Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[CH:4]1.[H][H].[CH3:10][O:11][C:12]([O:27][CH3:28])([C:23](CBr)=O)[C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=1>CN(C)C=O.O>[CH:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:21]=[CH:22][C:13]=1[C:12]([O:11][CH3:10])([O:27][CH3:28])[CH2:23][N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1
Reactant: c1c[nH]cn1
Reactant: COC(OC)(C(=O)CBr)c1ccc2ccccc2c1
Reactant: [H][H]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: COC(Cn1ccnc1)(OC)c1ccc2ccccc2c1
Reaction time: 24 h

Procedure:
Sodium hydroxide (0.40 g. of 50% dispersion in mineral oil) is added to 0.61 g. imidazole in 10 ml dimethylformamide and the mixture stirred at room temperature until the evolution of hydrogen is complete. Bromomethyl 2-naphthoyl ketone dimethyl ketal (2.21 g.) in 5 ml. dimethylformamide is then added and the mixture stirred for 24 hours at 110° under nitrogen. The resulting solution is poured into water (400 ml), extracted with ether (400 ml total), and the extracts washed, dried (MgSO4) and evaporated. The resulting crude solid (2.2 g) is recrystallized from toluene to give 1-[2-(2-naphthyl)-2,2-dimethoxyethyl]imidazole as a colorless solid.
Reaction SMILES: [CH3:1][N:2](S(C1C=CC(C)=CC=1)(=O)=O)[N:3]=[C:4](Cl)[C:5]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:12].[CH3:24][C:25]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][C:26]=1[O:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][N:35]=1.ClC1C=CC=CC=1Cl>C(Cl)(Cl)Cl.[Fe](Cl)(Cl)Cl>[Cl:12][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]([F:11])[C:5]=1[C:4]1[N:30]=[C:29]([C:28]2[CH:31]=[CH:32][C:25]([CH3:24])=[C:26]([O:33][C:34]3[CH:39]=[CH:38][C:37]([C:40]([F:42])([F:43])[F:41])=[CH:36][N:35]=3)[CH:27]=2)[N:2]([CH3:1])[N:3]=1
Reactant: Cc1ccc(S(=O)(=O)N(C)N=C(Cl)c2c(F)cccc2Cl)cc1
Reactant: Cc1ccc(C#N)cc1Oc1ccc(C(F)(F)F)cn1
Agent: Cl[Fe](Cl)Cl
Solvent: Clc1ccccc1Cl
Solvent: ClC(Cl)Cl
Product: Cc1ccc(-c2nc(-c3c(F)cccc3Cl)nn2C)cc1Oc1ccc(C(F)(F)F)cn1
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 44.2 %

Procedure:
A mixture of N-methyl-N-(p-toluenesulfonyl)-2-chloro-6-fluorobenzohydrazonoyl chloride (1.10 g), 4-methyl-3-(5-trifluoromethylpyridine-2-yloxy)benzonitrile (0.90 g), anhydrous iron (III) chloride (0.60 g) and o-dichlorobenzene (5 ml) is stirred at an oil bath temperature of 140° C. for 30 minutes. After cooling, it is dissolved in chloroform (100 ml) and washed with dilute hydrochloric acid, dilute aqueous solution of sodium hydroxide and saline. Then, it is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate is purified by silica gel column chromatography using mixed solvent of hexane-ethyl acetate as eluent to give 0.60 g of desired compound.
Reaction SMILES: [C:1]1([CH:7]([NH2:10])[CH2:8][CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:11][C:12]1[CH:32]=[CH:31][CH:30]=[CH:29][C:13]=1[CH2:14][N:15]1[C:23]2[C:18](=[CH:19][C:20]([C:24](O)=[O:25])=[CH:21][CH:22]=2)[C:17](C)=[C:16]1C>>[Br:11][C:12]1[CH:32]=[CH:31][CH:30]=[CH:29][C:13]=1[CH2:14][N:15]1[C:23]2[C:18](=[CH:19][C:20]([C:24]([NH:10][CH:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:8][CH3:9])=[O:25])=[CH:21][CH:22]=2)[CH:17]=[CH:16]1
Reactant: Cc1c(C)n(Cc2ccccc2Br)c2ccc(C(=O)O)cc12
Reactant: CCC(N)c1ccccc1
Product: CCC(NC(=O)c1ccc2c(ccn2Cc2ccccc2Br)c1)c1ccccc1

Procedure:
The title compound was prepared following the same protocol as described in Step 4, Example 38, using 1-phenylpropan-1-amine instead of the (S)-1-(4-nitrophenyl)ethanamine hydrochloride, and 1-(2-Bromobenzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid instead of the 1-(4-bromobenzyl)-1H-indole-5-carboxylic acid. ESI-MS (m/z): 447/449 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[O:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([CH:18]=[CH:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.[H][H]>[Pd].C(O)C>[F:31][C:28]1[CH:27]=[CH:26][C:25]([CH:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[O:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:14][CH2:13]2)=[CH:30][CH:29]=1
Reactant: CCOC(=O)C=CC1CCN(CCOC(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCC1CCN(CCOC(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Yield: 92.6 %

Procedure:
0.14 g of 10% w/w palladium-on-charcoal and 1.569 g of ethyl 3-{1-[2-bis(4-fluorophenyl)methoxyethyl]-4-piperidyl}acrylate (prepared as described in Example 1) were added to 30 ml of ethanol, and the mixture was stirred in an atmosphere of hydrogen at room temperature for 30 minutes. At the end of this time, the catalyst was removed by filtration, and the filtrate was freed from the solvent by distillation under reduced pressure, to afford 1.46 g (93% yield) of the title compound as a yellow oil.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C:21](O)=[O:22])[CH:7]=[C:8]2[C:13]=1[O:12][C:11]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)=[CH:10][C:9]2=[O:20])(=[O:3])[CH3:2].CCN(C(C)C)C(C)C.[B-](F)(F)(F)F.CN(C(ON1C(=O)CCC1=O)=[N+](C)C)C.[CH3:53][N:54]([CH3:58])[CH2:55][CH2:56][NH2:57]>C(Cl)Cl>[C:1]([C:4]1[CH:5]=[C:6]([C:21]([NH:57][CH2:56][CH2:55][N:54]([CH3:58])[CH3:53])=[O:22])[CH:7]=[C:8]2[C:13]=1[O:12][C:11]([N:14]1[CH2:15][CH2:16][O:17][CH2:18][CH2:19]1)=[CH:10][C:9]2=[O:20])(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc(C(=O)O)cc2c(=O)cc(N3CCOCC3)oc12
Reactant: CN(C)CCN
Agent: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)c1cc(C(=O)NCCN(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Reaction time: 0.25 h
Yield: 61.4 %

Procedure:
To a suspension of 8-acetyl-2-morpholino-4-oxo-4H-chromene-6-carboxylic acid (470 mg, 1.48 mmol) in DCM (10 mL) at room temperature, were added to DIPEA (0.284 mL, 1.63 mmol) and TSTU (491 mg, 1.63 mmol). The mixture was stirred for 15 minutes, N1,N1-dimethylethane-1,2-diamine (0.171 mL, 1.56 mmol) was added stirring was maintained for an additional hour. The mixture was adsorbed on silica gel and purified by flash chromatography on silica gel eluting with 5 to 10% methanol in DCM then with 10% methanolic ammonia (7 N) in DCM. The solvent was evaporated to dryness to afford 8-acetyl-N-(2-(dimethylamino)ethyl)-2-morpholino-4-oxo-4H-chromene-6-carboxamide (352 mg, 61.3%) as a beige solid. Mass Spectrum: M+H+ 388.
Reaction SMILES: C(OP([CH:9]([CH2:17][CH3:18])[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])(OCC)=O)C.C([Li])CCC.[O:24]([C@@H:42]1[CH2:47][CH2:46][CH2:45][C@H:44]([CH2:48][CH:49]=O)[CH2:43]1)[Si:25]([C:38]([CH3:41])([CH3:40])[CH3:39])([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.O>O1CCCC1.CCCCCC>[Si:25]([O:24][C@@H:42]1[CH2:47][CH2:46][CH2:45][C@H:44]([CH2:48][CH:49]=[C:9]([CH2:17][CH3:18])[C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])[CH2:43]1)([C:38]([CH3:41])([CH3:40])[CH3:39])([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CCOP(=O)(OCC)C(CC)C(=O)OC(C)(C)C
Reactant: CC(C)(C)[Si](O[C@@H]1CCC[C@H](CC=O)C1)(c1ccccc1)c1ccccc1
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCC(=CC[C@H]1CCC[C@@H](O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C1)C(=O)OC(C)(C)C
Temperature: -20 °C
Reaction time: 1 h

Procedure:
6.43 g of tert-butyl 2-(diethoxyphosphoryl)butyrate are dissolved in 90 ml of tetrahydrofuran, and 7.32 ml of a 2.7 M solution of n-butyllithium in n-hexane are added at −20° C. After 1 hour of stirring at −20° C., 4.36 g of [cis-3-(tert-butyl-diphenylsilanoxy)cyclohexyl]acetaldehyde, dissolved in 40 ml of tetrahydrofuran, are added dropwise. The reaction mixture is slowly warmed to room temperature. 50 ml of water are then added, and the mixture is extracted three times with in each case 200 ml of ethyl acetate. The combined organic phases are dried over magnesium sulfate and the solvent is then removed under reduced pressure. The residue is purified on silica gel using the mobile phase n-heptane:ethyl acetate=30:1. This gives 3.11 g of tert-butyl 4-[cis-3-(tert-butyl-diphenylsilanyloxy)cyclohexyl]-2-ethylbut-2-enoate as an oil. C32H46O3Si (506.81), Rf(n-heptane:ethyl acetate=5:1)=0.73.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[CH2:7]2)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[CH2:7]2
Reactant: O=C1Cc2cc([N+](=O)[O-])ccc2N1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc2c(c1)CC(=O)N2
Yield: 57.3 %

Procedure:
5-Nitro-2-oxindole (6.3 g) was hydrogenated in methanol over 10% palladium on carbon to give 3.0 g (60% yield) of the title compound as a white solid.
Reaction SMILES: BrBr.[K+].[Br-:4].[CH2:5]([C:7]1[CH:8]=[CH:9][C:10]([CH:13]=[CH2:14])=[N:11][CH:12]=1)[CH3:6].[OH2:15]>>[Br:4][CH2:14][CH:13]([C:10]1[CH:9]=[CH:8][C:7]([CH2:5][CH3:6])=[CH:12][N:11]=1)[OH:15]
Reactant: C=Cc1ccc(CC)cn1
Reactant: [Br-]
Reactant: O
Agent: BrBr
Agent: [K+]
Product: CCc1ccc(C(O)CBr)nc1
Temperature: 62.5 °C
Reaction time: 0.5 h
Yield: 86 %

Procedure:
5.5 g (0.0344 mol) liq. Bromine was added to a solution of 7.83 g (0.0658 mol) KBr dissolved in 100 mL water. Reaction mixture was heated to 60-65° C. and 5 g (0.0376 mol) of 5-ethyl-2-vinyl-pyridine was added into it in 10 min. Reaction mixture was stirred for 30 min. and quenched with excess of water. Product was extracted with dichloromethane, which was separated, dried, concentrated and purified to get 7.43 g (86%) of the titled product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([NH2:13])[CH:7]=1.C([O:17][C:18](=O)[CH:19]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1)[C:20](=O)[CH3:21])C>O>[CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]2[C:7]=1[C:20]([CH3:21])=[C:19]([CH2:23][C:24]1[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=1)[C:18](=[O:17])[NH:13]2.[CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]2[C:7]=1[C:18](=[O:17])[C:19]([CH2:23][C:24]1[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=1)=[C:20]([CH3:21])[NH:13]2
Reactant: CCOC(=O)C(Cc1ccc(F)cc1)C(C)=O
Reactant: COC(=O)COc1ccc(Cl)c(N)c1
Solvent: O
Product: COC(=O)COc1ccc(Cl)c2[nH]c(=O)c(Cc3ccc(F)cc3)c(C)c12
Product: COC(=O)COc1ccc(Cl)c2[nH]c(C)c(Cc3ccc(F)cc3)c(=O)c12
Temperature: 100 °C

Procedure:
A mixture of (3-amino-4-chlorophenoxy)acetic acid methyl ester (1.5 g), 2-(4-fluorobenzyl)-3-oxobutyric acid ethyl ester (1.7 g) and polyphosphoric acid (15 g) was heated at 100° C. for 3 hours. The mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The combined extracts were washed with water and saturated aqueous sodium chloride solution and then dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue purified by column chromatography on silica gel, eluting with a mixture of ethyl acetate and cyclohexane (3:7 by volume) to afford [8-chloro-3-(4-fluorobenzyl)-4-methyl-2-oxo-1,2-dihydroquinolin-5-yloxy]acetic acid methyl ester as a yellow-brown solid, 0.13 g and [8-chloro-3-(4-fluorobenzyl)-2-methyl-4-oxo-1,4-dihydroquinolin-5-yloxy]acetic acid methyl ester as a brown oil, 0.21 g.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)=O.[S-:12][C:13]#[N:14].[Na+].C([OH:18])C>>[F:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:14]=[C:13]([OH:18])[S:12][CH:2]=2)=[CH:6][CH:7]=1
Reactant: N#C[S-]
Reactant: O=C(CBr)c1ccc(F)cc1
Reactant: CCO
Agent: [Na+]
Product: Oc1nc(-c2ccc(F)cc2)cs1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
1.085 g (5 mmol) of 2-bromo-1-(4-fluoro-phenyl)-ethanone and 405 mg (5 mmol) of sodium thiocyanate in 40 ml of ethanol were heated under reflux for 30 min. Then 20 ml of ethanol were distilled off, water was added, the precipitate was filtered off, 10 ml of acetic acid, 0.5 ml of water and 0.2 ml of concentrated sulfuric acid were added, and the mixture was stirred at 100° C. for 1 h. After dilution with water, the precipitated product was filtered off, washed with water and dried. Yield: 782 mg.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[N:9][NH:10][C:11]2=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:24])=CC=1>C(#N)C>[N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[N:9][NH:10][C:11]2=[S:24])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=c1[nH]ncc2ccc([N+](=O)[O-])cc12
Solvent: CC#N
Product: O=[N+]([O-])c1ccc2cn[nH]c(=S)c2c1

Procedure:
13.9 g of 7-nitro-1(2H)-phthalazinone and 16.3 g of Lawesson reagent in 170 ml of acetonitrile are heated under reflux for 45 minutes. The reaction mixture is filtered while hot. The filtrate is cooled in an ice-bath and the crystals obtained are removed by filtration under suction. After drying in vacuo and recrystallization there is obtained 7-nitro-1(2H)-phthalazinethione as yellow crystals of m.p. 233+-234° (methanol/acetonitrile).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[OH:13])[C:6]([O:8][CH3:9])=[O:7])=[O:2].Br[CH2:15][CH3:16].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(Cl)Cl.CCOCC>[CH2:15]([O:13][C:12]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH:1]=[O:2])[CH3:16]
Reactant: CCBr
Reactant: COC(=O)c1ccc(O)c(C=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOc1ccc(C(=O)OC)cc1C=O
Temperature: 40 °C
Reaction time: 16 h
Yield: 101.2 %

Procedure:
A suspension of methyl 3-formyl-4-hydroxy-benzoate (3.0 g, 16.7 mmol), bromoethane (2.7 g, 1.85 mL, 24.9 mmol) and powdered K2CO3 (6.9 g, 49.9 mmol) in DMF (15 mL) was heated at 40° C. for 16 hours. After 16 hours, a further aliquot of bromoethane (1 mL) was added and the reaction mixture was heated for a further 2 hours. The reaction mixture was diluted with DCM (50 mL), filtered and concentrated in vacuo to give a yellow solid, which was diluted with ether (200 mL), washed sequentially with water (50 mL), sat. aq. NaHCO3 (50 mL) and brine solution (50 mL). The organics were separated, dried over MgSO4 and concentrated in vacuo to give methyl 4-ethoxy-3-formylbenzoate (3.52 g, 100%) as a white solid. ESI-MS m/z calc. 208.0. Found 209.3 (M+1)+; Retention time: 1.34 minutes (3 min run). Methyl 4-ethoxy-3-formylbenzoate (1.73 g, 8.91 mmol) was dissolved in THF (20 mL) and cooled to 0° C. LiBH4 (100 mg, 4.59 mmol) was added and the reaction mixture was stirred for 1 hour, then slowly quenched with dropwise addition of acetic acid. The reaction mixture was concentrated in vacuo, diluted with ethyl acetate (50 mL), washed sequentially with sat. aq. NaHCO3 (20 mL) and brine (20 mL). The organics were separated, dried over MgSO4 and purified by silica gel column chromatography using 0-100% EtOAc/DCM as eluent to give methyl 4-ethoxy-3-(hydroxymethyl)benzoate (1.6 g, 46%) as a white solid. ESI-MS m/z calc. 210.0. Found 211.3 (M+1)+; Retention time: 1.11 minutes (3 min run); 1H NMR (400 MHz, CDCl3) δ 8.05-7.86 (m, 2H), 6.99-6.79 (m, 1H), 4.72 (s, 2H), 4.16 (q, J=7.0 Hz, 2H), 3.89 (s, 3H), 1.64 (d, J=7.0 Hz, 2H), 1.47 (t, J=7.0 Hz, 3H).
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[S:7][CH:8]=[CH:9][N:10]=1)CCC.Br[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]2[N:31]=[CH:30][CH:29]=[CH:28][N:27]=2)[N:21]=1>C1(C)C=CC=CC=1.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>[S:7]1[CH:8]=[CH:9][N:10]=[C:6]1[C:20]1[N:21]=[C:22]([C:26]2[N:27]=[CH:28][CH:29]=[CH:30][N:31]=2)[CH:23]=[CH:24][CH:25]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Reactant: Brc1cccc(-c2ncccn2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: c1cnc(-c2cccc(-c3nccs3)n2)nc1
Reaction time: 16 h

Procedure:
Under argon, 2.69 g (7.18 mmol) of 2-tributylstannylthiazole, 1.69 g (7.18 mmol) of 2-bromo-6-pyrimidylpyridine and 0.49 g (0.43 mmol) of tetrakis(triphenylphosphine)palladium were stirred in 100 ml of toluene at 100° C. for 16 hours. For work-up, the solvent was removed under reduced pressure, the crude product was dissolved in dichloromethane and stirred with saturated potassium fluoride solution for 16 hours, the mixture was filtered through Celite and the organic phase was concentrated. Further purification by column chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate). This gave 0.93 g (54% of theory) of 2-[6-(1,3-thiazol-2-yl)pyridin-2-yl]pyrimidine which was used for subsequent reactions.
Reaction SMILES: [N+]([C:4]([CH:7]1[CH:11]([O:12]C)[O:10][C:9](=[O:14])[CH2:8]1)([CH3:6])[CH3:5])([O-])=O.C(=O)([O-])[O-].[Na+].[Na+]>CO.O>[CH:11]([C:7](=[C:4]([CH3:6])[CH3:5])[CH2:8][C:9]([OH:14])=[O:10])=[O:12]
Reactant: COC1OC(=O)CC1C(C)(C)[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)=C(C=O)CC(=O)O
Temperature: 0 °C
Reaction time: 120 h
Yield: 74.6 %

Procedure:
A solution of 18.2 g of the product of Step A in 25 ml of methanol were added all at once to a solution of 18.9 g of sodium carbonate in 180 ml of water cooled to 0° C. and the mixture stood at room temperature for 120 hours. The mixture was washed with ether and cooled to 0° C. after which concentrated sulfuric acid was added to the mixture under an inert atmosphere until the pH was ≅1. The mixture was extracted with chloroform and then with ethyl acetate and the combined organic phases were dried and evaporated to dryness under reduced pressure to obtain 9.5 g of residue. The latter was crystallized from water to obtain 7.4 g of pure 3-formyl-4-methyl-pent-3-one-1-oic acid melting at 102° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH2:9])[CH:3]=1.[CH3:10][O:11][C:12](N1C=CN=C1)=[O:13]>O1CCCC1.CCOCC>[NH2:8][C:6]1[N:5]=[C:4]([NH:9][C:12]([O:11][CH3:10])=[O:13])[CH:3]=[C:2]([Cl:1])[N:7]=1
Reactant: COC(=O)n1ccnc1
Reactant: Nc1cc(Cl)nc(N)n1
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC(=O)Nc1cc(Cl)nc(N)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
46.3 g (0.32 mol) of 6-chloro-2,4-diamino-pyrimidine are dissolved in 1000 ml of tetrahydrofuran and treated with 57.9 g (0.517 mol) of potassium tert.butylate. The gel-like precipitate is stirred at room temperature for 1 hour. A solution of 60.5 g (0.48 mol) of 1-methoxycarbonylimidazole in 100 ml of ether is added thereto at a temperature of 10° within 90 minutes. The mixture is thereafter stirred at 25° for a further 2 hours, the solvent is then evaporated under reduced pressure and the residue is dissolved in ethyl acetate. The organic solution is washed with cold water and dried over sodium sulfate. After evaporation of the solvent under reduced pressure, the residue is crystallized from acetone/ether. After recrystallization from chloroform/methanol/hexane, there is obtained methyl 2-amino-6-chloro-4-pyrimidinecarbamate of melting point 225°-226°.
Reaction SMILES: S(=O)(=O)(O)[OH:2].[OH:6][OH:7].[C:8]([OH:23])(=[O:22])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19](O)=[O:20]>>[C:8]([O:23][OH:2])(=[O:22])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:6][OH:7])=[O:20]
Reactant: O=S(=O)(O)O
Reactant: OO
Reactant: O=C(O)CCCCCCCCCCC(=O)O
Product: O=C(CCCCCCCCCCC(=O)OO)OO

Procedure:
A mixture comprising 5750 g of 96% sulfuric acid and 2350 g of 40% hydrogen peroxide was introduced into a stirred vessel and treated with 1060 g of powdered dodecanedioic acid (DDA) at 45° C. over 30 minutes. After 4 hours of reaction time, a mixture of the following composition was obtained:
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[NH:7]1[CH:11]=[N:10][CH:9]=[N:8]1.CC1C=CC(S(O[CH2:23][C@@H:24]2[C@@H:29]([OH:30])[C@H:28]([OH:31])[C@@H:27]([OH:32])[C@H:26]([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[S:42][C:43]([C:46]5[O:47][CH:48]=[CH:49][CH:50]=5)=[CH:44][N:45]=4)[CH:34]=3)[O:25]2)(=O)=O)=CC=1.O>CN(C=O)C>[N:7]1([CH2:23][C@@H:24]2[C@@H:29]([OH:30])[C@H:28]([OH:31])[C@H:27]([OH:32])[C@H:26]([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[S:42][C:43]([C:46]5[O:47][CH:48]=[CH:49][CH:50]=5)=[CH:44][N:45]=4)[CH:34]=3)[O:25]2)[CH:11]=[N:10][CH:9]=[N:8]1
Reactant: c1nc[nH]n1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2O[C@@H](c3ccc(Cl)c(Cc4ncc(-c5ccco5)s4)c3)[C@H](O)[C@@H](O)[C@@H]2O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O[C@H]1[C@H](O)[C@@H](Cn2cncn2)O[C@@H](c2ccc(Cl)c(Cc3ncc(-c4ccco4)s3)c2)[C@H]1O
Temperature: 0 °C
Reaction time: 1 h
Yield: 14 %

Procedure:
Cesium carbonate (660 mg, 2.02 mmol) was added to the solution of 1,2,4-triazole (140 mg, 2.02 mmol) in DMF (2.0 mL) at 0° C. The reaction mixture was stirred at 0° C. for 1 h. The solution of toluenesulfonate 90 (240 mg, 0.41 mmol) in DMF (1.0 mL) was added to the reaction mixture. The reaction mixture was warmed up to room temperature, stirred at room temperature for 3 d. H2O was added to the reaction mixture and then extracted with EtOAc. The organic extract was dried over anhydrous MgSO4, filtered and concentrated in vacuo. Purification by prep HPLC (C18) provided desired triazole 97 (28 mg, 14%) as a solid.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:21][C:22]1[O:23][C:24](=[O:38])[C:25]2[C:30]([C:31]=1[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[CH:29][CH:28]=[CH:27][CH:26]=2.[Br:39]C(Br)(Br)Br.C(Cl)Cl>CO>[Br:39][CH2:21][C:22]1[O:23][C:24](=[O:38])[C:25]2[C:30]([C:31]=1[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[CH:29][CH:28]=[CH:27][CH:26]=2
Reactant: O=c1oc(CO)c(-c2ccccc2)c2ccccc12
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: ClCCl
Product: O=c1oc(CBr)c(-c2ccccc2)c2ccccc12
Temperature: 25 °C
Reaction time: 72 h
Yield: 47.6 %

Procedure:
Triphenylphosphine (250 mg, 0.953 mmol) was added to a solution of 3-(hydroxymethyl)-4-phenyl-1H-isochromen-1-one (intermediate B2, 185 mg, 0.733 mmol) and perbromomethane (316 mg, 0.953 mmol) in DCM (3.7 ml, 57.5 mmol), and the resulting mixture was stirred at RT for 3 days, adding the reagents several times to achieve completion (overall 4 equivalents). The reaction was taken up with MeOH then concentrated under reduced pressure. The crude was purified over a Biotage Silica 50 g SNAP cartridge with a gradient of hexane and EtOAc to give the title compound (0.11 g, 47.6%).