Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[C:8]([C:12]([NH:14][C:15]2[CH:16]=[C:17]([CH:34]=[CH:35][CH:36]=2)[O:18][C:19]2[CH:20]=[CH:21][C:22]([NH:25][C:26]([NH:28]C(=O)OCC)=S)=[N:23][CH:24]=2)=[O:13])[CH:9]=[CH:10][CH:11]=1)([CH3:5])[CH3:4])#[N:2].C(O)C.Cl.NO.C([N:46](CC)C(C)C)(C)C>CO>[NH2:46][C:26]1[N:25]=[C:22]2[CH:21]=[CH:20][C:19]([O:18][C:17]3[CH:16]=[C:15]([NH:14][C:12](=[O:13])[C:8]4[CH:9]=[CH:10][CH:11]=[C:6]([C:3]([C:1]#[N:2])([CH3:5])[CH3:4])[CH:7]=4)[CH:36]=[CH:35][CH:34]=3)=[CH:24][N:23]2[N:28]=1
Reactant: CCOC(=O)NC(=S)Nc1ccc(Oc2cccc(NC(=O)c3cccc(C(C)(C)C#N)c3)c2)cn1
Reactant: CCN(C(C)C)C(C)C
Agent: Cl
Agent: NO
Solvent: CCO
Solvent: CO
Product: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(Oc3ccc4nc(N)nn4c3)c2)c1
Temperature: 60 °C
Yield: 76 %

Procedure:
To a solution of the above-mentioned crude product, ethyl ({5-[3-({[3-(1-cyano-1-methylethyl)phenyl]carbonyl}amino)phenoxy]pyridin-2-yl}carbamothioyl)carbamate, in methanol (100 mL)/ethanol (100 mL) were added hydroxylamine hydrochloride (4.84 g, 69.6 mmol) and N,N-diisopropylethylamine (14.6 mL, 83.5 mmol), and the mixture was stirred with heating at 60° C. for 3 hr. The reaction mixture was concentrated under reduced pressure, water (100 mL) was added to the residue, and the mixture was extracted with ethyl acetate (150 mL, 2×50 mL). The combined organic layer was washed with saturated brine (30 mL) and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH silica gel, hexane/ethyl acetate=30/70→0/100), and fractions containing the desired product were concentrated under reduced pressure to give the title compound (3.65 g, 76%) as a pale-yellow amorphous solid.
Reaction SMILES: [O:1]([CH2:8][C:9]([OH:11])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.O1CCCC1.Cl.Cl.[N:31]1([CH2:36][CH2:37][CH2:38][NH2:39])[CH:35]=[CH:34][N:33]=[CH:32]1>O>[N:31]1([CH2:36][CH2:37][CH2:38][NH:39][C:9](=[O:11])[CH2:8][O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:35]=[CH:34][N:33]=[CH:32]1
Reactant: NCCCn1ccnc1
Reactant: O=C(O)COc1ccccc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: O
Product: O=C(COc1ccccc1)NCCCn1ccnc1
Reaction time: 18 h

Procedure:
A mixture of 2.28 g. of phenoxyacetic acid, 2.43 g. of 1,1'-carbonyldiimidazole and 50 ml. of tetrahydrofuran was stirred at room temperature for 2 hours, then 3.0 g. of 1H-imidazole-1-propanamine dihydrochloride was added. The reaction mixture was stirred for 18 hours, then heated at reflux temperature for 5 hours, 5 ml. of water was added, the mixture was heated for 30 minutes and then concentrated to remove the tetrahydrofuran. The residue was treated with methylene chloride and 50 ml. of 1N sodium hydroxide and the layers separated. The organic layer was washed with water, dried over magnesium sulfate and concentrated. The residue was washed onto a filter with ether, giving the desired product, m.p. 91°-93° C.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[C:13]1([CH2:19][C:20]#N)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CN(P([N:30]([CH3:32])C)(N(C)C)=O)C.ClC[C:35]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH:38]=[CH:37][CH:36]=1>O1CCCC1>[C:43]1([CH2:20][CH2:19][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=2[C:32]#[N:30])[C:44]2[C:39](=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:40]=[CH:41][CH:42]=1
Reactant: N#CCc1ccccc1
Reactant: ClCc1cccc2ccccc12
Reactant: CN(C)P(=O)(N(C)C)N(C)C
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: N#Cc1ccccc1CCc1cccc2ccccc12
Temperature: -78 °C
Reaction time: 1 h
Yield: 95.2 %

Procedure:
5.6 mL (9.0 mmol) of n-butyllithium, 1.6 M in hexanes, was added to a solution of 1.26 mL (911 mg, 9.00 mmol) of diisopropylamine in 50 mL of THF (tetrahydrofuran) was cooled to −78° C. under nitrogen and via syringe. The mixture was stirred at −78° C. for 1 hour and a solution of 353 mg (3.00 mmol) of α-tolunitrile in 10 mL of THF was added. The solution was stirred at −78° C. for one additional hour and a solution of 1.57 mL (9.00 mmol) of HMPA and 583 mg (3.30 mmol) of 1-chloromethylnaphthalene in 10 mL of THF was added dropwise. After stirring for one additional hour at −78° C., the reaction was quenched with water and extracted with Et2O (diethyl ether) (2×30 mL). The organic layer was washed with aqueous 1 N HCl (30 mL), water (3×30 mL), brine (30 mL) and dried (Na2SO4). The solvent was evaporated to give 735 mg of crude product which is used directly next steps.
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH:6]([CH2:16][C:17]([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)=O)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl.[NH2:26][OH:27].C([O-])(O)=O.[Na+]>>[CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH:6]([CH2:16][C:17]([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)=[N:26][OH:27])[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(CC1c2ccccc2CCc2ccccc21)c1ccncc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: ON=C(CC1c2ccccc2CCc2ccccc21)c1ccncc1

Procedure:
In analogy to example 1, step 2, from 2-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)-1-pyridin-4-yl-ethanone and hydroxylamine hydrochloride in the presence of NaHCO3 was prepared the title compound containing less than 5% of the Z-isomer as a white solid, MS (ESI+): m/z=([M+H]+).
Reaction SMILES: C([O:9][C@H:10]1[C@:14]([F:16])([CH3:15])[C@H:13]([N:17]2[CH:25]=[N:24][C:23]3[C:18]2=[N:19][C:20]([NH2:27])=[N:21][C:22]=3Cl)[O:12][C@@H:11]1[CH2:28][O:29]C(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C[O-].[Na+].C[C:42](O)=[O:43]>CO>[NH2:27][C:20]1[N:19]=[C:18]2[C:23]([N:24]=[CH:25][N:17]2[C@@H:13]2[O:12][C@H:11]([CH2:28][OH:29])[C@@H:10]([OH:9])[C@:14]2([F:16])[CH3:15])=[C:22]([O:43][CH3:42])[N:21]=1
Reactant: C[C@@]1(F)[C@H](OC(=O)c2ccccc2)[C@@H](COC(=O)c2ccccc2)O[C@H]1n1cnc2c(Cl)nc(N)nc21
Reactant: CC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1nc(N)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@@]1(C)F
Temperature: 50 °C
Yield: 68.3 %

Procedure:
To a suspension of 4 (500 mg, 0.951 mmol) in MeOH (10 ml) was added NaOMe in MeOH (25%, 0.90 ml). The mixture was heated to 50° C. for 3 h. Then, it was neutralized with AcOH. It was concentrated and EtOAC (30 ml) was added. The insoluble solid was filtered off The filtrate was concentrated and purified by flash column chromatography on silica gel using 0 to 15% MeOH in CH2Cl2 as eluents. Compound 7 (203 mg, 68.3%) was obtained as a white solid: 1H NMR (400 MHz, DMSO-d6) δ 8.17 (s, 1H), 6.61 (s, 2H), 6.05 (d, J=17.6 Hz, 1H), 5.67 (d, J=7.2 Hz, 1H), 5.25 (t, J=4.8 Hz, 1H), 4.18 (dt, J=25.6, 8.0 Hz, 1H), 3.96 (s, 3H), 3.91 (dm, J=9.2 Hz, 1H), 3.85 (ddd, J=2.0, 5.2, 12.8 Hz, 1H), 3.69 (ddd, J=2.8, 3.2, 12.0 Hz, 1H), 1.06 (d, J=22.8 Hz, 3H); tR=0.52 (99.1%); LRMS (ESI) [M+H]+ calculated for C12H17FN5O4 314.3, found 314.2.
Reaction SMILES: [C:1]([C:5]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:6]=1[C:7]1[C:8](=[O:18])[CH2:9][CH2:10][CH2:11][C:12]=1[NH:13]2)([O:3][CH3:4])=[O:2].[I:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[I:19][C:20]1[CH:21]=[C:22]([CH2:23][N:13]2[C:12]3[CH2:11][CH2:10][CH2:9][C:8](=[O:18])[C:7]=3[C:6]3[C:14]2=[CH:15][CH:16]=[CH:17][C:5]=3[C:1]([O:3][CH3:4])=[O:2])[CH:25]=[CH:26][CH:27]=1
Reactant: COC(=O)c1cccc2[nH]c3c(c12)C(=O)CCC3
Reactant: BrCc1cccc(I)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc2c1c1c(n2Cc2cccc(I)c2)CCCC1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 54.5 %

Procedure:
A suspension of 5-carbomethoxy-1,2-dihydro-9H-carbazol-4(3H)-one (680 mg, 3.5 mM), 3-iodobenzyl bromide (1.2 g, 4.7 mM), and potassium carbonate (500 mg, 3.61 mM) in 20 mL DMF was stirred at room temperature for 18 hours. The mixture was diluted with ethyl acetate, washed with H2O and saturated brine, dried over anhydrous magnesium sulfate, filtered, concentrated. The residue was purified trituration with methylene chloride-diethyl ether) to afford 0.70 g (55%) of the 9-[(3-iodophenyl)methyl]-5-carbomethoxy-1,2-dihydrocarbazol-4(3H)-one as a white solid. 1H NMR (DMSO-d6) δ7.7-7.6 (m, 3H), 7.2 (m, 2H), 7.1 (t, 1H, J=8 Hz), 6.95 (d, 1H, J=8Hz), 5.6 (s, 2H), 3.8 (s, 3H), 3.0 (t, 2H, J=6 Hz), 2.5 (t, 2H, J=6 Hz), and 2.2 (m, 2H). IR (KBr, cm−1) 1732, 1639, 1441, 1421, 1273, 1117, and 763. MS (ES) m/e 458, 460.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:48][CH3:49])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:40]5[CH:45]=[CH:44][CH:43]=[C:42]([CH:46]=O)[CH:41]=5)[C:36]([F:39])=[CH:37][CH:38]=4)=[O:30])[N:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[CH3:50][C@@H:51]1[CH2:56][NH:55][CH2:54][C@H:53]([CH3:57])[NH:52]1.C(O)(=O)C>CS(C)=O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:48][CH3:49])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:40]5[CH:45]=[CH:44][CH:43]=[C:42]([CH2:46][N:55]6[CH2:54][C@H:53]([CH3:57])[NH:52][C@H:51]([CH3:50])[CH2:56]6)[CH:41]=5)[C:36]([F:39])=[CH:37][CH:38]=4)=[O:30])[N:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(F)c(-c3cccc(C=O)c3)c2)n1
Reactant: C[C@@H]1CNC[C@H](C)N1
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(F)c(-c3cccc(CN4C[C@@H](C)N[C@@H](C)C4)c3)c2)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 66.5 %

Procedure:
N-{[1,6-Diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-[(6-fluoro-3′-formyl-3-biphenylyl)methyl]-2,6-pyridinedicarboxamide (0.059 mmol) was diluted in DMSO (1.5 mL) and dispensed into a 1 dram vial containing (2R,6S)-2,6-dimethylpiperazine (0.177 mmol, 3.0 eq) and acetic acid (3.55 mg, 0.059 mmol) and fitted a magnetic stir bar. The resulting solution was stirred at room temperature for 4 h. MP-B(OAc)3H (0.591 mmol, 138 mg, 10.0 eq) was added and the solution was stirred for another 12 h. The polymer reagent was filtered. Purification was completed via a Gilson HPLC (acidic conditions). The product was dissolved in 3 mL of MeOH and passed through 0.5 g amine columns (washed with 8 mL of MeOH) to afford 29.9 mg of the title compound (66.5%). LC-MS m/z 763 (M+H)+, 1.31 min (ret time).
Reaction SMILES: C1(C)C=CC=CC=1.[NH2:8][C:9]1[CH:10]=[C:11]([CH:23]=[CH:24][CH:25]=1)/[CH:12]=[CH:13]/[C:14]1[S:15][C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[N:18]=1.Br[CH2:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31]>C(N(CC)CC)C>[CH2:33]([O:32][C:30]([CH2:29][CH2:28][CH2:27][NH:8][C:9]1[CH:10]=[C:11]([CH:23]=[CH:24][CH:25]=1)/[CH:12]=[CH:13]/[C:14]1[S:15][C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[N:18]=1)=[O:31])[CH3:34]
Reactant: CCOC(=O)CCCBr
Reactant: Nc1cccc(/C=C/c2nc3ccccc3s2)c1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)CCCNc1cccc(/C=C/c2nc3ccccc3s2)c1
Temperature: 100 °C
Reaction time: 20 h
Yield: 65.5 %

Procedure:
To 10 ml of toluene were added 1.0 g of 2-(trans-3-aminostyryl)benzothiazole, 0.78 g of ethyl 4-bromobutyrate and 0.4 g of triethylamine, and the mixture was stirred at 100° C. for 20 hours. After cooled to room temperature, the mixture was extracted with toluene, dried over anhydrous magnesium sulfate and then the solvent was evaporated under reduced pressure. The residue was purified through silica gel column chromatography by use of ethyl acetate-n-hexane to obtain 951 mg of the title compound (yield 66%).
Reaction SMILES: C[O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][CH3:14])=[C:5]([CH3:15])[C:4]=1[C:16]([C:18]1[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][C:19]=1[F:28])=[O:17]>C(Cl)Cl.C1CCCCC1>[F:28][C:19]1[CH:20]=[C:21]([C:24]([F:25])([F:27])[F:26])[CH:22]=[CH:23][C:18]=1[C:16]([C:4]1[C:5]([CH3:15])=[C:6]([O:13][CH3:14])[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[OH:2])=[O:17]
Reactant: COc1c(C)c(C(=O)c2ccc(C(F)(F)F)cc2F)c(OC)c2ccccc12
Solvent: ClCCl
Solvent: C1CCCCC1
Product: COc1c(C)c(C(=O)c2ccc(C(F)(F)F)cc2F)c(O)c2ccccc12

Procedure:
(1,4-dimethoxy-3-methylnaphthalen-2-yl)(2-fluoro-4-(trifluoromethyl) phenyl)methanone LJ123 (23 mg, 0.060 mmol) was used as a starting material and treated according to general procedure 12.1. The resulting yellow oil was purified through flash chromatography (DCM:Cyclohexane 1:1). The product was obtained as a yellow solid. Rf(DCM:Cyclohexane 1:1)=0.55. Yield=15 mg (68%).
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]([OH:42])([CH2:27][C:28]2([C:31]3[CH:36]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:34]=[CH:33][C:32]=3[F:41])[CH2:30][CH2:29]2)[C:14]([NH:16][C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[C:22](=[O:23])[O:21][CH2:20]3)=[O:15])=[CH:7][CH:6]=1)(=O)C.C(=O)(O)[O-].[Na+]>CO.C(OCC)(=O)C>[OH:42][C:13]([C:12]#[C:11][C:8]1[CH:9]=[CH:10][C:5]([OH:4])=[CH:6][CH:7]=1)([CH2:27][C:28]1([C:31]2[CH:36]=[C:35]([C:37]([F:38])([F:40])[F:39])[CH:34]=[CH:33][C:32]=2[F:41])[CH2:29][CH2:30]1)[C:14]([NH:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[C:22](=[O:23])[O:21][CH2:20]2)=[O:15]
Reactant: CC(=O)Oc1ccc(C#CC(O)(CC2(c3cc(C(F)(F)F)ccc3F)CC2)C(=O)Nc2ccc3c(c2)COC3=O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C1OCc2cc(NC(=O)C(O)(C#Cc3ccc(O)cc3)CC3(c4cc(C(F)(F)F)ccc4F)CC3)ccc21
Yield: 91 %

Procedure:
A solution of the compound described under 6 (45 mg) in 5 ml of methanol was mixed with sodium bicarbonate (130 mg). Stirring was continued for 2 more hours at 23° C. Then, the reaction mixture was diluted with ethyl acetate. Then, it was washed twice with saturated sodium chloride solution. After drying on sodium sulfate, the crude product was purified on silica gel by column chromatography. 38 mg of product was obtained.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]=[CH:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.C[C:19](C)=[O:20].C[O-:23].[Na+]>CO>[CH2:1]([N:8]1[CH2:12][CH:11]([O:20][CH3:19])[CH:10]([OH:23])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[O-]
Reactant: CC(C)=O
Reactant: C1=CCN(Cc2ccccc2)C1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC1CN(Cc2ccccc2)CC1O
Yield: 76 %

Procedure:
To a solution of 15.9 g (0.1 mol) of 1-benzyl-3-pyrroline, 12.0 g (0.12 mol) of 98% sulfuric acid, and 60.0 g of acetone in a quartz round flask reactor, 45.6 g (0.20 mol) of (NH4)2S2O8 (ammonium peroxydisulfate produced by Mitsubishi Gas Chemical Industry Co., Ltd.) was added with stirring and allowed to react for 5 days at room temperature with irradiation by 500W Xe lamps (UXL-500D xenon lamp produced by Ushio). 57.9 g (0.3 mol) of 28 wt % NaOMe in methanol solution (produced by Katayama Chemical Industry Co., Ltd.) was continuously added to the reaction mixture and stirred for 5 hours under reflux. After completion, acetone and methanol were evaporated under reduced pressure, and extracted with toluene and water. After the solvent was evaporated under reduced pressure, 15.8 g of 1-benzyl-4-methoxy-3-pyrrolidinol (yield 76.0%) was obtained.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:17][CH2:18][O:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][O:21]1>CN(C=O)C>[CH3:13][O:12][C:10](=[O:11])[CH2:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:17][CH2:18][O:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21]2)=[CH:7][CH:6]=1
Reactant: COC(=O)CCc1ccc(O)cc1
Reactant: BrCCOC1CCCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CCc1ccc(OCCOC2CCCCO2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Methyl 3-(4-hydroxyphenyl)propionate (0.1 g, 0.55 mmol) is dissolved in DMF (5 ml) and NaH (0.033 g of a 60% dispersion in mineral oil, 0.83 mmol) is added. The reaction mixture is stirred at room temperature for 15 minutes then 2-(2-bromethoxy)tetrahydro-2-H-pyran (0.109 ml, 0.72 mmol) is added and the reaction mixture is left to stir for 18 hours. Dilution with EtOAc (50 ml), washing with water (25 ml), saturated NaHCO3 (25 ml) and brine (25 ml), drying over MgSO4, and concentration in vacuo yields 3-{-4-[2-(Tetrahydro-pyran-2-yloxy)-ethoxy]-phenyl}-propionic acid methyl ester as a colourless oil; [M+H]+ 309
Reaction SMILES: [CH3:1][O-:2].[Na+].[Br:4][C:5]1[CH:10]=[C:9](F)[CH:8]=[CH:7][C:6]=1[C:12]([C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH3:21])=[CH:16][CH:15]=1)=[O:13].O>CN(C=O)C>[Br:4][C:5]1[CH:10]=[C:9]([O:2][CH3:1])[CH:8]=[CH:7][C:6]=1[C:12]([C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH3:21])=[CH:16][CH:15]=1)=[O:13]
Reactant: C[O-]
Reactant: CCc1ccc(C(=O)c2ccc(F)cc2Br)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1ccc(C(=O)c2ccc(OC)cc2Br)cc1
Reaction time: 3 h

Procedure:
Sodium methoxide (10.5 g) is added portionwise to (2-bromo-4-fluoro-phenyl)-(4-ethyl-phenyl)-methanone (43.0 g) dissolved in DMF (200 mL). The solution is stirred overnight, before another portion of sodium methoxide (5.5 g) is added. After another 3 h of stirring, water is added and the resulting mixture is extracted with ethyl acetate. The organic phase is dried (sodium sulphate), the solvent is removed and the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 20:1->9:1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:16])[C:13]=2[F:15])[N:8]=[CH:7][C:6]=1[O:17][C:18](=[O:20])[CH3:19])=[O:4].[C:21]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.CO.ClCCl>[CH3:1][O:2][C:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:16][CH3:21])[C:13]=2[F:15])[N:8]=[CH:7][C:6]=1[O:17][C:18](=[O:20])[CH3:19])=[O:4]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: COC(=O)c1c(OC(C)=O)cnc2ccc(O)c(F)c12
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: ClCCl
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1c(OC(C)=O)cnc2ccc(OC)c(F)c12
Temperature: 25 °C
Reaction time: 3 h
Yield: 65.1 %

Procedure:
Methanol (0.52 mL, 12.72 mmol, 3.0 eq) is added at room temperature to a stirred solution of 3-acetoxy-5-fluoro-6-hydroxy-quinoline-4-carboxylic acid methyl ester (1.18 g, 4.24 mmol, 1.0 eq) in tetrahydrofuran (50 mL), followed by triphenylphosphine (2.22 g, 12.72 mmol, 3.0 eq) and diethyl azodicarboxylate (1.48 g, 12.72 mmol, 3.0 eq). After 3 hours stirring at room temperature, solvent is evaporated to give a crude product that is purified by column chromatography (silica gel, eluent: dichloromethane:methanol, 30:1, v/v) to afford 3-acetoxy-5-fluoro-6-methoxy-quinoline-4-carboxylic acid methyl ester as a yellow oil (0.81 g, 65% yield).
Reaction SMILES: [C:1]1([C:7]2[N:11]3[CH:12]=[N:13][N:14]=[C:15]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[C:10]3=[N:9][C:8]=2[OH:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.Cl[CH2:25][C:26]1[N:27]([CH3:31])[N:28]=[CH:29][N:30]=1.[H-].[Na+].C(Cl)Cl>CN(C)C=O>[C:1]1([C:7]2[N:11]3[CH:12]=[N:13][N:14]=[C:15]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)[C:10]3=[N:9][C:8]=2[O:22][CH2:25][C:26]2[N:27]([CH3:31])[N:28]=[CH:29][N:30]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Oc1nc2c(-c3ccccc3)nncn2c1-c1ccccc1
Reactant: Cn1ncnc1CCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cn1ncnc1COc1nc2c(-c3ccccc3)nncn2c1-c1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 3,8-diphenylimidazo[1,2-d][1,2,4]triazin-2-ol (500 mg, 1.74 mmol) and 3-chloromethyl-2-methyl-2H-[1,2,4]triazole hydrochloride (320 mg, 1.91 mmol) in anhydrous N,N-dimethylformamide under an atmosphere of nitrogen was added sodium hydride (153 mg of a 60% dispersion in oil, 3.8 mmol). The reaction mixture was stirred at room temperature for 72 h. The mixture was partitioned between EtOAc (80 ml) and water (150 ml), the organic layer was separated, and the aqueous layer extracted with a further two portions of EtOAc (80 ml). The combined EtOAc layers were washed with saturated NaCl solution (100 ml), separated, dried over MgSO4 and evaporated in vacuo. The residue was purified by flash chromatography (SiO2; 2% MeOH in CH2Cl2+0.5% NH3), and the product recrystallised from CH2Cl2 to afford 235 mg (0.6 mmol, 35%) as a white solid. (Found: C, 63.66; H, 4.23; N, 24.54; C21H17N7O.0.5H2O.0.07CH2Cl2 requires C, 63.47; H, 4.59; N, 24.59%); m.p. 179° C. (from CH2Cl2); δH (400 MHz; CDCl3) 3.95 (3H, s, NCH3), 5.75 (2H, s, OCH2), 7.46 (1H, t, J 7.3, aromatic), 7.52-7.60 (5H, m, aromatics), 7.63 (2H, d, J 7.6, aromatics), 7.88 (1H, s, triazole H5), 8.57-8.65 (2H, br m, aromatics), 9.43 (1H, s, imidazotriazine H5); m/z (ES+) 384 (M++H, 100%).
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[NH:6][C:5](=[O:7])[N:4]([C:8]2[CH:13]=[CH:12][C:11](I)=[C:10]([C:15]([F:18])([F:17])[F:16])[CH:9]=2)[C:3]1=[O:19].[Cu](C#N)[C:22]#[N:23]>CN(C)C=O>[CH3:1][C:2]1([CH3:20])[C:3](=[O:19])[N:4]([C:8]2[CH:13]=[CH:12][C:11]([C:22]#[N:23])=[C:10]([C:15]([F:18])([F:17])[F:16])[CH:9]=2)[C:5](=[O:7])[NH:6]1
Reactant: N#C[Cu]C#N
Reactant: CC1(C)NC(=O)N(c2ccc(I)c(C(F)(F)F)c2)C1=O
Solvent: CN(C)C=O
Product: CC1(C)NC(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C1=O
Reaction time: 1 h
Yield: 75.5 %

Procedure:
184 g of the product of Example 2 is introduced at 20°±2° C. and 66.15 g of copper cyanide and 420 ml of dimethylformamide are added under agitation the whole is heated while distilling the methylene chloride until a temperature of 130° C. is obtained in the reaction medium and then it is maintained for 5 hours under agitation at this temperature. The medium is cooled down to 20°±2° C. under agitation, maintained for 1 hour under these conditions followed by separation and washing with 3×0.3 vol of dimethylformamide. Then 700 ml of pure 22°Be ammonium hydroxide and 700 ml of demineralized water are added to the mixture agitated at 20°±2° C. Agitation is carried out for 1 hour at 20°±2° C. then the whole is cooled down to 0°±5° C., maintained for 1 hour under agitation at 0°±5° C., followed by separating and washing with 2×140 ml of pure 22°Be ammonium hydroxide at 20°±2° C. then with 4×140 ml of demineralized water then drying. Purification is carried out by adding 1105 ml of ethyl acetate then taking to reflux under agitation and then 12.3 g of acticarbon black CX is added. The reaction medium is maintained under agitation under reflux for 30 minutes, then filtered, followed by washing with 3×61 ml of boiling ethyl acetate, concentration under agitation, cooling down under agitation to 0°±2° C. and maintaining under these conditions for 2 hours. Separation, washing with 3×37 ml of ethyl acetate at 0°±2° C. and drying are carried out. In this way 103.7 g of expected product (clear beige powder) is obtained.
Reaction SMILES: [CH3:1][S:2]([N:5]([C:10]1[CH:19]=[C:18]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:17]=[CH:16][C:11]=1[C:12]([O:14]C)=[O:13])S(C)(=O)=O)(=[O:4])=[O:3].O.[OH-].[Li+].Cl>CO>[CH3:1][S:2]([NH:5][C:10]1[CH:19]=[C:18]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:17]=[CH:16][C:11]=1[C:12]([OH:14])=[O:13])(=[O:3])=[O:4]
Reactant: COC(=O)c1ccc(S(C)(=O)=O)cc1N(S(C)(=O)=O)S(C)(=O)=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CS(=O)(=O)Nc1cc(S(C)(=O)=O)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A suspension of methyl 2-[N,N-bis(methylsulphonyl)amino]-4-methylsulphonylbenzoate (22.9 g) and lithium hydroxide monohydrate (7.5 g) in aqueous methanol (50%) was stirred at room temperature for 18 hours. The resulting solution was acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The combined organic extracts were dried (magnesium sulphate), filtered and evaporated to yield 2-methylsulphonylamino-4-methylsulphonylbenzoic acid as a beige solid. NMR (acetone d6): 3.1(2s,6H). 7.57(dd,1H), 8.15(d,1H), 8.23(d,1H).