Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH2:13][CH:12]([CH2:14][N:15]3[CH:19]=[CH:18][N:17]=[N:16]3)[O:11][N:10]=2)[CH:5]=[CH:6][C:7]=1F.C(=O)([O-])[O-].[K+].[K+].[NH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH2:13][CH:12]([CH2:14][N:15]3[CH:19]=[CH:18][N:17]=[N:16]3)[O:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1
Reactant: Fc1ccc(C2=NOC(Cn3ccnn3)C2)cc1F
Reactant: C1CNCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Fc1cc(C2=NOC(Cn3ccnn3)C2)ccc1N1CCNCC1
Yield: 93 %

Procedure:
A mixture of (5RS)-3-(3,4-difluorophenyl)-5-(1,2,3-triazol-1-ylmethyl)-4,5-dihydroisoxazole (528 mg, 2 mM), potassium carbonate (414 mg, 3 mM), and piperazine (7.5 g) was heated under nitrogen at 130° for 4 hours. After cooling, the mixture was partitioned between water (150 ml) and ethyl acetate (150 ml). The organic extract was washed with sodium bicarbonate (75 ml), and brine (75 ml). After drying (magnesium sulfate) and evaporation, the desired product (614 mg) was obtained sufficiently pure without chromatography. MS (ESP): 331 (MH+) for C16H19FN6O NMR (DMSO-d6) δ: 2.81 (t, 4H); 2.97 (t, 4H); 3.20 (dd overlapped by H2O, 1H); 3.52 (dd, 1H); 4.58 (dd, 1H); 4.64 (dd, 1H); 5.08 (m, 1H); 7.02 (t, 1H); 7.30 (overlapping m, 2H); 7.70 (d, 1H); 8.11 (d, 1H); NH missing—exchanged.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl[C:10]([F:15])([F:14])C([O-])=O.[Na+].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH:10]([F:15])[F:14])=[CH:6][N:7]=1
Reactant: O=C([O-])C(F)(F)Cl
Reactant: Oc1ccc(Br)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: FC(F)Oc1ccc(Br)nc1
Temperature: 85 °C
Yield: 55 %

Procedure:
A mixture of 6-bromopyridin-3-ol (1.20 g, 6.90 mmol), sodium 2-chloro-2,2-difluoroacetate (1.577 g, 10.35 mmol), and potassium carbonate (1.239 g, 8.97 mmol) in 10 mL of anhydrous DMF was heated at 85° C. for 1.5 days. The reaction mixture was diluted with 50 mL of EtOAc, washed with 50 mL of H2O, followed by washing with 50 mL of NaOH (1N) solution, the EtOAc layer was dried (Na2SO4) and concentrated to give a light brown oil that was purified by Shoko silica gel chromatography instrument eluting with 0-10% EtOAc in hexanes (0-10% over 25 min; GRACE column: 80 g pre-packed). Desired fraction were combined and concentrated to give the titled compound as a colorless oil: 0.85 g, 55% yield. MS m/z=223.9, 225.9 [M+H]+. Calculated for C6H4BrF2NO: 222.9, 224.9.
Reaction SMILES: Cl.C[O:3]C(=O)[C@H](CC(C)C)N.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.COC(=O)[C@H](CC(C)C)N[C:42](=[O:65])[C@@H:43]([CH2:55][C:56]1[C:64]2[C:59](=[CH:60][CH:61]=[CH:62][CH:63]=2)[NH:58][CH:57]=1)[NH:44][C:45]([O:47][CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)=[O:46]>CO.C(N(CC)CC)C.CN(C)C=O>[CH2:48]([O:47][C:45]([NH:44][C@@H:43]([C:42]([OH:65])=[O:3])[CH2:55][C:56]1[C:64]2[C:59](=[CH:60][CH:61]=[CH:62][CH:63]=2)[NH:58][CH:57]=1)=[O:46])[C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=1
Reactant: COC(=O)[C@H](CC(C)C)NC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)OCc1ccccc1
Reactant: COC(=O)[C@@H](N)CC(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CO
Product: O=C(N[C@H](Cc1c[nH]c2ccccc12)C(=O)O)OCc1ccccc1
Temperature: 0 °C

Procedure:
, and L-leucine methyl ester hydrochloride 3.96 g., are dissolved in 60 ml. of dimethylformamide, cooled in an ice bath and 2.77 ml., of triethylamine added dropwise. The stirred and cooled solution is then treated with 2.97 g. of 1-hydroxy-benzotriazole and 4.53 g. of dicyclohexylcarbodiimide. The reaction is stirred to room temperature in the melting ice bath and for twenty-four additional hours at room temperature. It is then filtered and the solvent evaporated under reduced pressure. The residue is dissolved in 300 ml. of ethyl acetate and the solution is washed with 0.5 N hydrochloric acid, saturated sodium chloride solution, twice with 5% sodium bicarbonate solution and finally with a saturated sodium chloride solution. The ethyl acetate solution is dried over magnesium sulfate and the solvent evaporated to leave a crystalline solid. The product is crystallized from 125 ml. of hot methanol to give 4.3 g. of Nα -benzyloxycarbonyl-D-tryptophyl-L-leucine methyl ester, mp. 155°-156° C; [α]D23 -21.8°, (c 2.03, methanol).
Reaction SMILES: C(N(C(C)C)CC)(C)C.O[C@@H:11]1[CH2:15][CH2:14][O:13][C:12]1=[O:16].FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[Cl:32][C:33]1[CH:41]=[CH:40][CH:39]=[C:38]2[C:34]=1[CH2:35][CH2:36][NH:37]2>ClCCl.C(OC(=O)C)C>[Cl:32][C:33]1[CH:41]=[CH:40][CH:39]=[C:38]2[C:34]=1[CH2:35][CH2:36][N:37]2[C@H:11]1[CH2:15][CH2:14][O:13][C:12]1=[O:16]
Reactant: O=C1OCC[C@H]1O
Reactant: Clc1cccc2c1CCN2
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C1OCC[C@@H]1N1CCc2c(Cl)cccc21
Temperature: -20 °C
Reaction time: 1 h
Yield: 78.3 %

Procedure:
Prepared using general procedure 57. Under an N2 atmosphere at −20° C., diisopropyl ethyl amine (7.59 g, 10.23 mL, 58.77 mmol) was added drop wise to a solution of solution of (R)-3-hydroxydihydrofuran-2(3H)-one (3 g, 29.38 mmol) in dichloromethane (50 mL). Then added trifluoromethanesulfonic anhydride (8.69 g, 5.18 mL, 30.81 mmol) drop wise by maintaining internal temperature of the reaction mixture <−20° C. Upon completion of addition, the mixture was stirred at −20° C. for 1 hour. Then added at −20° C., 4-chloro-indoline (6.74 gm, 44.07 mmol) drop wise. The reaction was allowed to warm to RT over a period of 30 minutes and continued to stir at RT for 16 hrs. The reaction mixture was diluted with 200 mL of ethylacetate and washed with saturated sodium bicarbonate (3×50 mL). The organic layer was washed with a saturated aqueous NaCl solution (2×50 mL). The solution was dried over magnesium sulfate, filtered, and concentrated. Purification via silica gel chromatography using 10-30% ethyl acetate in hexane gave (S)-3-(4-chloroindolin-1-yl)dihydrofuran-2(3H)-one as a white solid (5.47 g, 80% yield). 1H NMR (400 MHz, DMSO-d6) δ 7.03 (t, J=8.0 Hz, 1H), 6.63 (dd, J=0.6, 8.0 Hz, 1H), 6.51 (d, J=7.9 Hz, 1H), 4.91 (dd, J=9.2, 11.2 Hz, 1H), 4.45-4.40 (m, 1H), 4.30-4.23 (m, 1H), 3.55-3.48 (m, 1H), 3.28 (dd, J=8.5, 18.0 Hz, 1H), 2.99-2.94 (m, 2H), 2.40-2.32 (m, 2H). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=237.9; tR=1.51 min.
Reaction SMILES: [OH:1][C@H:2]([C:16]1[S:17][CH:18]=[CH:19][CH:20]=1)[C@@H:3]1[N:7]([CH3:8])[C:6](=[O:9])[CH2:5][C@@H:4]1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Br:21]Br.O>CC(O)=O>[Br:21][C:18]1[S:17][C:16]([C@@H:2]([OH:1])[C@@H:3]2[N:7]([CH3:8])[C:6](=[O:9])[CH2:5][C@@H:4]2[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:20][CH:19]=1
Reactant: CN1C(=O)C[C@H](c2ccccc2)[C@@H]1[C@H](O)c1cccs1
Reactant: BrBr
Solvent: O
Solvent: CC(=O)O
Product: CN1C(=O)C[C@H](c2ccccc2)[C@@H]1[C@H](O)c1ccc(Br)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 52 %

Procedure:
To 0° C. solution of (±)-(4R*,5R*)-5-((1S*)-hydroxy-2-thienylmethyl)-1-methyl-4-phenylpyrrolidin-2-one (9.76 g, 34 mmol) in AcOH (246 mL) was added bromine (2 mL 38.8 mmol). The reaction mixture was allowed to warm to room temperature, stirred for 2 h, then poured into water (500 mL). The resulting mustard colored precipitate was isolated via filtration and washed with water to yield (±)-(4R*,5R*)-5-[(1S*)(5-bromo(2-thienyl))hydroxymethyl]-1-methyl-4-phenylpyrrolidin-2-one (6.47 g, 52%): mp 105° C.; TLC (EtOAc) Rf 0.48.
Reaction SMILES: [N+](=[CH2:3])=[N-].[Cl:4][C:5]1[CH:6]=[CH:7][C:8]2[N:14]=[C:13]([C:15]([N+:18]([O-:20])=[O:19])=[N:16][OH:17])[CH2:12][N+:11]([O-:21])=[C:10]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[F:28])[C:9]=2[CH:29]=1>CCOCC.C(Cl)Cl>[Cl:4][C:5]1[CH:6]=[CH:7][C:8]2[N:14]=[C:13]([C:15]([N+:18]([O-:20])=[O:19])=[N:16][O:17][CH3:3])[CH2:12][N+:11]([O-:21])=[C:10]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[F:28])[C:9]=2[CH:29]=1
Reactant: C=[N+]=[N-]
Reactant: O=[N+]([O-])C(=NO)C1=Nc2ccc(Cl)cc2C(c2ccccc2F)=[N+]([O-])C1
Solvent: ClCCl
Solvent: CCOCC
Product: CON=C(C1=Nc2ccc(Cl)cc2C(c2ccccc2F)=[N+]([O-])C1)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of diazomethane in ether was added to a suspension of 3.8 g (0.01 mol) of 7-chloro-5-(2-fluorophenyl)-N-hydroxy-α-nitro-3H-1,4-benzodiazepine-2-methanimine 4-oxide in 200 ml of methylene chloride. The mixture was stirred for 1 hr at room temperature whereby a clear solution resulted. The excess diazomethane was destroyed by addition of acetic acid. The reaction mixture was washed with aqueous sodium bicarbonate solution, dried over sodium sulfate and evaporated. Crystallization of the residue from ether yielded yellow crystals. The analytical sample was recrystallized from ether, mp 207°-209°.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:9]=2)[N:4]([C:16]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:3]=1.[N:35]1[CH:40]=[CH:39][C:38](B2OC(C)(C)C(C)(C)O2)=[CH:37][CH:36]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[N:35]1[CH:40]=[CH:39][C:38]([C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:9]=3)[N:4]([C:16]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:3]=2)=[CH:37][CH:36]=1
Reactant: CC1(C)OB(c2ccncc2)OC1(C)C
Reactant: CCOC(=O)c1ccc2c(c1)c(Br)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)c1ccc2c(c1)c(-c1ccncc1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
To a 5 ml microwave vial equipped with a stir bar was added ethyl 3-bromo-1-trityl-1H-indazole-5-carboxylate (1095.3 mg, 2.142 mmol), pyridine-4-boronic acid pinacol ester (679 mg, 3.21 mmol), sodium carbonate (2142 μl, 4.28 mmol), dioxane (1.07E+04 μl), and PalladiumTetrakis (247 mg, 0.214 mmol). The vial was purged with nitrogen, and was then sealed and heated to 80° C. for 24 h. LCMS taken after 24 hours indicates formation of the desired product. The crude reaction mixture was filtered through a column pre-packed with celite. The combined organics were concentrated under reduced pressure and the material was dry loaded onto a 100 g column. A column was run from 100% hexanes to 100% ethyl acetate. The desired product eluted; fractions were collected and concentrated in vacuo
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:3]=1[CH:4]([OH:20])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:6]=1.[CH:26](=O)[CH:27]=[CH:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(O)(=O)C.[BH4-].C([Na])#N>CO>[C:16]([O:15][C:13]([NH:12][CH2:11][C:7]1[CH:6]=[C:5]([CH:4]([OH:20])[C:3]2[CH:21]=[C:22]([Cl:25])[CH:23]=[CH:24][C:2]=2[NH:1][CH2:26][CH:27]=[CH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:10]=[CH:9][CH:8]=1)=[O:14])([CH3:18])([CH3:19])[CH3:17]
Reactant: CC(C)(C)OC(=O)NCc1cccc(C(O)c2cc(Cl)ccc2N)c1
Reactant: O=CC=Cc1ccccc1
Agent: N#C[Na]
Agent: [BH4-]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)NCc1cccc(C(O)c2cc(Cl)ccc2NCC=Cc2ccccc2)c1
Temperature: 25 °C

Procedure:
In methanol (15 ml) were dissolved 2-amino-5-chloro-α-(3-tert-butoxycarbonylaminomethylphenyl)benzyl alcohol (0.6 g) produced in Example (1) and cinnamaldehyde.(0.5 g). To the solution was added acetic acid (0.11 g). To the mixture was added, while stirring at room temperature, cyano sodium borohydride (0.12 g). The reaction mixture was stirred for 40 minutes at 60° C., which was concentrated. The concentrate was subjected to extraction by the addition of water (30 ml) and ethyl acetate (50 ml). The organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by means of a silica gel column chromatography to give a-(3-tert-butoxycarbonylaminomethylphenyl)-5-chloro-2-[(3-phenyl)-2-propenyl]amino-benzyl alcohol (0.8 g) as a colorless oily product.
Reaction SMILES: [CH:1](OCC)=[O:2].[NH2:6][C:7]1[N:12]=[C:11]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[C:10]([O:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=[CH:9][N:8]=1>CO>[NH2:6][C:7]1[N:12]=[C:11]([N:13]2[CH2:14][CH2:15][N:16]([CH:1]=[O:2])[CH2:17][CH2:18]2)[C:10]([O:19][C:20]2[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=2)=[CH:9][N:8]=1
Reactant: CCOC=O
Reactant: Nc1ncc(Oc2ccc(Cl)cc2)c(N2CCNCC2)n1
Solvent: CO
Product: Nc1ncc(Oc2ccc(Cl)cc2)c(N2CCN(C=O)CC2)n1
Reaction time: 16 h
Yield: 53 %

Procedure:
Ethyl formate (Acros) (11 mL) was added to a solution of 2-amino-5-(4-chlorophenoxy)-4-(piperazino)pyrimidine (0.433 g, 1.41 mmoles) in methanol, and after 16 hours the solution was spin evaporated in vacuo to give a colorless syrup. The syrup was triturated under hexanes containing 1% ethyl acetate to give a solid that was collected and recrystallized from ethyl acetate to give 0.250 g (53% yield) of 2-amino-5-(4-chlorophenoxy)-4-(4-formylpiperazino)pyrimidine as white crystals, mp 159-161° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][N:6]([C:14](=[O:27])[C@@H:15]([NH:19][C:20]([O:22]C(C)(C)C)=O)[CH:16]([CH3:18])[CH3:17])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:2].CCN(C(C)C)C(C)C.C(Cl)(=O)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>CCOC(C)=O.Cl>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][N:6]([C:14](=[O:27])[C@@H:15]([NH:19][C:20](=[O:22])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH:16]([CH3:17])[CH3:18])[CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[CH3:2]
Reactant: CCOC(=O)CN(Cc1ccccc1)C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCOC(=O)CN(Cc1ccccc1)C(=O)[C@@H](NC(=O)c1ccccc1)C(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.9 %

Procedure:
To a solution of compound 702 (3.45 g, 8.8 mmol) in EtOAc at 0° C. was bubbled in gaseous HCl until saturated. The reaction was warmed to rt and stirred for 3 hr. Nitrogen was bubbled through the reaction to remove excess HCl, followed by concentration in vacuo. The residue suspended in CH2Cl2 (50 mL), treated with DIEA (3.4 mL, 19.5 mmol) followed by benzoyl chloride (1.2 mL, 10.3 mmol) and the reaction allowed to stir overnight. The reaction was concentrated in vacuo and the residue taken up into EtOAc and H2O. The layers were separated and the organic phase washed with sat. aq. NaHCO3, sat. aq. KHSO4, brine, dried over MgSO4, filtered and concentrated in vacuo to provide 3.45 g of compound 703. ##STR82##
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:4]2[C:5]([O:7][C:8](=[O:9])[C:3]=12)=[O:6].[NH3:13]>>[F:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:4]([C:5]([O-:7])=[O:6])[C:3]=1[C:8]([NH2:13])=[O:9].[NH4+:13]
Reactant: O=C1OC(=O)c2c(F)cccc21
Reactant: N
Product: NC(=O)c1c(F)cccc1C(=O)[O-]
Product: [NH4+]

Procedure:
reacting the fluorophthalic anhydride with ammonia to form ammonium fluorophthalamate.
Reaction SMILES: C([O:3][CH2:4][CH2:5][CH2:6][N:7]1[C:12](=[O:13])[C:11]2[C:14]([CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])=[C:15]([O:18][CH:19]([CH3:21])[CH3:20])[CH:16]=[N:17][C:10]=2[N:9]([CH3:27])[C:8]1=[O:28])=O.O[Li].O>C1COCC1.O.CC(=O)OCC>[OH:3][CH2:4][CH2:5][CH2:6][N:7]1[C:12](=[O:13])[C:11]2[C:14]([CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])=[C:15]([O:18][CH:19]([CH3:21])[CH3:20])[CH:16]=[N:17][C:10]=2[N:9]([CH3:27])[C:8]1=[O:28]
Reactant: CC(C)CCc1c(OC(C)C)cnc2c1c(=O)n(CCCOC=O)c(=O)n2C
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)CCc1c(OC(C)C)cnc2c1c(=O)n(CCCO)c(=O)n2C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 50.6 %

Procedure:
To a solution of 3-(5-isopentyl-6-isopropoxy-1-methyl-2,4-dioxo-1,2-dihydropyrido[2,3-d]pyrimidin-3(4H)-yl)propyl formate (48 mg, 0.123 mmol) in THF (1 mL) and water (1 mL) was added LiOH.H2O (10.3 mg, 0.246 mmol). The reaction was stirred at RT for 15 min then diluted with EA (5 mL) and water (5 mL). The organic layer was dried over Na2SO4 and concentrated to a residue which was purified by Prep HPLC to give 3-(3-hydroxypropyl)-5-isopentyl-6-isopropoxy-1-methylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (22.6 mg, 50.5% yield) as a white solid. 1H NMR (CDCl3) δ: 8.24 (s, 1H), 4.61-4.56 (m, 1H), 4.32-4.13 (m, 2H), 3.68 (s, 3H), 3.55 (d, J=5.3 Hz, 2H), 3.32 (dd, J=17.2, 9.1 Hz, 3H), 2.02-1.84 (m, 2H), 1.71 (dd, J=13.2, 6.6 Hz, 1H), 1.39 (d, J=6.0 Hz, 6H), 0.99 (d, J=6.6 Hz, 6H). LCMS: MH+ 364 and TR=3.032 min.
Reaction SMILES: [H-].[Na+].[CH:3]1([CH2:9][OH:10])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]Cl.O>CN(C)C=O>[CH:3]1([CH2:9][O:10][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][Br:11])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: ClCCCCCBr
Reactant: OCC1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: BrCCCCCOCC1CCCCC1
Yield: 419.4 %

Procedure:
60% Sodium hydride (1.16 g) was suspended in dimethylformamide (40 ml), and a solution of cyclohexanemethanol (0.3 g) in dimethylformamide (10 ml) was dropwise added under ice-cooling with stirring, which was followed by stirring at room temperature for 1 hr. The mixture was again ice-cooled, and a solution of 1-bromo-5-chloropentane (4.88 g) in dimethylformamide (10 ml) was dropwise added, which was followed by stirring at room temperature for 2.5 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and brine, dried and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to give 2.9 g of 5-(cyclohexylmethoxy)pentyl bromide.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([OH:18])=[O:17])=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].CN(C)C=O.[C:24](Cl)(=O)C(Cl)=O.[Cl-].[NH4+].[C:32]1([CH3:38])[CH:37]=CC=C[CH:33]=1>>[Br:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([O:18][CH2:33][C:32]([CH3:38])([CH3:24])[CH3:37])=[O:17])=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: Cc1ccccc1
Reactant: COc1ccc(-c2ccc(C(=O)O)cc2)cc1Br
Reactant: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2ccc(C(=O)OCC(C)(C)C)cc2)cc1Br
Temperature: 50 °C
Reaction time: 2 h

Procedure:
A stirred mixture of 3'-bromo-4'-methoxy-[1,1'-biphenyl]-4-carboxylic acid (19.2 g, 62.5 mmol) and dimethylformamide (0.1 mL) in toluene (200 mL) at 20° C. is treated with oxalyl chloride (11.0 mL, 126 mmol).The mixture is then heated at 50° C. for 1 h and then evaporated to dryness under reduced pressure. The resulting crude acid chloride is dissolved in dry tetrahydrofuran (250 mL) and added dropwise to a stirred solution of lithium tert-butylate in tetrahydrofuran (prepared by the slow addition of 32.5 mL of n-butyl lithium to a solution of 23.5 mL of dry t-butanol in 200 mL of dry tetrahydrofuran at 20° C.). The mixture is stirred for an additional 2 h, then treated with a saturated aqueous solution of ammonium chloride (400 mL) and extracted with t-butylethyl ether (2×300 mL). The combined extracts are dried (Na2SO4), filtered and the solvent is evaporated off under reduced pressure to yield the crude product which is purified by chromatography (silica gel, 20% ethyl acetate in cyclohexane) and recrystallised from t-butylethyl ether-hexane to give 3'-bromo-4'-methoxy-[1,1'-biphenyl]-4-carboxylic acid, 2,2-dimethylpropyl ester as a colourless crystalline solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[O:10])[CH:5]=[C:6]([Br:8])[CH:7]=1.ClC(OC1C=CC([N+]([O-])=O)=CC=1)=[O:19].[CH:30]([N:33]([CH:36](C)C)[CH2:34]C)(C)C.CNC>C(Cl)Cl.C1COCC1.N1C=CC=CC=1>[Br:8][C:6]1[CH:7]=[C:2]([NH:1][C:34](=[O:19])[N:33]([CH3:36])[CH3:30])[CH:3]=[C:4]([C:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[O:10])[CH:5]=1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CCN(C(C)C)C(C)C
Reactant: Nc1cc(Br)cc(C(=O)c2cccnc2)c1
Agent: CNC
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CN(C)C(=O)Nc1cc(Br)cc(C(=O)c2cccnc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 0.2 g (3-amino-5-bromo-phenyl)-pyridin-3-yl-methanone (0.72 mmol) in 5 mL of methylene chloride was added 0.16 g of 4-nitrophenyl chloroformate (0.79 mmol) and 0.12 mL of pyridine. An additional 10 mL of methylene chloride was added, and the reaction was stirred for 3 hours at room temperature at which time 0.15 mL (0.866 mmol) diisopropylethyl amine and 0.873 mL (1.75 mmol) 2 N dimethylamine in THF were added. The reaction was stirred at ambient temperature overnight, then transferred to a separatory funnel. The methylene chloride phase was washed with saturated sodium bicarbonate, dried over anhydrous sodium sulfate and concentrated. The crude product was chromatographed to give 3-[3-bromo-5-(pyridine-3-carbonyl)-phenyl]-1,1-dimethyl-urea. This material was converted to 3-[3-(1H-Indol-4-yl)-5-(pyridine-3-carbonyl)-phenyl]-1,1-dimethyl-urea as described for Example 75. 1H NMR (400 MHz, CD3OD) δ 8.97 (s, 1H), 8.75 (d, J=3.7 Hz, 1H), 8.25 (td, J=7.9, 1.9 Hz, 1H), 8.09 (t, J=1.9 Hz, 1H), 7.84 (t, J=1.9 Hz, 1H), 7.73 (t, J=1.6 Hz, 1H), 7.58 (dd, J=7.8, 4.9 Hz, 1H), 7.39 (td, J=8.0, 1.0 Hz, 1H), 7.28 (d, J=3.1 Hz, 1H), 7.17 (t, J=7.6 Hz, 1H), 7.12 (dd, J=7.3, 1.1 Hz, 1H), 6.67 (dd, J=3.1, 1.0 Hz, 1H), 3.02 (s, 6H).
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[Na].[CH3:13][O:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23]Br)=[CH:18][CH:17]=1.Cl>CO>[CH2:10]([O:9][C:1]([CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH2:23][CH2:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][O:14][CH3:13])=[CH:17][CH:18]=1)=[O:8])[CH3:11]
Reactant: COCc1ccc(CCBr)cc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: Cl
Agent: [Na]
Solvent: CO
Product: CCOC(=O)C(CCc1ccc(COC)cc1)C(=O)OCC

Procedure:
Diethyl malonate (0.32 g) is added to a solution of 0.05 g sodium in 10 mL of methanol. The 1-(methoxymethyl)-4-(2-bromoethyl)benzene (13) (0.5 g) is then added and allowed to react for 8 h. The solution is neutralized with methanolic HCl and is extracted with ether. The ether extract is dried over Na2SO4, and evaporated to yield 1-[3,3-di(ethoxycarbonyl)propyl]-4-methoxymethylbenzene (14). The methyl group is removed by treatment with aqueous HBr in acetic acid, followed by neutralization with aqueous NaOH and extraction with ether. The ether extract is dried over Na2SO4, and evaporated to yield 1-[3,3-di(ethoxycarbonyl)propyl]-4-hydroxymethylbenzene (4).
Reaction SMILES: [CH2:1]([NH:5][C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([S:22](=[O:25])(=[O:24])[NH2:23])[C:14]=1[O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:9]([OH:11])=[O:10])[CH2:2][CH2:3][CH3:4].Cl.[CH3:27]O>>[CH3:27][O:10][C:9](=[O:11])[C:8]1[CH:12]=[C:13]([S:22](=[O:25])(=[O:24])[NH2:23])[C:14]([O:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[C:6]([NH:5][CH2:1][CH2:2][CH2:3][CH3:4])[CH:7]=1
Reactant: CO
Reactant: CCCCNc1cc(C(=O)O)cc(S(N)(=O)=O)c1Oc1ccccc1
Agent: Cl
Product: CCCCNc1cc(C(=O)OC)cc(S(N)(=O)=O)c1Oc1ccccc1
Reaction time: 5 h

Procedure:
A mixture of 3-n-butylamino-4-phenoxy-5-sulphamyl-benzoic acid (3 g) and methanol (60 ml) was saturated with gaseous hydrogen chloride. The reaction mixture was allowed to warm during the saturation. After cooling and standing for 5 hours, the reaction mixture was evaporated in vacuo, and the residue was recrystallized from methanol (12 ml), whereby the methyl-3-n-butylamino-4-phenoxy-5-sulphamyl-benzoate was obtained with a melting point of 148°C.