Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.[C:10]([OH:18])(=O)[C:11]1[CH:16]=[CH:15]C=NC=1.O1C=CCC1>CN(C)C=O>[O:18]1[CH2:10][CH2:11][CH2:16][CH:15]1[N:6]1[CH:7]=[C:2]([F:1])[C:3](=[O:9])[NH:4][C:5]1=[O:8]
Reactant: O=C(O)c1cccnc1
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Agent: C1=COCC1
Solvent: CN(C)C=O
Product: O=c1[nH]c(=O)n(C2CCCO2)cc1F
Temperature: 140 °C
Yield: 462.5 %

Procedure:
In 30 ml of dimethylformamide were dissolved 2.6 g of 5-fluorouracil and 0.246 g of nicotinic acid. 2.8 Grams of 2,3-dihydrofuran in several portions were added in 4 hours to the solution while heating it at 140° C. The mixture was then reacted for 4 hours at the same temperature. After completion of the reaction, dimethylformamide was distilled off from the reaction liquid and 50 ml of chloroform were added to the residue. After stirring, the solution was filtered to remove insoluble matters and the filrate was washed with water and dried over anhydrous sodium sulfate. Then, chloroform was distilled off from the dried filtrate to obtain 1.85 g of 1-(2-tetrahydrofuryl)-5-fluorouracil which had a melting point of 165°-168° C. The chloroform insoluble matters were 5-fluorouracil containing 0.24 g of nicotinic acid. The yield of the end product was 61% based on the consumed 5-fluorouracil.
Reaction SMILES: [Br:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]([OH:9])=[O:8].[C:10](Cl)(=O)C(Cl)=O>C(Cl)Cl.CN(C=O)C>[Br:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccsc1Br
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)c1ccsc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.1 %

Procedure:
2-bromo-3-thiophene carboxylic acid (1.0 eq, 12.56 g, 60.66 mmol) was suspended in CH2Cl2 (200 ml). Oxalyl chloride (1.1 eq, 5.9 ml, 67.16 mmol) and 5 drops of DMF were added, inducing formation of gas. The mixture was stirred overnight at room temperature and the volatiles were removed in vacuo. The resulting solid was suspended in dry methanol (150 ml) and the mixture heated to ebullition. Evaporation of the solvents afforded methyl 2-bromo-3-thiophene carboxylate (13.16 g, 98% yield) as a crude brown oil. LCMS (ES): 99% pure, m/z not detected;
Reaction SMILES: [C:1]([OH:10])(=[O:9])[CH:2]([CH:4]([C:6]([OH:8])=[O:7])[OH:5])[OH:3].C([O-])(=O)C.[Na+:15]>C(O)(=O)C>[C:6]([CH:4]([CH:2]([C:1]([O-:10])=[O:9])[OH:3])[OH:5])([OH:8])=[O:7].[Na+:15]
Reactant: O=C(O)C(O)C(O)C(=O)O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C([O-])C(O)C(O)C(=O)O

Procedure:
In reaction ii, sodium bisulfate is reacted with sodium acetate to produce sodium sulfate and solid acetic acid. In reaction iii., malic acid is reacted with sodium acetate to produce sodium hydrogen diglycolate and solid acetic acid. In reaction iv., fumaric acid is reacted with sodium acetate to produce sodium hydrogen fumarate and solid acetic acid. In reaction v., tartaric acid is reacted with sodium acetate to produce sodium hydrogen tartrate and solid acetic acid. In reaction vi., adipic acid is reacted with sodium acetate to produce sodium hydrogen adipate and solid acetic acid. In reaction vii, sulfamic acid is reacted with sodium acetate to produce sodium sulfamate and solid acetic acid.
Reaction SMILES: [C:1]1([CH:7]([NH2:15])[CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Na+].[Na+].Cl[C:23]([O:25][CH2:26][CH3:27])=[O:24]>C(Cl)Cl.O>[C:23]([NH:15][CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)([O:25][CH2:26][CH3:27])=[O:24]
Reactant: NC(Cc1ccccc1)c1ccccc1
Reactant: CCOC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)NC(Cc1ccccc1)c1ccccc1
Temperature: 10 °C
Reaction time: 3 h

Procedure:
To a stirred two phase solution of 1,2-diphenylethylamine (30.0 g, 0.15 mol) in 300 ml of methylene chloride and 500 ml of water was added sodium carbonate (23.9 g, 0.225 mol) and the solution was cooled to 10° C. under nitrogen. Ethyl chloroformate (21.5 ml, 0.225 mol) was added dropwise over a one hour period. The reaction was warmed to ambient temperature and stirred at that temperature for 3 hours. The phases were separated and the aqueous phase was extracted with methylene chloride (75 ml). The combined methylene chloride extracts were washed with 1N HCl (200 ml), brine (200 ml), dried and evaporated to a white solid, 40.3 g. Recrystallization from cyclohexane gave N-carboethoxy-1,2-diphenylethylamine, mp 74°-75° C.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[C@H:12]2[CH2:13][CH2:14][N:15]([C:16]([C@H:18]3[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]3[NH:24][C:25](=[O:32])[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:17])[C@H:11]2[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[NH:4]1.[C:33](OC(=O)C)(=[O:35])[CH3:34]>O1CCCC1>[C:33]([NH:1][CH2:2][C@H:3]1[C@H:12]2[CH2:13][CH2:14][N:15]([C:16]([C@H:18]3[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]3[NH:24][C:25](=[O:32])[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)=[O:17])[C@H:11]2[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[NH:4]1)(=[O:35])[CH3:34]
Reactant: NC[C@@H]1Nc2ccccc2[C@H]2[C@@H]1CCN2C(=O)[C@H]1CCCC[C@H]1NC(=O)c1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: CC(=O)NC[C@@H]1Nc2ccccc2[C@H]2[C@@H]1CCN2C(=O)[C@H]1CCCC[C@H]1NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 65.4 %

Procedure:
To a solution of the compound (163 mg, 0.377 mmol) synthesized in Example 73 in tetrahydrofuran (3 ml) was added acetic anhydride (0.179 ml, 1.88 mmol) under ice-cooling, and the mixture was stirred at room temperature for 10 min. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to column chromatography using basic silica gel and eluted with hexane-ethyl acetate (8:2-0:1, v/v) to give the title compound (117 mg, 60%) as an amorphous form.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]1[C:13]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[C:12]([C:21]2[CH:26]=[C:25]([C:27]3[N:28]=[N:29][NH:30][N:31]=3)[CH:24]=[CH:23][N:22]=2)[N:11]=[CH:10]1.Br[CH2:33][O:34][C:35](=[O:37])[CH3:36].CC([O-])(C)C.[K+].O>CN(C=O)C>[C:35]([O:34][CH2:33][N:29]1[N:30]=[N:31][C:27]([C:25]2[CH:24]=[CH:23][N:22]=[C:21]([C:12]3[N:11]=[CH:10][N:9]([CH2:8][C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])[C:13]=3[C:14]3[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=3)[CH:26]=2)=[N:28]1)(=[O:37])[CH3:36]
Reactant: CC(=O)OCBr
Reactant: Fc1ccc(-c2c(-c3cc(-c4nn[nH]n4)ccn3)ncn2Cc2ccccc2Cl)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)OCn1nnc(-c2ccnc(-c3ncn(Cc4ccccc4Cl)c3-c3ccc(F)cc3)c2)n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 8.3 %

Procedure:
To a solution of 2-[1-[(2-chlorophenyl)methyl]-5-(4-fluorophenyl)imidazol-4-yl]-4-(2H-tetrazol-5-yl)pyridine (50 mg, 0.12 mmol, Example 137) in DMF (5 mL) was added acetic acid bromomethyl ester (20 mg, 0.12 mmol), t-BuOK (27 mg, 0.24 mmol) and KI (40 mg, 0.24 mmol) at 0° C., then the mixture was stirred for 72 hr at rt, H2O was added, extracted with EA, dried, concentrated and purified by HPLC to give the title compound (5 mg, 8.6%). 1H NMR (300 MHz, CD3OD): δ 2.13 (3H, s), 5.38 (2H, s), 6.55 (2H, s), 6.97-6.98 (1H, m), 7.23-7.49 (7H, m), 7.85 (1H, s), 8.10 (1H, d, J=6.0 Hz), 8.28 (1H, m), 8.64 (1H, m). [M+H] Calc'd for C25H19ClFN7O2, 504. Found, 504.
Reaction SMILES: CS(O[CH2:6][C:7]1([F:13])[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1)(=O)=O.[C:14]1(=[O:24])[NH:18][C:17](=[O:19])[C:16]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:15]12.[K]>CN(C)C=O.C(OCC)(=O)C>[F:13][C:7]1([CH2:6][N:18]2[C:14](=[O:24])[C:15]3[C:16](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:17]2=[O:19])[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CS(=O)(=O)OCC1(F)CCOCC1
Agent: [K]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CC1(F)CCOCC1

Procedure:
A mixture of EXAMPLE 337A (1.8 g) and potassium phthalimide (2.356 g) in N,N-dimethylformamide (30 mL) was heated at 150° C. overnight, diluted with ethyl acetate, washed with water and brine, dried (MgSO4), filtered, concentrated and chromatographed on silica gel with 30% ethyl acetate in hexanes as eluent to give the product.
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]([NH2:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.O.[C:16]1(C)[CH:21]=CC(S(O)(=O)=O)=C[CH:17]=1.C(OCC)C>C(OCC)(OCC)(OCC)CC>[CH2:16]([C:21]1[NH:1][C:2]2=[N:3][C:4]3[C:9]([CH:10]=[C:11]2[C:12](=[O:13])[N:14]=1)=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH3:17]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: NC(=O)c1cc2ccccc2nc1N
Agent: CCOC(CC)(OCC)OCC
Solvent: CCOCC
Solvent: O
Product: CCc1nc(=O)c2cc3ccccc3nc2[nH]1
Yield: 236.5 %

Procedure:
A slurry of 2-aminoquinoline-3-carboxamide (1.0 g, 5.3 mmol), (Campaigne, E.; Randau, G. J. Het. Chem. 1971, Vol. 8, p. 111) and p-toluenesulfonic acid-monohydrate (50 mg) in triethyl orthopropionate (25 mL) was refluxed for 24 hours. After cooling, the reaction mixture was diluted into diethyl ether (50 mL), the resulting solids filtered and washed with diethyl ether. The solids were recrystallized from formamide to afford 0.14 g of the title compound; m.p. 240-245° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:16])=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[N:9]=2)[CH:7]=1.C([Sn](CCCC)(CCCC)[C:22]1[N:26]2[CH:27]=[CH:28][C:29]([C:31]([F:34])([F:33])[F:32])=[N:30][C:25]2=[N:24][CH:23]=1)CCC>>[F:16][C:5]1[CH:4]=[CH:3][C:2]([C:22]2[N:26]3[CH:27]=[CH:28][C:29]([C:31]([F:32])([F:33])[F:34])=[N:30][C:25]3=[N:24][CH:23]=2)=[CH:7][C:6]=1[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[N:9]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc2nc(C(F)(F)F)ccn12
Reactant: COc1cccc(-c2cc(Br)ccc2F)n1
Product: COc1cccc(-c2cc(-c3cnc4nc(C(F)(F)F)ccn34)ccc2F)n1

Procedure:
2-(5-Bromo-2-fluorophenyl)-6-methoxypyridine (595 mg, 2.1 mmol) was coupled to 3-tributylstannyl-7-trifluoromethylimidazol[1,2-α]pyrimidine (3.2 mmol) by the method of Example 32. Purification by chromatography on silica gel eluting with dichloromethane containing 1% methanol, then crystallisation from methanol, gave 3-[4-fluoro-3-(6-methoxypyridin-2-yl)phenyl]-7-trifluoromethylimidazo[1,2-α]pyrimidine as a yellow solid: δH (400 MHz, CDCl3) 3.98 (3H, s), 6.79 (1H, d, J 8), 7.26 (1H, d, J 10), 7.38 (1H, dd, J 11 and 9), 7.52-7.56 (2H, m), 7.70 (1H, t, J 8), 8.12 (1H, s), 8.36 (1H, dd, J 7 and 2), 8.85 (1H, d, J 7).
Reaction SMILES: [CH2:1]([O:8][CH2:9][N:10]1[C:14](Br)=[C:13]([Br:16])[N:12]=[C:11]1[CH2:17][CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]CCCC.CCCCCC.CN([CH:33]=[O:34])C>C1COCC1>[CH2:1]([O:8][CH2:9][N:10]1[C:14]([CH:33]=[O:34])=[C:13]([Br:16])[N:12]=[C:11]1[CH2:17][CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCc1nc(Br)c(Br)n1COCc1ccccc1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCc1nc(Br)c(C=O)n1COCc1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 93.2 %

Procedure:
A solution of 1-[(Benzyloxy)methyl]-4,5-dibromo-2-ethylimidazole (28.0 g, 75.0 mmol, Part A of example 544) in THF (300 mL) was cooled to −78° C. under nitrogen atmosphere and then added dropwise 1.6 M n-BuLi in hexane (51.75 mL, 82.5 mmol, Aldrich) over 30 mins. The mixture was stirred at −78° C. for 30 mins and then added DMF (16.5 g, 225 mmol, Aldrich) dropwise over 15 mins. The mixture was stirred at −78° C. for 30 mins. A small portion of the reaction mixture was quenched with satd. NH4Cl at −78° C. TLC (30:70 EtOAc/hexane) revealed both starting material and product showed almost identical Rf values (0.71 & 0.70) along with another minor spot at Rf=0.15. However, mass spectrum (CI—NH3) revealed absence of starting material and formation of product (m/z=325, M+2H). The reaction mixture was quenched with satd. ammonium chloride (20 mL) at −78° C. and brought to room temp. The reaction mixture was extracted with ethyl acetate (3×100 mL), washed with brine and dried with anhydrous MgSO4. The solvent was evaporated under reduced pressure to afford crude yellow oil. The crude was purified by flah column chromatography on a silica gel using dichloromethane as eluent to afford 22.6 g (93%) of colorless oil. HRMS calcd. for C14H16N2O2Br: 323.0395. Found: 323.0394 (M+H).
Reaction SMILES: [ClH:1].[NH2:2][C:3]([C:6]1[N:7]=[N:8][N:9]([CH2:11][CH2:12][N+:13]([CH3:16])([CH3:15])[CH3:14])[CH:10]=1)([CH3:5])[CH3:4].[Cl:17]OC(C)(C)C>CO>[Cl-:17].[Cl:1][N:2]([Cl:17])[C:3]([C:6]1[N:7]=[N:8][N:9]([CH2:11][CH2:12][N+:13]([CH3:14])([CH3:16])[CH3:15])[CH:10]=1)([CH3:5])[CH3:4]
Reactant: CC(C)(N)c1cn(CC[N+](C)(C)C)nn1
Reactant: CC(C)(C)OCl
Reactant: Cl
Solvent: CO
Product: CC(C)(c1cn(CC[N+](C)(C)C)nn1)N(Cl)Cl
Product: [Cl-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 41.9 %

Procedure:
A solution of 2-(4-(2-aminopropan-2-yl)-1H-1,2,3-triazol-1-yl)-N,N,N-trimethylethanaminium hydrochloride (1.45 g, 5.8 mmol) in methanol (100 ml) was stirred at room temperature. t-Butyl hypochlorite (1.90 g, 17.5 mmol) was added to the mixture, and the combined mixture was stirred for 1 hour at room temperature. The reaction mixture was concentrated in vacuo, and purified by prep-HPLC to give 769 mg (42% yield) of 2-(4-(2-(dichloroamino)propan-2-yl)-1H-1,2,3-triazol-1-yl)-N,N,N-trimethylethanaminium chloride. 1H NMR (D2O) δ 8.41 (s, 1 H), 5.10 (t, J=4.7, 2 H), 4.06 (t, J=4.7, 2 H), 3.18 (s, 9 H), 1.83 (s, 6H); MS (ESI+) calculated for C10H20Cl2N5+: 280.11. Found: 280.1 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[H-].[Na+:10].Cl>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O-:8])=[CH:4][CH:3]=1.[Na+:10]
Reactant: Oc1ccc(Cl)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: [O-]c1ccc(Cl)cc1

Procedure:
A large batch of sodium p-chlorophenoxide salt was prepared by the reaction of 529.4 grams (4.12 moles) of p-chlorophenol with 99.0 grams (4.12 moles) of sodium hydride in THF at room temperature. A light yellow solution was obtained after 2 hours. A sample of the salt was neutralized with HCl and analyzed. The analysis showed 100% p-chlorophenol.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C@H:10]([CH2:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=1)[C:11](O)=[O:12])[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2N=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[CH2:47]([N:54]([C:56]([NH:58][CH2:59][CH3:60])=[O:57])[NH2:55])[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1.C(N(C(C)C)CC)(C)C>ClCCl>[CH2:47]([N:54]([C:56]([NH:58][CH2:59][CH3:60])=[O:57])[NH:55][C:11](=[O:12])[C@H:10]([N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH3:9])[CH2:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=1)[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1
Reactant: CN(C(=O)OC(C)(C)C)[C@H](Cc1ccc2ccccc2c1)C(=O)O
Reactant: CCNC(=O)N(N)Cc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCNC(=O)N(Cc1ccccc1)NC(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.1 %

Procedure:
To a solution of (2R)-2-(N-tert-butoxycarbonyl-N-methylamino)-3-(2-naphthyl)propionic acid (2.6 g, 7.9 mmol) in dichloromethane (20 ml) was added 1-hydroxy-7-azabenzotriazole (1.1 g, 8.0 mmol) and 1-ethyl-3-dimethylaminopropyl carbodiimide hydrochloride (1.6 g, 8.6 mmol) and the mixture was stirred at 30 min at room temperature. Then 2-benzyl-4-ethylsemicarbazide (1.3 g, 6.6 mmol) and diisopropylethylamine (1.5 ml, 8.6 mmol) in dichloromethane (20 ml) were added and the mixture was stirred overnight. The mixture was washed with saturated sodium bicarbonate (2×50 ml), dried (magnesium sulfate) and concentrated in vacuo. The obtained product was chromatographed on silica (100 g) with petrol ether/ethyl acetate 1:1 to give 3.0 g (90%) of 2-benzyl-1-[(2R)-2-(N-(tert-butoxycarbonyl)-N-methylamino)-3-(2-naphtyl)propionyl]-4-ethylsemicarbazide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:18]([CH3:24])([CH3:23])[C:19]([O:21]C)=[O:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.O.[OH-].[Li+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O.CCOCC.O1CCOCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([CH2:25][C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[C:18]([CH3:23])([CH3:24])[C:19]([OH:21])=[O:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: COC(=O)C(C)(C)C(Cc1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOCC
Product: CC(C)(C(=O)O)C(Cc1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Temperature: 90 °C
Reaction time: 24 h
Yield: 100 %

Procedure:
A mixture of methyl 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,2-dimethyl-4-phenylbutanoate (210 mg, 0.50 mmol), lithium hydroxide monohydrate (80 mg, 1.9 mmol), water (3 mL), and dioxane (6 mL) was stirred at 90° C. for 24 hr under nitrogen. The reaction mixture was cooled to rt before diethyl ether (20 mL) was added. The ether layer was reextracted with water (2×3 mL). The combined aqueous solutions were acidified with aqueous 10% citric acid solution and extracted with ethyl acetate (3×6 mL). The combined ethyl acetate extracts were dried (Na2SO4) and concentrated to give 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,2-dimethyl-4-phenylbutanoic acid (200 mg, 0.50 mmol, 100% yield) as a solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]=[C:7]([CH:9]1[CH:14]([CH:15]=[C:16]([CH3:18])[CH3:17])[CH:13]2[CH2:19][CH:10]1[CH2:11][CH2:12]2)[CH3:8])=[O:5])[CH3:2].[H][H]>C(OCC)(=O)C.[Pd]>[CH2:1]([O:3][C:4]([CH2:6][CH:7]([CH:9]1[CH:14]([CH2:15][CH:16]([CH3:18])[CH3:17])[CH:13]2[CH2:19][CH:10]1[CH2:11][CH2:12]2)[CH3:8])=[O:5])[CH3:2]
Reactant: CCOC(=O)C=C(C)C1C2CCC(C2)C1C=C(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)CC(C)C1C2CCC(C2)C1CC(C)C
Reaction time: 5 h

Procedure:
A solution of 60 g (0.22 mole) of 2-(1-ethoxycarbonylprop-1-en-2-yl)-3-(2-methylprop-1-en-1-yl)-bicyclo[2.2.1]heptane in 100 ml of ethyl acetate was stirred together with 1.6 g of palladium on alumina (0.5% strength) at 90° C. in a hydrogen atmosphere under 150 bar until the pressure remained constant for 5 hours.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([NH:11]C(=O)C)=[C:6]([N+:15]([O-:17])=[O:16])[C:5]=1[O:18][CH3:19]>CO>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([NH2:11])=[C:6]([N+:15]([O-:17])=[O:16])[C:5]=1[O:18][CH3:19]
Reactant: COC(=O)c1cc(Cl)c(NC(C)=O)c([N+](=O)[O-])c1OC
Solvent: CO
Product: COC(=O)c1cc(Cl)c(N)c([N+](=O)[O-])c1OC
Temperature: 25 °C
Yield: 93.6 %

Procedure:
Compound 11 (6.2 g, 20.5 mmol) was dissolved in methanol (70 mL), H2SO4 concentrated (4 mL) was added and the solution heated to reflux for 9 h. After cooling to r.t., the mixture was poured into ice (600 mL) and the precipitate formed was collected by filtration. Drying under hv gave 5.0 g (94%) of 12 as a yellow solid. Data of 12: Rf 0.85 (hexane/EtOAc 1:4). 1H NMR (300 MHz, DMSO-d6): δ 3.77 (s, 6H), 6.85 (brs, 2H), 7.82 (s, 1H). 13C NMR (75 MHz, DMSO-d6): δ 52.80, 64.68, 110.40, 114.21, 133.80, 142.29, 153.60, 163.48. MS (ESI): m/z (rel intensity) 261 (100). HRMS (FAB): m/z calcd for C9H9N2O5Cl, 260.0200; found, 260.0197.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8](=[O:10])[NH:7][C:6]=2[CH:11]=1.[C-:12]#[N:13].[Na+]>CN1CCCC1=O.[Ni](Br)Br>[O:10]=[C:8]1[NH:7][C:6]2[CH:11]=[C:2]([C:12]#[N:13])[CH:3]=[CH:4][C:5]=2[S:9]1
Reactant: [C-]#N
Reactant: O=c1[nH]c2cc(Cl)ccc2s1
Agent: Br[Ni]Br
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: N#Cc1ccc2sc(=O)[nH]c2c1
Reaction time: 1 h
Yield: 36.3 %

Procedure:
Heat a mixture of 5-chloro-3H-benzothiazol-2-one (9.3 g, 50 mmol), nickel(II) bromide (10.9 g, 50 mmol) and sodium cyanide (4.91 g, 100 mmol) in 1-methyl-pyrrolidinone (100 mL) in a microwave reactor to 200° C. over 15 min and hold 1 h. Filter the cooled mixture through a glass frit, add diethyl ether and brine and filter again. Wash the organic phase with brine three times and concentrate in vacuo. Pass the residue through a plug of silica gel eluting with hexane/EtOAc (2:1) and then dichloromethane/methanol (9:1) to obtain the desired intermediate (3.2 g, 36%). MS (ES+) m/z: 177 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:4]=1[NH2:5].CN(C=O)C.[CH2:18]([O:25][C:26](Cl)=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CC(C)=O>[CH3:1][O:2][C:3]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:4]=1[NH:5][C:26](=[O:27])[O:25][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COc1cc([N+](=O)[O-])ccc1N
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: COc1cc([N+](=O)[O-])ccc1NC(=O)OCc1ccccc1
Reaction time: 8 h

Procedure:
2-Methoxy-4-nitroaniline, 51 g (0.3 mol), was dissolved in 135 ml of acetone containing 12 g of MgO, and 65 ml of commercial benzylchloroformate was slowly added to the stirred mixture. After 4 hours the flask was warmed to redissolve the precipitate and the mixture was stirred overnight. DMF (100 ml) was added, and the mixture was heated to dissolve all of the product before being filtered through celite. After dilution with 250 ml of ethanol the hot solution was further diluted with water until almost cloudy, and allowed to cool. The pale yellow crystals were collected, washed well with 50% aqueous ethanol, and dried. Yield 86.0 g, 94%, m.p. 130°-131° C.
Reaction SMILES: [F:1][C:2]([F:10])([CH2:5][CH2:6][CH2:7][O:8][CH3:9])[C:3]#[N:4].[CH:11]([Mg]Br)=[CH2:12].[BH4-].[Na+].Cl>O1CCCC1.CO.O>[NH2:4][CH:3]([C:2]([F:10])([F:1])[CH2:5][CH2:6][CH2:7][O:8][CH3:9])[CH:11]=[CH2:12]
Reactant: COCCCC(F)(F)C#N
Reactant: C=C[Mg]Br
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: C=CC(N)C(F)(F)CCCOC
Temperature: -12 °C
Reaction time: 0.5 h

Procedure:
Under an atmosphere of nitrogen, 2,2-difluoro-5-methoxyvaleronitrile (4.85 mg, 3.25 mmoles), dissolved in tetrahydrofuran (5 ml), is slowly added to vinyl magnesium bromide (8 ml, 0.5M in tetrahydrofuran, 4 mmoles) previously cooled to -12° C. The reaction mixture is kept at -10° C. for 1/2 hour and then cooled to -40° C. A solution/suspension of sodium borohydride (133 mg, 3.5 mmoles) in methanol (14 ml) and water (0.5 ml), cooled to -40° C., is poured into the mixture, The temperature is allowed to rise to 0° C., and the mixture kept at this temperature for 10 min. The mixture is acidified with 6N HCl and concentrated under reduced pressure. The residue is dissolved in water, the aqueous solution is extracted twice to remove by-products, made alkaline with 4N NaOH, saturated with sodium chloride, and extracted again twice with ether. Usual work-up gives the title compound as a yellowish oil which is used for the next step without further purification: 420 mg (70)%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:9][CH:8]=[C:7]([Br:23])[CH:6]=2.C(N(CC)CC)C.[Cl:31][CH2:32][C:33](Cl)=O>C(O)C>[Br:23][C:7]1[CH:8]=[CH:9][C:10]2[C:11]3[N:12]([CH2:13][CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:20])[CH3:21])[C:33]([CH2:32][Cl:31])=[N:1][C:2]=3[CH:3]=[N:4][C:5]=2[CH:6]=1
Reactant: CC(C)(C)OC(=O)NCCNc1c(N)cnc2cc(Br)ccc12
Reactant: O=C(Cl)CCl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCn1c(CCl)nc2cnc3cc(Br)ccc3c21
Yield: 50 %

Procedure:
A modification of the method described in Part C of Example 365 was used to treat tert-butyl 2-[(3-amino-7-bromoquinolin-4-yl)amino]ethylcarbamate (66.69 g, 174.9 mmol, U.S. patent application publication no. US 2004/0147543, Example 386, Parts A and B) with triethylamine (35.4 g, 350 mmol) and chloroacetyl chloride (20.7 g, 183 mmol). After the reaction in ethanol was complete, a precipitate was present and was isolated by filtration to provide 38.42 g of tert-butyl 2-[7-bromo-2-(chloromethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethylcarbamate as white crystals. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluting with 2 N ammonia in methanol/chloroform in a 33-minute gradient from 0:100 to 5:95) to provide an additional 4.89 g of product.