C@@H:33]([C:28]1[CH:27]=[C:26]([CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][O:20][C:17]2[CH:18]=[CH:19][C:14]([CH2:13][CH2:12][NH:11][CH2:10][C@@H:9]([C:49]3[CH:50]=[CH:51][C:52]([OH:60])=[C:53]([NH:55][S:56]([CH3:59])(=[O:58])=[O:57])[CH:54]=3)[OH:8])=[CH:15][CH:16]=2)[CH:31]=[CH:30][C:29]=1[OH:32])[C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)([CH3:42])[CH3:41]
Reactant: CC(C)N(CC[C@H](c1ccccc1)c1cc(CCCCCOc2ccc(CCNC[C@H](O[Si](C)(C)C(C)(C)C)c3ccc(O)c(NS(C)(=O)=O)c3)cc2)ccc1O)C(C)C
Agent: F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C)N(CC[C@H](c1ccccc1)c1cc(CCCCCOc2ccc(CCNC[C@H](O)c3ccc(O)c(NS(C)(=O)=O)c3)cc2)ccc1O)C(C)C
Product: N
Reaction time: 72 h

Procedure:
N-(5-{(1R)-1-{[tert-butyl(dimethyl)silyl]oxy}-2-[(2-{4-[(5-{3-[(1R)-3-(diisopropylamino)-1-phenylpropyl]-4-hydroxyphenyl}pentyl)oxy]phenyl}ethyl)amino]ethyl}-2-hydroxyphenyl)methanesulfonamide (Preparation 61, 250 mg, 0.29 mmol) was dissolved in tetrahydrofuran (10 ml) and methanol (0.5 ml) and triethylaminetrihydrofluoride (1.0 ml, 6.1 mmol) was added. The reaction was stirred for 3 days and the solvent removed in vacuo. The residue was dissolved in 880 ammonia (1 ml) and the solvent removed under reduced pressure, this was repeated 3 times. The residue was purified by column chromatography on silica gel eluting with dichloromethane:methanol:880 ammonia (95/5/0.5 by volume) to furnish the title compound as a pale yellow foam, 100 mg.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:2]1.C([O-])([O-])=O.[Na+].[Na+].[C:18](Cl)(=[O:27])[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1COCC1.O>[N:1]1([C:18]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:27])[CH2:6][CH2:5][CH2:4][CH:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:2]1
Reactant: CCOC(=O)C1CCCNC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C1CCCN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 80.7 %

Procedure:
To a solution of ethyl piperidine-3-carboxylate (4 g, 25.4 mmol) in THF (30 mL) and water (30.0 mL) was added Na2CO3 (6.74 g, 63.6 mmol). The resulting suspension was stirred at rt for 20 min. After this time, benzyl carbonochloridate (4.12 g, 24.17 mmol) was added dropwise. After addition, the stirring solution became milky, and a white precipitate formed. After stirring at rt for 2 h, the reaction was partitioned between EtOAc and water. The separated aqueous phase was extracted with EtOAc (2×). The combined organics were washed with water and saturated aqueous NaCl. The organic layer was dried over Na2SO4, filtered and concentrated. The oily residue was purified using silica gel chromatography (ISCO system) eluting with a gradient of 0-40% EtOAc/Hex. The desired fractions were concentrated to afford the desired product, 1-benzyl 3-ethyl piperidine-1,3-dicarboxylate (5.68 g, 19.50 mmol, 77% yield) as a colorless oil. Anal. Calcd. for C16H21NO4 m/z 291.3, found: 292.1 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 7.41-7.28 (m, 5H), 5.26-4.97 (m, 2H), 4.34-4.06 (m, 3H), 4.06-3.91 (m, 1H), 3.13 (br. s., 1H), 2.96-2.81 (m, 1H), 2.46 (br. s., 1H), 2.15-1.96 (m, 1H), 1.78-1.56 (m, 2H), 1.49 (br. s., 1H), 1.33-1.17 (m, 3H).
Reaction SMILES: C[Mg+].[Br-].CCO[CH2:7][CH3:8].ClC1[C:11]2[N:12]([CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[N:18]=2)[CH:13]=[CH:14][N:15]=1.C1COCC1>CN1C(=O)CCC1>[F:25][C:22]1[CH:21]=[CH:20][C:19]([C:17]2[N:18]=[C:11]3[C:7]([CH3:8])=[N:15][CH:14]=[CH:13][N:12]3[CH:16]=2)=[CH:24][CH:23]=1
Reactant: CCOCC
Reactant: Fc1ccc(-c2cn3ccnc(Cl)c3n2)cc1
Agent: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Product: Cc1nccn2cc(-c3ccc(F)cc3)nc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 104.1 %

Procedure:
A solution of 3M MeMgBr in Et2O (16.1 mL, 48.3 mmol) was added drop-wise to a mixture of 8-chloro-2-(4-fluorophenyl)-imidazo[1,2-a]pyrazine (10.0 g, 40.6 mmol), ferric acetylacetonate (0.71 g, 2.0 mmol), THF (240 mL), and NMP (23 mL) at about 0° C. The mixture was warmed to ambient temperature over about 1 hour. After about 1 hour, the reaction was cooled to about 0° C. and treated with additional 3M MeMgBr in Et2O (4 mL, 12 mmol). The mixture was allowed to warm to ambient temperature over about 1 h. After about an additional 1 h, the mixture was quenched with water and extracted with EtOAc. The organic layers were combined and dried with Na2SO4. After concentration, the crude material was purified by FCC on silica gel using EtOAc as an eluent to afford the expected product as an off-white solid (9.6 g, 100%): LC/MS (Table 1, Method b) Rt=1.8 min; MS m/z: 228.2 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[S:6][CH:5]=[C:4]([C:7]([OH:9])=[O:8])[CH:3]=1.[CH2:10](O)[CH3:11]>OS(O)(=O)=O.C(OCC)(=O)C.[Cl-].[Na+].O>[CH2:10]([O:8][C:7]([C:4]1[CH:3]=[C:2]([Br:1])[S:6][CH:5]=1)=[O:9])[CH3:11]
Reactant: CCO
Reactant: O=C(O)c1csc(Br)c1
Agent: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)c1csc(Br)c1

Procedure:
5-bromo-thiophene-3-carboxylic acid (18.2 g, 0.09 mol) was dissolved in absolute ethanol (150 ml) and H2SO4 (5 ml), and the mixture was refluxed for 5 hours. The mixture was concentrated under vacuum to give a yellow oil, then diluted with a mixture of ethyl acetate (100 ml) and saturated brine (200 ml), and mixed, let standing for layer separation. The aqueous layer was washed with ethyl acetate (25 ml twice). The extract and the organic layer was adjusted with Na2CO3 (10%) to pH=8, and the organic phase was separated and washed with saturated brine to pH=7□ dried over anhydrous Na2SO4 over night. The organic layer was concentrated under reduced pressure to give 5-bromo-thiophene-3-carboxylic acid ethyl ester as yellow oil (15 g).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11](=[O:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6][CH:5]=1)([O-:3])=[O:2].[F:18]F>C(#N)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:10]([F:18])[C:11](=[O:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: FF
Reactant: CCOC(=O)C(=O)Cc1ccc([N+](=O)[O-])cc1
Solvent: CC#N
Product: CCOC(=O)C(=O)C(F)c1ccc([N+](=O)[O-])cc1

Procedure:
In the same manner as described in Example 1, ethyl 3-(4-nitrophenyl)pyruvate (11.86 g) is dissolved in acetonitrile (500 ml) and reacted with fluorine at -10° C. After the same work-up as above described, the residue is rectified to give syrupy ethyl 3-(4-nitrophenyl)-3-fluoropyruvate (3.83 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([C:9]([CH:16]=[O:17])=[CH:10][N:11]2[CH2:14][CH3:15])=[CH:7][CH:6]=1)=[O:4].CC1C=CC(S([CH2:28][N+:29]#[C-:30])(=O)=O)=CC=1.C([O-])([O-])=O.[K+].[K+]>CO>[CH2:14]([N:11]1[C:12]2[C:8](=[CH:7][CH:6]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:13]=2)[C:9]([C:16]2[O:17][CH:30]=[N:29][CH:28]=2)=[CH:10]1)[CH3:15]
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: CCn1cc(C=O)c2ccc(C(=O)OC)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CCn1cc(-c2cnco2)c2ccc(C(=O)OC)cc21
Yield: 22.9 %

Procedure:
1-Ethyl-3-formyl-1H-indole-6-carboxylic acid methyl ester (100 mg, 0.42 mmol), TOSMIC (100 mg, 0.52 mmol), K2CO3 (178 mg, 1.29 mmol), and MeOH (800 μL) are heated at 80° C. overnight. The reaction mixture is then partitioned between H2O and ether. After drying and concentrating the organic phase, the product is purified by silica gel chromatography (EtOAc/CH2Cl2, 10/90) to give methyl 1-ethyl-3-oxazol-5-yl-1H-indole-6-carboxylate (26 mg, 23%) as an off-white solid.
Reaction SMILES: C([O:3][C:4](=O)[NH:5][N:6]=[CH:7][C:8]1[N:9]=[C:10]([CH3:13])[NH:11][CH:12]=1)C.C1(OC2C=CC=CC=2)C=CC=CC=1>>[CH3:13][C:10]1[N:9]2[C:4](=[O:3])[NH:5][N:6]=[CH:7][C:8]2=[CH:12][N:11]=1
Reactant: CCOC(=O)NN=Cc1c[nH]c(C)n1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Cc1ncc2cn[nH]c(=O)n12

Procedure:
A 27.2 gm. portion of 3-(2-methyl-4-imidazolylmethylene)carbazic acid ethyl ester in 200 ml. of diphenyl ether is reacted as described in Example 70 giving the desired product, m.p. 303°-305.5° C.