Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][CH2:10][CH2:11][N:12]=[N+]=[N-])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]>CO.[Pd]>[CH2:6]([O:5][P:4]([CH2:9][CH2:10][CH2:11][NH2:12])(=[O:8])[O:3][CH2:1][CH3:2])[CH3:7]
Reactant: CCOP(=O)(CCCN=[N+]=[N-])OCC
Agent: [Pd]
Solvent: CO
Product: CCOP(=O)(CCCN)OCC
Reaction time: 3 h
Yield: 97.2 %

Procedure:
(3-Azidopropyl)phosphonic acid diethyl ester (240 mg, 1.08 mmol) and activated Pd/C (20 mg) were suspended in methanol (50 ml) and stirred under H2 atmosphere at 40 psi for 3 hours. The black suspension was filtered on Celite, and the solvent was removed under vacuum to give pure (3-aminopropyl)phosphonic acid diethyl ester (205 mg, 99% yield).
Reaction SMILES: C1C=C[NH+]=CC=1.[Br:7][Br-]Br.[BrH:10].[C:11]([C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1)(=[O:13])[CH3:12]>C(O)(=O)C>[BrH:7].[Br:10][CH2:12][C:11]([C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1)=[O:13]
Reactant: CC(=O)c1ccncc1
Agent: Br
Agent: c1cc[nH+]cc1
Solvent: CC(=O)O
Product: O=C(CBr)c1ccncc1
Temperature: 25 °C

Procedure:
A twelve-liter three neck flask fitted with an efficient mechanical stirrer, 250 mL dropping funnel, and internal thermometer was charged with glacial acetic acid (5000 mL), pyridinium bromide perbromide (90%, 830 g, 2.60 mol) and 30% hydrobromic acid in acetic acid (525 mL). After stirring at room temperature for ninety minutes, 4-acetylpyridine (250 g, 2.07 mol) was added dropwise over forty-five minutes. Upon completion of the addition the reaction mixture was cooled with an ice bath to 15° C. and the product, which had precipitated, was collected by filtration, washed with ether and air dried. The crude α-bromo-4-acetylpyridine hydrobromide (566.3 g, 97%) was sufficiently pure for subsequent reactions. mp. 177.5°-182.0° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[NH:9]1[CH2:14][CH2:13][CH:12]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:11][CH2:10]1>CN1C(=O)CCC1.CCOC(C)=O>[Cl:8][C:4]1[N:3]=[C:2]([N:9]2[CH2:10][CH2:11][CH:12]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:20])([CH3:19])[CH3:21])[CH2:13][CH2:14]2)[CH:7]=[CH:6][CH:5]=1
Reactant: Clc1cccc(Cl)n1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC1CCN(c2cccc(Cl)n2)CC1

Procedure:
TEA (0.13 ml, 0.99 mmol) and 2,6-dichloropyridine (0.14 g, 0.99 mmol) were added to a solution of tert-butyl piperidin-4-ylcarbamate (0.20 g, 0.99 mmol) in NMP (2 ml) at room temperature. Using a Smith Microwave Synthesizer, the mixture was subjected to single-mode microwave at 150° C. for 30 minutes. The mixture was diluted with EtOAc and washed with water three times. The organic phase was dried over magnesium sulfate and concentrated to give the title compound. (300 mg).
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#N)=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[H-].C([Al+]CC(C)C)C(C)C.S(=O)(=O)(O)[OH:31]>C1(C)C=CC=CC=1>[CH:18]([C:15]1[CH:16]=[CH:17][C:12]([C:9]2[CH:10]=[CH:11][C:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])=[CH:7][CH:8]=2)=[CH:13][CH:14]=1)=[O:31]
Reactant: O=S(=O)(O)O
Reactant: CCCCCc1ccc(-c2ccc(C#N)cc2)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: CCCCCc1ccc(-c2ccc(C=O)cc2)cc1
Temperature: 25 °C
Reaction time: 22 h
Yield: 93 %

Procedure:
A solution of 6.23 g of 4'-pentyl-4-cyanobiphenyl in 50 ml of absolute toluene was placed at 0° C. in a sulphonation flask under argon gasification and treated within 10 minutes with 27 ml of a 1.36N solution of diisobutylaluminium hydride in toluene. After completion of the addition, the mixture was stirred at room temperature for a further 22 hours, then poured cautiously into 50 ml of 1N sulphuric acid and extracted three times with 100 ml of diethyl ether each time. The organic phases were washed once with 50 ml of 1N sulphuric acid and twice with 50 ml of water each time, dried over magnesium sulphate and concentrated. Low-pressure chromatography (0.5 bar) of the oily residue (6.0 g on silica gel with 10% ethyl acetate/petroleum ether gave 5.86 g (93%) of 4-formyl-4'-pentylbiphenyl as a colourless viscous oil (purity 99.7%).
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:6]2[C:7]([O:9][C:10](=O)[C:5]=12)=[O:8])([O-:3])=[O:2].O.[NH2:16][NH2:17]>C(O)(=O)C>[N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:6]2[C:5]=1[C:10](=[O:9])[NH:16][NH:17][C:7]2=[O:8])([O-:3])=[O:2]
Reactant: NN
Reactant: O=C1OC(=O)c2c1cccc2[N+](=O)[O-]
Solvent: O
Solvent: CC(=O)O
Product: O=c1[nH][nH]c(=O)c2c([N+](=O)[O-])cccc12
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
A glass flask of the volume 1 l provided with an agitator, a thermometer, a condenser and a capillary was filled with 600 ml of icy acetic acid and 154.5 g (0.8 mole) of 3-nitrophthalic acid anhydride, thereafter it was heated to the temperature of 110° C. and gradually 44.1 g (0.88 mole) of hydrazine hydrate was added. Next the reaction mixture was kept at the state of boiling for 30 minutes thereafter it was cooled to the temperature of 80° C., the crystals of 5-nitro-2,3-dihydrophthalazine-1,4-dione were filtered, the sediment was washed on a filter with 50 ml of acetic acid and two times with 40 ml of distilled water. The total amount of 5-nitro-2,3-dihydrophthalazine-1,4-dione was 228.7 g, the yield was 92%.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[C:10]([O:12][CH2:13][CH:14]([CH3:16])[CH3:15])[CH:9]=[CH:8][C:7]=1[C:17](=[N:36][OH:37])[C:18]1[CH:19]=[CH:20][C:21]([O:31][CH2:32][CH:33]([CH3:35])[CH3:34])=[C:22]([CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:23]=1)[CH:2]([CH3:4])[CH3:3].[H-].[Na+].Br[CH2:41][C:42]([NH2:44])=[O:43].Cl>CN(C)C=O.O.C(OCC)(=O)C>[NH2:44][C:42](=[O:43])[CH2:41][O:37][N:36]=[C:17]([C:7]1[CH:8]=[CH:9][C:10]([O:12][CH2:13][CH:14]([CH3:15])[CH3:16])=[CH:11][C:6]=1[O:5][CH2:1][CH:2]([CH3:4])[CH3:3])[C:18]1[CH:19]=[CH:20][C:21]([O:31][CH2:32][CH:33]([CH3:35])[CH3:34])=[C:22]([CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:23]=1
Reactant: CCOC(=O)CCc1cc(C(=NO)c2ccc(OCC(C)C)cc2OCC(C)C)ccc1OCC(C)C
Reactant: NC(=O)CBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CCc1cc(C(=NOCC(N)=O)c2ccc(OCC(C)C)cc2OCC(C)C)ccc1OCC(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49.1 %

Procedure:
In 5 ml of N,N-dimethylformamide is dissolved 2.0 g of ethyl 3-{5-[(2,4-diisobutoxyphenyl)-(hydroxyimino)methyl]-2-isobutoxyphenyl}propanoate, to which is added 0.19 g of 60% sodium hydride. The mixture thus obtained is stirred at ambient temperature for 30 minutes. Then, 1.07 g of 2-bromoacetamide is added and the mixture thus obtained is stirred at ambient temperature for one hour and further at 80° C. for 15 minutes. The reaction mixture is added to a mixture of ethyl acetate and water, pH is adjusted to 2 with 6 mol/L hydrochloric acid, and the organic layer is separated. The organic layer thus obtained is washed with water and saturated aqueous solution of sodium chloride successively and dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue thus obtained is purified by silica gel column chromatography (eluent; hexane:ethyl acetate=2:1) to obtain 1.09 g of ethyl 3-{5-[[(2-amino-2-oxoethoxy)imino](2,4-diisobutoxyphenyl)methyl]-2-isobutoxyphenyl}propanoate as a colorless oily product.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:32][CH3:33])[CH2:4][NH:5][CH:6]([C:10]1[N:11]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24][CH:23]=2)[C:12](=[O:20])[C:13]2[CH:19]=[CH:18][N:17]=[CH:16][C:14]=2[N:15]=1)[CH:7]([CH3:9])[CH3:8].[C:34](Cl)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][O:2][CH:3]([O:32][CH3:33])[CH2:4][N:5]([CH:6]([C:10]1[N:11]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24][CH:23]=2)[C:12](=[O:20])[C:13]2[CH:19]=[CH:18][N:17]=[CH:16][C:14]=2[N:15]=1)[CH:7]([CH3:9])[CH3:8])[C:34](=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COC(CNC(c1nc2cnccc2c(=O)n1Cc1cccc2ccccc12)C(C)C)OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(CN(C(=O)c1ccccc1)C(c1nc2cnccc2c(=O)n1Cc1cccc2ccccc12)C(C)C)OC

Procedure:
A solution of 2-[1-(2,2-dimethoxy-ethylamino)-2-methyl-propyl]-3-naphthalen-1-ylmethyl-3H-pyrido-[3,4-d]pyrimidin-4-one (522 mg, 1.17 mmol), benzoyl chloride (247 mg, 1.76 mmol), and triethylamine (179 mg, 1.76 mmol) in methylene chloride (10 mL) is stirred at room temperature for 18 h. The reaction is washed sequentially with 0.5 N HCl, water, 5% NaHCO3, water, and brine. The organic layer is dried (Na2SO4) and concentrated to yield the title compound, N-(2,2-dimethoxy-ethyl)-N-[2-methyl-1-(3-naphthalen-1-ylmethyl-4-oxo-3,4-dihydro-pyrido[3,4-d]pyrimidin-2-yl)-propyl]-benzamide.
Reaction SMILES: ClC1C=C(S([NH:12][C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[N:18]([CH3:22])[C:17](=[O:23])[CH2:16]3)(=O)=O)C=C(Cl)C=1>CO>[NH2:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[N:18]([CH3:22])[C:17](=[O:23])[CH2:16]2
Reactant: CN1C(=O)Cc2cc(NS(=O)(=O)c3cc(Cl)cc(Cl)c3)ccc21
Solvent: CO
Product: CN1C(=O)Cc2cc(N)ccc21

Procedure:
The reaction is carried out in methanol. The crude product is further reacted directly in V (5).
Reaction SMILES: [CH2:1]([CH:8]([CH2:19][OH:20])[CH:9]([C:11]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][C:12]=1F)[OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+]>O1CCCC1>[CH2:1]([C@@H:8]1[C@@H:9]([OH:10])[C:11]2[C:16](=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=2)[O:20][CH2:19]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCC(Cc1ccccc1)C(O)c1ccc(Br)cc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O[C@H]1c2ccc(Br)cc2OC[C@@H]1Cc1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of (1 R, 2S)-2-benzyl 1-(4-bromo-2-fluoro-phenyl)-propane-1,3-diol (prepared from 33.5 kg (54.8 moles) of [4R-[3(2R,3R)]]-4-benzyl-3-[2-benzyl-3-(4-bromo-2- fluoro-phenyl)-3-hydroxy-propionyl]-oxazolidin-2-one, 1-methyl-2-pyrrolidinone solvate without isolation) in 185 L of tetrahydrofuran was added 12.9 kg (115 mol) of potassium tert-butoxide. The reaction mixture was heated at reflux for 4 hours at which point the reaction was found to be complete by thin layer chromatography (hexanes/ethyl acetate, 3:1). The reaction mixture was cooled to ambient temperature, quenched with 170 L of water, diluted with 83 L of ethyl acetate, and acidified to pH 5.3 (aqueous layer) with 7.5 L of concentrated hydrochloric acid. The organic layer was concentrated under vacuum to approximately 38 L of a slurry, diluted with 76 L of isopropyl ether, warmed to dissolve the solids, slowly cooled to 0° C., and granulated at 0° C. for 12 hours. (3S, 4R)-3-Benzyl-7-bromo-chroman-4-ol, 5.1 kg of white solid, was isolated by filtration. The mother liquor was washed with 4 L of saturated aqueous sodium chloride, concentrated to a final volume of 57 L, and granulated at 0° C. for 12 hours affording a 4.3 kg second crop of (3S, 4R)-3-benzyl-7-bromo-chroman-4-ol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:10]=1[O:19]CC1C=CC=CC=1>C(O)C.[Pt]>[NH2:8][C:6]1[CH:5]=[CH:4][C:3]([C:9]2[C:10]([OH:19])=[CH:11][CH:12]=[C:13]([C:15]([F:16])([F:17])[F:18])[CH:14]=2)=[C:2]([Cl:1])[CH:7]=1
Reactant: Nc1ccc(-c2cc(C(F)(F)F)ccc2OCc2ccccc2)c(Cl)c1
Agent: [Pt]
Solvent: CCO
Product: Nc1ccc(-c2cc(C(F)(F)F)ccc2O)c(Cl)c1
Reaction time: 18 h

Procedure:
5% Pt/C (0.088 g) was added to a solution of the product from step (i) in ethanol (20 ml) and hydrogenated at RT and 1 bar for 18 h. Extra Pt/C (0.1 g) was added and hydrogenated for a further 3 h at 2 bar. The catalyst was removed by filtration and the filtrate evaporated to leave a solid residue. The residue was purified by chromatography on silica eluting with 50% EtOAc/isohexane. Yield 0.083 g.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.Br[C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH2:14][OH:15].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CCOC(C)=O.O.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>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:12]2[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=2[CH2:14][OH:15])=[CH:4][CH:3]=1
Reactant: OCc1ccccc1Br
Reactant: OB(O)c1ccc(F)cc1
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: CCOC(C)=O
Solvent: COCCOC
Solvent: O
Product: OCc1ccccc1-c1ccc(F)cc1
Temperature: 115 °C

Procedure:
To a mixture of 4-fluorophenylboronic acid (2.5 g, 13.4 mmol), 2-bromobenzyl alcohol (2.131 g, 20.1 mmol) and Pd(PPh3)4 (0.25 g, 0.216 mmol) in DME (20 mL) is added an aqueous solution of Na2CO3 (11.5 mL, 2.7 M, 31 mmol). The mixture is heated to 115° C. in sealed vessel overnight. The reaction is allowed to cool to room temperature and is diluted with EtOAc and water. The aqueous layer is extracted further with EtOAc (2×). The combined organic layers are washed with water, saturated NH4Cl, brine and dried over Na2SO4. After concentration, the resulting residue is purified by flash chromatography (hexane/CH2Cl2) to give (4′-fluorobiphenyl-2-yl)-methanol as oil. (cas #773871-75-3) 1H NMR (400 MHz, CDCl3) δ (ppm) 7.46-7.43 (m, 1H), 7.32-7.22 (m, 4H), 7.18-7.16 (m, 1H), 7.04-6.99 (m, 2H), 4.48 (d, J=5.5 Hz, 2H), 1.68 (br s, 1H).
Reaction SMILES: [N:1]1([C:6]([O:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([NH:15][C:16]3[N:24]=[C:23]4[C:19]([NH:20][C:21](=[O:33])[N:22]4[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[O:31][CH3:32])=[C:18]([C:34]([O:36]CC)=O)[N:17]=3)[CH2:11][CH2:10]2)=[O:7])C=CN=C1.[NH2:39]C1C(C(OCC)=O)=NC(N[C@H]2CC[C@H](O)CC2)=NC=1NC1C=CC=CC=1OC>ClCCl>[C:6](=[O:7])([O:8][C@H:9]1[CH2:10][CH2:11][C@H:12]([NH:15][C:16]2[N:24]=[C:23]3[C:19]([NH:20][C:21](=[O:33])[N:22]3[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[O:31][CH3:32])=[C:18]([C:34](=[O:36])[NH2:39])[N:17]=2)[CH2:13][CH2:14]1)[NH2:1]
Reactant: CCOC(=O)c1nc(N[C@H]2CC[C@H](OC(=O)n3ccnc3)CC2)nc2c1[nH]c(=O)n2-c1ccccc1OC
Reactant: CCOC(=O)c1nc(N[C@H]2CC[C@H](O)CC2)nc(Nc2ccccc2OC)c1N
Solvent: ClCCl
Product: COc1ccccc1-n1c(=O)[nH]c2c(C(N)=O)nc(N[C@H]3CC[C@H](OC(N)=O)CC3)nc21

Procedure:
Ethyl 2-(trans-4-(1H-imidazole-1-carbonyloxy)cyclohexylamino)-9-(2-methoxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxylate. Ethyl 5-amino-2-(trans-4-hydroxycyclohexyl amino)-6-(2-methoxyphenylamino)pyrimidine-4-carboxylate (0.240 g, 0.598 mmol) and 1,1′-1,1′-carbonyldiimidazole (0.968 g, 5.98 mmol) in dichloromethane (20 mL) were reacted according to general procedure F and purified using biotage chromatography (40-100% ethyl acetate in hexanes) to afford a mixture of the title product and the cleaved free hydroxyl product. MS (ESI) m/z 522.5 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[NH:9]1[CH2:17][CH2:16][CH:12]([C:13](O)=O)[CH2:11][CH2:10]1.[OH-].[Na+]>>[O:8]1[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=[C:13]1[CH:12]1[CH2:16][CH2:17][NH:9][CH2:10][CH2:11]1
Reactant: O=C(O)C1CCNCC1
Reactant: Nc1ccccc1O
Agent: [Na+]
Agent: [OH-]
Product: c1ccc2oc(C3CCNCC3)nc2c1
Yield: 12.2 %

Procedure:
A mixture of 2-aminophenol (20 g, 183 mmol), isonipecotic acid (23.7 g, 1 mol. equiv.) and polyphosphoric acid (50 ml) was heated together for 2 hours with stirring. The reaction mixture was cooled, poured onto ice (400 g) and solid sodium hydroxide (85 g) added until the solution achieved pH8. The solid was filtered off, slurried in water (500 ml) and filtered to give the title compound (4.5 g).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=O)=[CH:2]1.C(Cl)(=O)C(Cl)=O.Cl.[CH3:20][NH:21][O:22][CH3:23].C(N(CC)CC)C>ClCCl.CN(C=O)C>[CH3:23][O:22][N:21]([CH3:20])[C:10]([C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1)=[O:12]
Reactant: CNOC
Reactant: O=C(O)c1c[nH]c2ccccc12
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.7 %

Procedure:
Indole-3-carboxylic acid (2.50 g, 0.0155 mol) was suspended in dichloromethane (60 ml) and treated with oxalyl chloride (1.62 ml, 0.0186 mol), followed by a drop of dry DMF. The reaction mixture was then stirred at room temperature overnight, before being evaporated under reduced pressure and dried in vacuo. The product was then redissolved in dichloromethane (50 ml) and added slowly to a solution of N,O-dimethylhydroxylamine hydrochloride (1.59 g, 0.0163 mol) in dichloromethane (50 ml) containing triethylamine (4.53 ml, 0.0326 mol) under argon. The resultant mixture was then stirred at room temperature for 2h, before being washed with water, followed by aq. NaHCO3. The organic layer was then dried (Na2SO4), evaporated under reduced pressure and dried in vacuo to yield the title compound as white solid (2.46 g, 78%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][C:14]([CH3:20])([CH3:19])[CH2:15][C:16](O)=[O:17])[CH2:11][O:10][C:9]1([CH3:22])[CH3:21])=[O:7])([CH3:4])([CH3:3])[CH3:2].O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.[CH3:38][O:39][C:40](=[O:52])[NH:41][CH:42]1[CH2:51][C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[NH:44][CH2:43]1.[OH-].[Na+]>C(Cl)Cl.C(N(CC)CC)C>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][C:14]([CH3:20])([CH3:19])[CH2:15][C:16]([N:44]2[C:45]3[C:50](=[CH:49][CH:48]=[CH:47][CH:46]=3)[CH2:51][CH:42]([NH:41][C:40]([O:39][CH3:38])=[O:52])[CH2:43]2)=[O:17])[CH2:11][O:10][C:9]1([CH3:22])[CH3:21])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)NC1CNc2ccccc2C1
Reactant: CC(C)(CC(=O)O)C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)NC1Cc2ccccc2N(C(=O)CC(C)(C)C[C@H]2COC(C)(C)N2C(=O)OC(C)(C)C)C1
Temperature: 15 °C
Reaction time: 2 h

Procedure:
8.88 ml of triethylamine are added to a solution of 6.67 g of 4(S)-(3-carboxy-2,2-dimethyl-propyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester in 200 ml of methylene chloride under argon. The mixture is cooled to 15° C. and 5.54 g of bis(2-oxo-3-oxazolidinyl)phosphinic chloride are added. The mixture is stirred at room temperature for 2 hours. A solution of 4.36 g of (1,2,3,4-tetrahydro-quinolin-3(R,S)-yl)-carbamic acid methyl ester [177202-73-2] in 100 ml of methylene chloride is added, followed by addition of 2.11 g of 4-N,N-dimethylaminopyridine. The reaction mixture is stirred at room temperature for 17 hours. The mixture is poured into 1M NaOH and extracted with tert-butyl methyl ether (2×). The combined organic layers are washed with water and brine, dried over sodium sulphate, filtered and concentrated. The title compound is obtained as a slightly yellow oil from the residue by means of flash chromatography (SiO2 60 F). Rf=0.39 (1:3 EtOAc-heptane); Rt=5.03 (gradient I).
Reaction SMILES: [N+:1]([C:4]1[N:5]=[CH:6][C:7]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[N:8][CH:9]=1)([O-])=O.[Cl-].[NH4+]>CO.O.[Zn]>[NH2:1][C:4]1[N:5]=[CH:6][C:7]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[N:8][CH:9]=1
Reactant: CS(=O)(=O)Nc1cnc([N+](=O)[O-])cn1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: O
Product: CS(=O)(=O)Nc1cnc(N)cn1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 109.2 %

Procedure:
A solution of N-(5-nitro-pyrazin-2-yl)-methanesulfonamide (583.9 mg, 2.67 mmol) in methanol (26.8 mL) was treated with a solution of ammonium chloride (300.6 mg, 5.62 mmol) in water (2 mL). This solution was stirred at 25° C. for 5 min. At this time, the reaction was treated with zinc dust (1.71 g, 26.2 mmol). The resulting mixture was heated under reflux for 2 h. At this time, the reaction was cooled to 25° C. and was filtered through a pad of silica gel (9/1 methylene chloride/methanol wash). The filtrate was concentrated in vacuo to afford N-(5-amino-pyrazin-2-yl)-methanesulfonamide (548.8 mg, 100%) as a dark-brown gum: EI-HRMS m/e calcd for C5H8N4O2S (M+H)+ 189.0441, found 189.0442.
Reaction SMILES: [CH2:1]([C:4]1[CH:23]=[C:22]([CH2:24]O)[CH:21]=[C:20]([CH2:26][CH2:27][CH3:28])[C:5]=1[O:6][CH:7]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:2][CH3:3].P(Br)(Br)[Br:30].Br>C(Cl)(Cl)(Cl)Cl>[CH2:1]([C:4]1[CH:23]=[C:22]([CH2:24][Br:30])[CH:21]=[C:20]([CH2:26][CH2:27][CH3:28])[C:5]=1[O:6][CH:7]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:2][CH3:3]
Reactant: CCCc1cc(CO)cc(CCC)c1OC(C(=O)OCC)c1cccc(C)c1
Reactant: BrP(Br)Br
Agent: Br
Solvent: ClC(Cl)(Cl)Cl
Product: CCCc1cc(CBr)cc(CCC)c1OC(C(=O)OCC)c1cccc(C)c1

Procedure:
To a solution of 2.03 g (5.29 mmol) of the product of Step B dissolved in 10 mL of carbon tetrachloride was added 0.50 mL (5.29 mmol) of phosphorous tribromide and the reaction mixture was magnetically stirred at room temperature for 1 hour as hydrogen bromide was evolved. The magnetic stir bar was removed, and the reaction mixture was concentrated in vacuo. The residue was redissolved and evaporated from methylene chloride three times to remove most of the hydrogen bromide. Finally, the residue was purified by rapid flash chromatography on a silica gel column eluted with 20% EtOAc-hexane. Combination and evaporation of the purified fractions in vacuo afforded 2.27 (96%) of the title compound.
Reaction SMILES: [N+](C1C=C[C:7]([C:8](Cl)=[O:9])=CC=1)([O-])=O.C(N)(C)C.[CH:17]([NH:20][C:21](=[O:31])[C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-])=O)=[CH:24][CH:23]=1)([CH3:19])[CH3:18]>>[CH:17]([NH:20][C:21](=[O:31])[C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:8](=[O:9])[CH3:7])=[CH:24][CH:23]=1)([CH3:19])[CH3:18]
Reactant: CC(C)NC(=O)c1ccc([N+](=O)[O-])cc1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: CC(C)N
Product: CC(=O)Nc1ccc(C(=O)NC(C)C)cc1

Procedure:
The method of Example 3 is repeated using 4-nitrobenzoyl chloride and iso-propyl amine in the amidation step. This yields N-iso-propyl-4-nitrobenzamide (CPI1026).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH2:9])=[N:6][CH:7]=1.N(C1C=CC=C(C)C=1)=[C:11]=[S:12].CCOCC>ClC1C=CC(Cl)=CC=1.CN1C(=O)CCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:11]([SH:12])=[N:9][N:8]=2)[CH:7]=1
Reactant: NNc1ccc(Br)cn1
Reactant: Cc1cccc(N=C=S)c1
Solvent: Clc1ccc(Cl)cc1
Solvent: CCOCC
Solvent: CN1CCCC1=O
Product: Sc1nnc2ccc(Br)cn12
Temperature: 70 °C
Reaction time: 0.25 h

Procedure:
To the suspended solution of 5-Bromo-2-hydrazinylpyridine (1.85 g, 10 mmol) in a mixture of 1,4-dichlorobenzene and NMP (5:1, 10 ml) was added isothiocyanato-3-methylbenzene (1.5 g 10 mmol). The mixture was stirred at rt for 5 min, 70° C. for 15 min, and then heated under microwave condition at 200° C. for 1.5 h. The mixture was poured into Ether (20 mL). Solid was filtered and the washed with ether to give title product.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH:6]1([CH2:11][C:12]2[N:17]=[C:16](O)[C:15]3[CH2:19][CH2:20][CH2:21][C:14]=3[N:13]=2)[CH2:10][CH2:9][CH2:8][CH2:7]1>>[Cl:3][C:16]1[C:15]2[CH2:19][CH2:20][CH2:21][C:14]=2[N:13]=[C:12]([CH2:11][CH:6]2[CH2:10][CH2:9][CH2:8][CH2:7]2)[N:17]=1
Reactant: Oc1nc(CC2CCCC2)nc2c1CCC2
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1nc(CC2CCCC2)nc2c1CCC2
Yield: 77 %

Procedure:
Phosphorus oxychloride (4.6 mL, 51 mmol) was added to 2-cyclopentylmethyl-6,7-dihydro-5H-cyclopentapyrimidin-4-ol (3.7 g, 17 mmol) and the mixture was heated at reflux for 2 hours. Thereafter, volatiles were evaporated under reduced pressure and the mixture was poured over ice-water. The mixture was extracted with dichloromethane (3×60 mL). The combined organic extracts were washed with water, treated with activated charcoal, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to afford the title compound as a light yellow solid (3.1 g, 78% yield).