Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:23])[CH2:5][C:6]1[O:10][C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:13][CH:12]=2)=[CH:8][CH:7]=1)C.[Li+].[OH-].Cl>C1COCC1>[C:14]1([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:15]=[CH:16][C:11]([C:9]2[O:10][C:6]([CH2:5][C:4]([OH:23])=[O:3])=[CH:7][CH:8]=2)=[CH:12][CH:13]=1
Reactant: CCOC(=O)Cc1ccc(-c2ccc(-c3ccccc3)cc2)o1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)Cc1ccc(-c2ccc(-c3ccccc3)cc2)o1
Yield: 99.8 %

Procedure:
To a solution of 2-(2-biphenyl-4-yl-furan-5-yl)-acetic acid ethyl ester (0.465 g, 1.44 mmol) in THF (10 mL) at 0° C. was added 2M aqueous LiOH (2 mL). The mixture was allowed to warm over 4 hours to ambient temperature and then poured into 0.5 M aqueous HCl (50 mL). The resultant pale orange perecipitate was filtered off, rinsed with water, and dried under vacuum over P2O5 to provide 400 mg(100%) of 2-(2-biphenyl-4-yl-furan-5-yl)-acetic acid as a light orange solid, mp 196-210° C., used without further purification. 1H NMR (acetone-d6): δ 7.78 (d, 2H, J=8.1 Hz), 7.72-7.67 (m, 4H), 7.46 (t, 2H, J=7.4 Hz), 7.35 (t, 1H, J=7.4 Hz), 6.84 (d, 1H, J=3.3 Hz), 6.41 (d, 1H, J=3.3 Hz), 3.81 (s, 2H). Anal. Calculated for C18H14O3: C, 77.68; H, 5.07. Found: C, 77.44; H, 5.16.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][N:14]=2)[C@H:10](C(O)=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC(P([N:37]=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1.C(N(CC)CC)C.[OH-].[Na+]>C1(C)C=CC=CC=1>[NH2:37][C@H:10]1[C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][N:14]=2)[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9]1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](C(=O)O)[C@H](c2ccc(F)cn2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1C[C@@H](N)[C@H](c2ccc(F)cn2)C1
Temperature: 65 °C
Reaction time: 1 h
Yield: 88.1 %

Procedure:
To a solution of the compound (2.29 g) obtained in step 8 in toluene (24.0 mL) were added DPPA (2.44 g) and triethylamine (1.23 mL), and the mixture was stirred at 65° C. for 1 hr. The mixture was cooled to −10° C., 8N aqueous sodium hydroxide solution (9.23 mL) was added dropwise, and the mixture was stirred at −10° C. to 0° C. for 1.5 hr. The mixture was diluted with toluene, and extracted with water and 1N aqueous sodium hydroxide solution. The combined aqueous layer was extracted with ethyl acetate (4 times), dried and concentrated under reduced pressure. The residue was diluted with ethyl acetate, and the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (1.83 g, 88%) as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([C:10](=O)[CH:11](Br)[F:12])=[CH:6][CH:5]=1.[CH3:16][N:17]1[CH2:22][CH2:21][N:20]([C:23](=[S:25])[NH2:24])[CH2:19][CH2:18]1>C(O)C>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:24]=[C:23]([N:20]3[CH2:21][CH2:22][N:17]([CH3:16])[CH2:18][CH2:19]3)[S:25][C:11]=2[F:12])=[CH:6][CH:5]=1
Reactant: CN1CCN(C(N)=S)CC1
Reactant: COC(=O)c1ccc(C(=O)C(F)Br)cc1
Solvent: CCO
Product: COC(=O)c1ccc(-c2nc(N3CCN(C)CC3)sc2F)cc1
Temperature: 25 °C
Yield: 74 %

Procedure:
4-(2-Bromo-2-fluoro-acetyl)-benzoic acid methyl ester (1.18 mmol) and 4-methyl-piperazine-1-carbothioic acid amide (1.18 mmol) were dissolved in ethanol (10 mL). The reaction was heated at reflux for 2 h. The reaction was cooled to RT causing the product to precipitate. The product was collected by filtration and washed with cold ethanol. The product was given an aqueous sodium bicarbonate work up to yield the title compound as a colourless oil (74%). MS (ES+) 337 (M+H, 100%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[N:12]1[CH2:17][CH2:16][CH:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=2)[CH2:14][CH2:13]1.[C:29]([N:48]1[CH:52]=[C:51](B(O)O)[CH:50]=[N:49]1)([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH3:28][S:25]([C:22]1[CH:23]=[CH:24][C:19]([O:18][CH:15]2[CH2:16][CH2:17][N:12]([C:5]3[C:4]4[C:9](=[CH:10][CH:11]=[C:2]([C:51]5[CH:50]=[N:49][N:48]([C:29]([C:36]6[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=6)([C:30]6[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=6)[C:42]6[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=6)[CH:52]=5)[CH:3]=4)[N:8]=[CH:7][CH:6]=3)[CH2:13][CH2:14]2)=[CH:20][CH:21]=1)(=[O:27])=[O:26]
Reactant: CS(=O)(=O)c1ccc(OC2CCN(c3ccnc4ccc(Br)cc34)CC2)cc1
Reactant: OB(O)c1cnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Product: CS(=O)(=O)c1ccc(OC2CCN(c3ccnc4ccc(-c5cnn(C(c6ccccc6)(c6ccccc6)c6ccccc6)c5)cc34)CC2)cc1
Yield: 85.1 %

Procedure:
80 mg 6-bromo-4-{4-[4-(methylsulfonyl)phenoxy]piperidino}quinoline (compound in Production Example 89) and 80 mg 1-trityl-1H-4-pyrazolylboronic acid were reacted in the same manner as in Example 9, to give 102 mg 4-[4-(4-methylsulfonylphenoxy)piperidin-1-yl]-6-(1-trityl-1H-pyrazol-4-yl) quinoline. This product was reacted in the same manner as in Example 67, to give 52 mg of the title compound as colorless crystals.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:14]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17][C:15]1=[O:16]>>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:15](=[O:16])[CH2:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=2[OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: O=C1CCc2ccccc2O1
Product: O=C(CCc1ccccc1O)N1CCN(Cc2ccccc2)CC1
Temperature: 90 °C
Reaction time: 3 h
Yield: 108.9 %

Procedure:
1-Benzylpiperazine (2.38 g) was added to 3,4-dihydrocoumarine (2.00 g) and stirred for 3 hours at 90° C., thereby yielding the entitled compound (4.77 g) as pale brown syrup.
Reaction SMILES: [F:1][C:2]([F:37])([CH2:8][C@H:9]([C@@H:11]1[C@:29]2([CH3:30])[C@H:14]([C@H:15]3[C@H:26]([CH2:27][CH2:28]2)[C@:24]2([CH3:25])[C:18]([CH2:19][C@@:20](C4CCCCO4)([CH2:22][CH2:23]2)[OH:21])=[CH:17][CH2:16]3)[CH2:13][CH2:12]1)[CH3:10])[CH2:3][C:4]([OH:7])([CH3:6])[CH3:5].C([O-])(=O)C>N1C(C)=CC(C)=CC=1C>[CH3:10][CH:9]([CH:11]1[C:29]2([CH3:30])[CH2:28][CH2:27][CH2:26]/[C:15](=[CH:16]/[CH:17]=[C:18]3/[CH2:19][CH:20]([OH:21])[CH2:22][CH2:23][C:24]/3=[CH2:25])/[CH:14]2[CH2:13][CH2:12]1)[CH2:8][C:2]([F:1])([F:37])[CH2:3][C:4]([OH:7])([CH3:5])[CH3:6]
Reactant: C[C@H](CC(F)(F)CC(C)(C)O)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@](O)(C5CCCCO5)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: CC(=O)[O-]
Solvent: Cc1cc(C)nc(C)c1
Product: C=C1CCC(O)C/C1=C/C=C1/CCCC2(C)C1CCC2C(C)CC(F)(F)CC(C)(C)O

Procedure:
The steroid i ether (1) is oxidized to the C-22 aldehyde by pyridium chlorochromate or other suitable alcohol oxidizing reagent. This C-22 aldehyde is converted to a silyl ether carboxy ester (3) by a Wittig type condensation. Hydrolysis in acetic acid and TsOH afford the corresponding C-23α keto methyl ester and converts the i ether to the 3 acetoxy function (4). The ketone is fluorinated with DAST (diethyl amino sulfur trifluoride) to provide the C-23 difluoro carboxymethyl-3 acetate. Hydrolysis of the acetoxy group and treatment with 2,3 dihydropyan and TsOH gave the 3-THP protected difluoro 24 ester. Reduction with Li aluminum hydride produced the C-24 alcohol (7). Treatment of this alcohol with a mixture of trifluoromethanesulfonic anhydride and pyridine provides the trifluoromethanesulfonyl ester which undergoes a malonic ester condensation to yield the C-26,27 diethyl ester (9). N chloro succinimide is used to convert (9) to the C-25 chloro derivative (10) which, upon reduction with lithium aluminum hydride, affords the C-26,27 chlorodialcohol (11). Treatment of that chlorodiol with sodium hydride in dimethoxyethane yields the 25,26 expoxy 26-alcohol (12). Treatment with methanesulfonyl chloride and triethylamine provided the mesylate that upon reduction with lithium aluminum hydride yielded 23,23-difluoro,25-hydroxyl-3β tetrahydropyranyl cholesterol (13) that was converted to the acetate (14). This compound was then converted to the 5,7-diene using the usual allylic bromination followed by dehydrobromination in collidine. This dien was then photolyzed to provide the corresponding previtamin which during the temperatures of work up result in the 23,23-difluoro-25-hydroxyvitamin D3 (16). ##STR1##
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][CH2:9][C:10](=[O:21])[CH:11]([CH:16]([CH3:20])[C:17]([CH3:19])=O)[C:12](OC)=O.CI>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C(#N)C.O>[CH3:7][O:8][C:9]1[C:10](=[O:21])[CH:11]([CH3:12])[CH:16]([CH3:20])[C:17]=1[CH3:19]
Reactant: COCC(=O)C(C(=O)OC)C(C)C(C)=O
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CC#N
Solvent: CI
Solvent: O
Product: COC1=C(C)C(C)C(C)C1=O
Reaction time: 0.5 h
Yield: 39.1 %

Procedure:
15.20 g (110 mmol) of potassium carbonate and 0.46 g (2 mmol) of benzyltriethylammonium chloride are suspended in 100 ml of acetonitrile. While stirring there are added thereto 21.60 g (100 mmol) of methyl 4-methoxy-2-[1 -methylacetonyl]-acetoacetate, the mixture is heated to 60° C. and 28.39 g (200 mmol) of methyl iodide are added dropwise thereto within 30 minutes. The mixture is stirred at 60° C. for a further 16 hours; then 6.91 g (50 mmol) of potassium carbonate and 7.10 g (50 mmol) of methyl iodide are again added and the mixture is stirred at 60° C. for a further 21 hours. 6.90 g (50 mmol) of potassium carbonate in 300 ml of distilled water are now added thereto. The reaction mixture is held at reflux temperature for 6 hours. It is then extracted 3 times with 100 ml of ether each time. The combined organic phases are dried over magnesium sulphate and concentrated on a rotary evaporator. The crude product distils at 70°-78° C./12 mm and yields 6.03 g (39.2%) of 2-methoxy-3,4,5-trimethyl-2-cyclopenten-1-one.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15]([OH:17])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:21]1([NH2:27])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:21]1([NH:27][C:15]([C:14]2[CH:13]=[C:12]([CH:20]=[CH:19][CH:18]=2)[O:11][CH2:10][CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:17])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: CC(C)(C)OC(=O)NCCOc1cccc(C(=O)O)c1
Reactant: NC1CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCOc1cccc(C(=O)NC2CCCCC2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 3-(2-(tert-butoxycarbonylamino)ethoxy)benzoic acid (0.73 g, 2.98 mmol), cyclohexylamine (0.34 ml, 2.98 mmol), EDCI (0.7 g, 3.58 mmol) and HOBT (0.49 g, 3.58 mmol) in DMF was added DIPEA (1.0 ml, 5.57 mmol). The resulting mixture was stirred at room temperature for 18 h, concentrated, and partitioned between ethyl acetate and water. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. Purification by flash chromatography (30 to 65% EtOAc-hexanes gradient) gave tert-butyl 2-(3-(cyclohexylcarbamoyl)phenoxy)ethylcarbamate as an orange oil. Yield (0.20 g, 20%): 1H NMR (400 MHz, CD3OD) δ 7.31-7.38 (m, 3H), 7.06-7.09 (m, 1H), 4.04 (t, J=5.6 Hz, 2H), 3.78-3.87 (m, 1H), 3.41-3.45 (m, 2H), 1.90-1.98 (m, 2H), 1.78-1.84 (m, 2H), 1.63-1.71 (m, 1H), 1.43 (s, 9H), 1.18-1.38 (m, 5H).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[N:8]([C:11]3[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=3[CH3:19])[CH:9]=[N:10][C:5]2=[C:4]([NH2:20])[CH:3]=1.C(N(CC)C(C)C)(C)C.[Cl:30][CH2:31][C:32](Cl)=[O:33].C(=O)([O-])[O-].[K+].[K+]>ClCCCl>[CH3:1][C:2]1[N:7]=[C:6]2[N:8]([C:11]3[C:12]([CH3:19])=[CH:13][C:14]([CH3:18])=[CH:15][C:16]=3[CH3:17])[CH:9]=[N:10][C:5]2=[C:4]([NH:20][C:32](=[O:33])[CH2:31][Cl:30])[CH:3]=1
Reactant: O=C(Cl)CCl
Reactant: Cc1cc(C)c(-n2cnc3c(N)cc(C)nc32)c(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C)c(-n2cnc3c(NC(=O)CCl)cc(C)nc32)c(C)c1
Temperature: 25 °C

Procedure:
Treat a solution of 5-methyl-3-(2,4,6-trimethylphenyl)imidazolo[5,4-b]pyridin-7-ylamine (0.05 g, 1.9 mmol), and N,N-diisopropylethylamine, (0.04 mL, 0.21 mmol) in 1,2-dichloroethane (5 mL) with chloroacetyl chloride (0.017 mL, 0.21 mmol). Heat the solution to reflux for 3 h, cool to ambient temperature, and pour into an aqueous potassium carbonate solution. Extract the resulting mixture with CH2Cl2 and wash with saturated aq NaCl. Separate the organic layer, dry over Na2SO4, filter, and concentrate. Purify by preparative TLC (5% MeOH in CH2Cl2) to obtain the title compound as a yellow solid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([C:9]1([CH2:14][C:15](OCC)=[O:16])[O:13][CH2:12][CH2:11][O:10]1)[CH3:8].[OH-].[Na+].S([O-])([O-])(=O)=O.[Mg+2]>O.O1CCCC1>[CH2:7]([C:9]1([CH2:14][CH2:15][OH:16])[O:13][CH2:12][CH2:11][O:10]1)[CH3:8]
Reactant: CCOC(=O)CC1(CC)OCCO1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: CCC1(CCO)OCCO1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.1 %

Procedure:
To a tetrahydrofuran (50 ml) suspension of lithium aluminum hydride (800 mg, 21.1 mmol), ethyl (2-ethyl-1,3-dioxolan-2-yl)acetate (3.85 g, 20.5 mmol) was added under ice-cool. The mixture was stirred at room temperature for one hour and 30 minutes and cooled on ice. Thereafter, water (0.8 ml), a 15% aqueous sodium hydroxide solution (0.8 ml), and water (2.4 ml) were sequentially added to the mixture under ice cool. Magnesium sulfate was added to the mixture and filtrated through silica gel. The filtrate was concentrated under reduced pressure to obtain the title compound (2.76 g, 92.1%) as an oil.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.C(N(CC)C(C)C)(C)C.[Cl:24][C:25]1[CH:30]=[C:29](Cl)[N:28]=[C:27]([C:32]([F:35])([F:34])[F:33])[N:26]=1>C(Cl)Cl.O>[Cl:24][C:25]1[N:26]=[C:27]([C:32]([F:35])([F:34])[F:33])[N:28]=[C:29]([NH:1][CH:2]2[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]2)[CH:30]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: FC(F)(F)c1nc(Cl)cc(Cl)n1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Nc2cc(Cl)nc(C(F)(F)F)n2)CC1
Reaction time: 8 h

Procedure:
tert-Butyl 4-aminopiperidine-1-carboxylate (1.4 g, 7.1 mmol, Aldrich) was dissolved in methylene chloride (10. mL) and to this solution was added N,N-diisopropylethylamine (2.5 mL, 14 mmol) and 4,6-dichloro-2-(trifluoromethyl)pyrimidine (1.7 g, 7.8 mmol, Synchem). The reaction was stirred overnight. The mixture was diluted with water and the product was extracted with EtOAc. The organic layer was washed twice with water, once with brine, dried over sodium sulfate, filtered and concentrated to afford product which was used without further purification in Step 2. LCMS (M+H)+: 381.1.
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[N:27]([CH:28]([CH3:30])[CH3:29])[CH2:26][CH2:25][N:13]3[C:14](=[O:24])[C:15]=2[O:16]CC2C=CC=CC=2)=[O:9])=[C:4]([S:33](=[O:38])(=[O:37])[N:34]([CH3:36])[CH3:35])[CH:3]=1>FC(F)(F)C(O)=O>[F:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[N:27]([CH:28]([CH3:30])[CH3:29])[CH2:26][CH2:25][N:13]3[C:14](=[O:24])[C:15]=2[OH:16])=[O:9])=[C:4]([S:33](=[O:37])(=[O:38])[N:34]([CH3:36])[CH3:35])[CH:3]=1
Reactant: CC(C)N1CCn2c1nc(C(=O)NCc1ccc(F)cc1S(=O)(=O)N(C)C)c(OCc1ccccc1)c2=O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)N1CCn2c1nc(C(=O)NCc1ccc(F)cc1S(=O)(=O)N(C)C)c(O)c2=O
Yield: 82.7 %

Procedure:
A solution of N-(4-fluoro-2-(N,N-dimethylsulfamoyl)benzyl)-6-benzyloxy-1-isopropyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide (0.155 g, 0.28 mmol) in trifluoroacetic acid (10 ml) was stirred at 25° C. for 72 h. The solvent was then evaporated under reduced pressure and the residue was purified by preparative HPLC (column YMC Pack C-18, 5μ, 20×250 mm, elution gradient acetonitrile-water 0.1% trifluoroacetic acid) to give 0.105 g (81% yield) of the title amide as a white solid.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[C:23]4=[C:24]([CH2:31][CH3:32])[C:25]([C:27]([O:29]C)=[O:28])=[CH:26][N:22]4[N:21]=[CH:20][N:19]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.O.[OH-].[Li+]>C1COCC1.O>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[C:23]4=[C:24]([CH2:31][CH3:32])[C:25]([C:27]([OH:29])=[O:28])=[CH:26][N:22]4[N:21]=[CH:20][N:19]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCc1c(C(=O)OC)cn2ncnc(Nc3ccc4c(cnn4Cc4ccccc4)c3)c12
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CCc1c(C(=O)O)cn2ncnc(Nc3ccc4c(cnn4Cc4ccccc4)c3)c12
Yield: 59 %

Procedure:
Methyl 4-(1-benzyl-1H-indazol-5-ylamino)-5-ethylpyrrolo[2,1-f][1,2,4]triazine-6-carboxylate (51.3 g, 0.12 mol) was dissolved in THF (750 mL) and the solution added to a 2 L round bottomed flask equipped with a reflux condenser. Methanol (250 mL) was then added to the flask followed by a solution of lithium hydroxide monohydrate (60.8 g, 1.45 mol) in water (300 mL). The reaction was then heated to reflux for 20 hrs. HPLC analysis of the mixture after this time indicated that the reaction was complete. The reaction was then cooled and the mixture concentrated under reduced pressure. Water (200 mL) was then added to the residue and the resulting solution extracted with ethyl acetate (2×100 mL). Hydrochloric acid (2N) was then added to the aqueous solution until a pH of 3-4 was obtained. This resulted in the formation of a thick white precipitate, which was filtered off. The filter cake was then slurried in ethyl ether (1 L), re-filtered and dried, affording 29.2 g of 4-(1-benzyl-1H-indazol-5-ylamino)-5-ethylpyrrolo[2,1-f][1,2,4]triazine-6-carboxylic acid. The filtrate was combined with the original ethyl acetate extract and the solvents removed under reduced pressure. Purification of the residue by trituration with a 2:1 mixture of ether and ethyl acetate (500 mL) followed by filtration and drying, afforded a further 13.4 g of the desired acid. The combined total yield of 4-(1-benzyl-1H-indazol-5-ylamino)-5-ethylpyrrolo[2,1-f][1,2,4]triazine-6-carboxylic acid was 42.6 g (86%) and the material had an HPLC purity of 98.2%.
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[C:10]2[C:5](=[CH:6][C:7]([N+:22]([O-])=O)=[C:8]([NH:11][C:12](=O)[CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:9]=2)[N:4]([CH2:25][C:26]#[C:27][CH2:28][CH3:29])[C:3]1=[O:30].Cl[Sn]Cl.O>C1COCC1.Cl>[CH3:1][C:2]1([CH3:31])[C:10]2[CH:9]=[C:8]3[NH:11][C:12]([CH2:13][CH2:14][C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)=[N:22][C:7]3=[CH:6][C:5]=2[N:4]([CH2:25][C:26]#[C:27][CH2:28][CH3:29])[C:3]1=[O:30]
Reactant: CCC#CCN1C(=O)C(C)(C)c2cc(NC(=O)CCc3ccccc3)c([N+](=O)[O-])cc21
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: C1CCOC1
Solvent: O
Product: CCC#CCN1C(=O)C(C)(C)c2cc3[nH]c(CCc4ccccc4)nc3cc21
Temperature: 40 °C
Reaction time: 2 h
Yield: 42.9 %

Procedure:
To a solution of N-(3,3-dimethyl-6-nitro-2-oxo-1-pent-2-ynyl-2,3-dihydro-1H-indol-5-yl)-3-phenyl-propionamide (50 mg) in THF (0.5 ml) is added a solution of SnCl2.H2O (107 mg; 476 μmol) in hydrochloric acid (1 M; 2 ml) at RT. The mixture is stirred 2 h at RT and subsequent 2 h at 40° C. The reaction mixture is adjusted to pH 12 and extracted with CH2Cl2 (3×15 ml). The combined organic layer is dried over MgSO4 and concentrated in vacuo. The desired compound (19 mg) is obtained by flash chromatography on silica gel eluting with CH2Cl2/MeOH (99:1).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH2:11][CH2:10][CH2:9][C:8](=[O:12])[CH:7]=1.C(Cl)Cl>CCOCC>[O:12]=[C:8]1[CH2:9][CH2:10][CH2:11][C:6]([CH2:5][CH2:4][CH2:3][CH:2]=[O:1])=[CH:7]1
Reactant: O=C1C=C(CCCCO)CCC1
Solvent: CCOCC
Solvent: ClCCl
Product: O=CCCCC1=CC(=O)CCC1
Reaction time: 25 h

Procedure:
Following the procedure of Corey, Tetrahedron Lett 2647 (1975), a mixture of 3-(4-hydroxybutyl)-cyclohex-2-en-1-one (539 mg) pyridinium dichromate (2.05 g) and methylene chloride (8.0 ml) is stirred for 25 hr at 20°-25°. The reaction is diluted with ether, filtered, dried over magnesium sulfate and concentrated to give the title compound, IR (neat) 2950, 1724, 1666, 1255, 1193, 888 cm-1.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH2:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[H-].[Na+].[CH3:13][O:14][C:15](=[O:31])[CH:16]([C:21]1[CH:26]=[C:25](F)[CH:24]=[CH:23][C:22]=1[N+:28]([O-:30])=[O:29])[C:17]([O:19][CH3:20])=[O:18].[NH4+].[Cl-]>CS(C)=O>[CH3:13][O:14][C:15](=[O:31])[CH:16]([C:21]1[CH:26]=[C:25]([NH:10][C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[CH:24]=[CH:23][C:22]=1[N+:28]([O-:30])=[O:29])[C:17]([O:19][CH3:20])=[O:18]
Reactant: Nc1cccc([N+](=O)[O-])c1
Reactant: COC(=O)C(C(=O)OC)c1cc(F)ccc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CS(C)=O
Product: COC(=O)C(C(=O)OC)c1cc(Nc2cccc([N+](=O)[O-])c2)ccc1[N+](=O)[O-]
Reaction time: 0.5 h

Procedure:
To a solution of 3-nitro-phenylamine (2.08 g, 15.1 mmol) in DMSO (40 ml) is added NaH (60% dispersion in mineral oil, 0.60 g, 15 mol). The reaction is stirred at this temperature for 30 minutes. After that, a solution of 2-(5-fluoro-2-nitro-phenyl)-malonic acid dimethyl ester (1.36 g, 5.02 mmol) in DMSO (10 ml) is added slowly. The reaction is stirred at 80° C. for 24 hours, and is poured into a saturated solution of NH4Cl (150 ml). The mixture is extracted with ethyl acetate (100 ml×3). The insoluble is filtered off. The organic layers are combined, dried and concentrated. The desired ester is obtained after flash column chromatography purification (silica gel, eluted by hexanes-ethyl acetate): LC-MS: 390.1 (MH+).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:18])[C:8]=2[N:7]=[C:6]1[CH3:19].[C:20](Cl)(=[O:24])[CH:21]([CH3:23])[CH3:22]>>[NH2:18][C:9]1[C:8]2[N:7]=[C:6]([CH3:19])[N:5]([CH2:4][CH2:3][CH2:2][NH:1][C:20](=[O:24])[CH:21]([CH3:23])[CH3:22])[C:17]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: CC(C)C(=O)Cl
Reactant: Cc1nc2c(N)nc3ccccc3c2n1CCCN
Product: Cc1nc2c(N)nc3ccccc3c2n1CCCNC(=O)C(C)C
Yield: 43.6 %

Procedure:
Using the general method of Example 205, 1-(3-aminopropyl)-2-methyl-1H-imidazo[4,5-c]quinolin-4-amine (2.00 g, 7.83 mmol) was reacted with isobutyryl chloride (835 mg, 7.83 mmol). The product was recrystallized from methyl acetate to provide 1.11 g of N-[3-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]-2-methylpropanamide as an off white powder, m.p. 239.0-240.1° C. Analysis: Calculated for C18H23N5O.0.20 C3H6O2: % C, 65.66; % H, 7.17; % N, 20.58. Found: % C, 65.51. % H, 7.05; % N, 20.71.