Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[N:16]3[C@@H:11]([CH2:12][CH2:13][CH2:14][CH2:15]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:17]1([C:23]#[CH:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(N(CC)CC)C.C1COCC1>[C:17]1([C:23]#[C:24][C:2]2[CH:7]=[CH:6][C:5]([C@H:8]3[N:16]4[C@@H:11]([CH2:12][CH2:13][CH2:14][CH2:15]4)[CH2:10][CH2:9]3)=[CH:4][CH:3]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Brc1ccc([C@@H]2CC[C@@H]3CCCCN32)cc1
Reactant: C#Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C(#Cc1ccc([C@@H]2CC[C@@H]3CCCCN32)cc1)c1ccccc1
Temperature: 25 °C
Yield: 42 %

Procedure:
A 27.7 g (0.099 mole sample of trans-3-(4-bromophenyl)octahydroindolizine was dissolved in a mixture of 55 mL of triethylamine and 225 mL of dry THF under an atmosphere of argon and 12.1 g (0.12 mole) of phenylacetylene was added. Then 2.3 g (2 mmol) of tetrakistriphenylphosphine palladium (O) and 0.75 g 3.9 mmol) of cuprous iodide were added to the reaction mixture and the reaction refluxed overnight. An additional 1.2 g (1 mmol) of tetrakistriphenylphosphine palladium (O) and 0.38 g (1.9 mmol) of cuprous iodide were added to the reaction mixture and the mixture allowed to reflux overnight. The reaction was allowed to cool to room temperature, the mixture was filtered, and the THF evaporated in vacuo to a brown oil. The oil was partially dissolved in EtOAc and the insoluble material was filtered off. The EtOAc was evaporated in vacuo to an oil. The oil was flash chromatographed using 99% hexane, 1% EtOAc as the eluant. The major product bearing fractions were pooled, and the solvent evaporated in vacuo to give 12.5 g (42% yield) of the title compound as an oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([N+:16]([O-])=O)[C:8]([CH3:15])=[C:9]([CH:14]=1)[C:10]([O:12][CH3:13])=[O:11].[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:16][C:7]1[C:8]([CH3:15])=[C:9]([CH:14]=[C:5]([O:4][CH2:3][CH2:2][OH:1])[CH:6]=1)[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)c1cc(OCCO)cc([N+](=O)[O-])c1C
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: COC(=O)c1cc(OCCO)cc(N)c1C
Temperature: 80 °C
Yield: 98.2 %

Procedure:
To a stirred solution of methyl 5-(2-hydroxyethoxy)-2-methyl-3-nitrobenzoate (1.5 g, 5.88 mmol) in ethanol (20 mL), were added ammonium chloride (1.5 g, 28 mmol) dissolved in water (20 mL) and iron powder (1.3 g, 23 mmol). The resulting reaction mixture was heated at 80° C. for 3 h. On completion, the reaction mixture was filtered and the residue washed well with hot ethanol. The filtrate was concentrated and the residue was basified by aqueous sodium bicarbonate. The aqueous phase was extracted with ethyl acetate. The combined organic layers were washed with water, dried, and concentrated under reduced pressure giving the crude title compound (1.3 g) which was used directly.
Reaction SMILES: [CH:1]([C:4]1[CH:21]=[CH:20][C:7]([O:8][CH:9]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH2:22]([O:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34]Cl)=[CH:32][CH:31]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[H-].[Na+]>>[CH2:22]([O:29][C:30]1[CH:31]=[CH:32][C:33]([CH2:34][C:9]([O:8][C:7]2[CH:20]=[CH:21][C:4]([CH:1]([CH3:2])[CH3:3])=[CH:5][CH:6]=2)([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:36][CH:37]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: ClCc1ccc(OCc2ccccc2)cc1
Reactant: CCOC(=O)C(Oc1ccc(C(C)C)cc1)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)C(Cc1ccc(OCc2ccccc2)cc1)(Oc1ccc(C(C)C)cc1)C(=O)OCC
Yield: 90.1 %

Procedure:
In a similar manner to that described in Reference example 2(a), a reaction was carried out using diethyl 2-(4-isopropylphenoxy)malonate (21.5 g), which is the product of Reference example 5(a), 4-benzyloxybenzyl chloride (19.7 g) and sodium hydride (55% suspension in oil, 3.53 g) and the reaction mixture was treated to afford the desired compound (32.3 g) as a syrup.
Reaction SMILES: O[C:2]1[CH:11]=[CH:10][C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1.CCN(C1C=CC=CC=1)CC.P(Cl)(Cl)([Cl:25])=O>>[Cl:25][C:2]1[CH:11]=[CH:10][C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ccc2c(n1)CCCC2
Solvent: CCN(CC)c1ccccc1
Product: Clc1ccc2c(n1)CCCC2

Procedure:
A solution of 0.7 g of 2-hydroxy-5,6,7,8-tetrahydroquinoline (prepared according to the methods outlined by Meyers et al., J. Org. Chem., 29: 1435-1438, 1964) and 0.1 g of diethylaniline in 7 mL of phosphorus oxychloride is refluxed for 2 h, cooled and concentrated. The residue taken is up in chloroform, washed with excess 3 N NaOH solution and the organic layer dried and concentrated to provide crude 2-chloro-5,6,7,8-tetrahydro-quinoline (0.45 g) as an oil.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][C:3]=1[CH2:4][O:5][CH2:6][CH:7]=[CH:8][CH2:9]Br.[CH3:16][NH2:17]>O1CCCC1>[CH3:16][NH:17][CH2:9]/[CH:8]=[CH:7]\[CH2:6][O:5][CH2:4][C:3]1[CH:11]=[C:12]([Br:15])[CH:13]=[CH:14][C:2]=1[F:1]
Reactant: CN
Reactant: Fc1ccc(Br)cc1COCC=CCBr
Solvent: C1CCOC1
Product: CNC/C=C\COCc1cc(Br)ccc1F
Temperature: 25 °C
Reaction time: 5 h

Procedure:
In a 250 ml flask 4-(2-fluoro-5-bromobenzyloxy)but-2-enyl bromide (1.968 g, 5.89 mmol) was dissolved in dry tetrahydrofuran (40 5 ml). To this solution methylamine (29.5 ml, 58.9 mmol) was added in one portion and the resulting mixture was stirred at ambient temperature for five hours. The progress of the reaciton was monitored by thin layer chromatography. The solvents were removed in vacuo and the residue was taken up in 1 M potassium carbonate and extracted thrice with methylene chloride. The organic fractions were combined, and dried over sodium sulfate. The solvents were removed in vacuo. The desired title intermediate was further purified by liquid chromatography.
Reaction SMILES: C([N:9]=[C:10]=[S:11])(=O)C1C=CC=CC=1.C(O[C:15]([C:17]1[NH:18][CH:19]=[CH:20][C:21]=1[NH:22][CH2:23][C:24]1[NH:25][C:26](=[O:30])[CH:27]=[CH:28][CH:29]=1)=[O:16])C.C(=O)([O-])[O-].[K+].[K+].Cl>C(Cl)Cl>[O:30]=[C:26]1[NH:25][C:24]([CH2:23][N:22]2[C:21]3[CH:20]=[CH:19][NH:18][C:17]=3[C:15](=[O:16])[NH:9][C:10]2=[S:11])=[CH:29][CH:28]=[CH:27]1
Reactant: CCOC(=O)c1[nH]ccc1NCc1cccc(=O)[nH]1
Reactant: O=C(N=C=S)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: O=c1cccc(Cn2c(=S)[nH]c(=O)c3[nH]ccc32)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.8 %

Procedure:
Benzoyl isothiocyanate (0.27 g, 1.6 mmol) dissolved in CH2Cl2 (3 mL) was added to 3-{[(6-oxo-1,6-dihydropyridin-2-yl)methyl]amino}-1H-pyrrole-2-carboxylic acid ethyl ester (0.25 g, 0.96 mmol) in CH2Cl2 (7 mL). The resulting mixture was stirred at r.t. overnight. The solvent was removed in vacuo and the residue was dissolved in methanol (15 mL) and potassium carbonate (0.50 g, 3.6 mmol) was added. The reaction mixture was stirred at 50° C. for 6.5 h. After cooling to r.t., 1M HCl was added dropwise until a neutral pH was obtained. The resulting precipitate was collected, washed with methanol and purified by preparative HPLC to obtain the title compound (0.097 g, 37%) as a solid.
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11](Br)[C:10]=1[C:16]([F:19])([F:18])[F:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][C:21]1=[O:26]>>[CH2:1]([S:8][C:9]1[C:10]([C:16]([F:19])([F:18])[F:17])=[C:11]([N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][C:21]2=[O:26])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: FC(F)(F)c1c(Br)cccc1SCc1ccccc1
Reactant: O=C1CCCCN1
Product: O=C1CCCCN1c1cccc(SCc2ccccc2)c1C(F)(F)F

Procedure:
Intermediate 24 (10.5 g, 30.24 mmol) was coupled with piperidin-2-one (3.597 g, 36.29 mmol) in close analogy to the procedure described in step 1.6). After workup the crude oil is purified by chromatography on silica gel (n-heptane-ethyl acetate 4:1).
Reaction SMILES: [Si]([O:8][CH2:9][CH:10]1[CH2:14][CH2:13][CH:12]([CH:15]([C:28]#[N:29])[N:16]([CH3:27])[C:17](=[O:26])[O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:11]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>C1COCC1>[C:28]([CH:15]([CH:12]1[CH2:13][CH2:14][CH:10]([CH2:9][OH:8])[CH2:11]1)[N:16]([CH3:27])[C:17](=[O:26])[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)#[N:29]
Reactant: CN(C(=O)OCc1ccccc1)C(C#N)C1CCC(CO[Si](C)(C)C(C)(C)C)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CN(C(=O)OCc1ccccc1)C(C#N)C1CCC(CO)C1
Temperature: 23 °C
Reaction time: 5 h
Yield: 37.9 %

Procedure:
To benzyl (3-((tert-butyldimethylsilyloxy)methyl)cyclopentyl)(cyano)methyl(methyl)-carbamate (2.0 g, 4.80 mmol) in dry THF (40 mL) cooled to 0° C. was added tetrabutyl-ammoniumfluoride (1M in THF 17.28 mL). The reaction mixture was stirred at 23° C. for 5 hours. H2O (20 mL) was added to the reaction mixture and the organic material extracted with ethyl acetate (3×30 mL). The combined organic fractions were dried (MgSO4) and concentrated in vacuo. The crude material was purified on a Silica gel column (Biotage flash chromatography system), eluted with a gradient of ethyl acetate:hexane (3:7) to ethyl acetate 100% to afford 0.550 g (38% yield) of the title compound. 1H NMR (400 MHz, CDCl3) δ ppm 7.39 (5 H, m), 5.13-5.25 (2 H, m), 5.07 (1 H, br s), 3.50-3.60 (2 H, m), 3.01 (3 H, s), 1.30-2.52 (8 H, m). LCMS (+ESI, M+H+) m/z 303.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([SH:8])[N:5]=[C:4]([OH:9])[CH:3]=1.C(N(CC)CC)C.Br[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[C:20]=1[Cl:28]>C(O)C>[Cl:28][C:20]1[C:21]([N+:25]([O-:27])=[O:26])=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][S:8][C:6]1[N:5]=[C:4]([OH:9])[CH:3]=[C:2]([CH3:1])[N:7]=1
Reactant: Cc1cc(O)nc(S)n1
Reactant: O=[N+]([O-])c1cccc(CBr)c1Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1cc(O)nc(SCc2cccc([N+](=O)[O-])c2Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.5 %

Procedure:
6-methyl-2-sulfanylpyrimidin-4-ol (200 mg, 1.4 mmol) was dissolved in absolute ethanol (15 mL), then triethylamine (230 μL, 1.7 mmol) and 1-(bromomethyl)-2-chloro-3-nitrobenzene (350 mg, 1.4 mmol) were added. The mixture was stirred overnight at room temperature. The solid was filtered, washed with methanol, and then dried in vacuo to afford 2-{[(2-chloro-3-nitrophenyl)methyl]sulfanyl}-6-methylpyrimidin-4-ol as white solid (277 mg, 64% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.23 (s, 3H), 4.56 (s, 2H), 6.00 (bs, 1H), 7.56 (t, J=7.9 Hz, 1H), 7.95 (d, J=8.2 Hz, 2H); LRMS (ES+) m/z 312 (100%, M+1), 314 (45%, M+3).
Reaction SMILES: [C:1]12([CH2:11][NH:12][C:13](=[O:22])[C:14]3[C:19]([Cl:20])=[CH:18][N:17]=[C:16](Br)[CH:15]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH2:23]([N:26]([CH2:34][CH2:35][CH2:36][O:37][CH:38]1[CH2:43][CH2:42][CH2:41][CH2:40][O:39]1)[C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[C:24]#[CH:25]>C(#N)C.C(N(CC)CC)C>[C:1]12([CH2:11][NH:12][C:13]([C:14]3[C:19]([Cl:20])=[CH:18][N:17]=[C:16]([C:25]#[C:24][CH2:23][N:26]([CH2:34][CH2:35][CH2:36][O:37][CH:38]4[CH2:43][CH2:42][CH2:41][CH2:40][O:39]4)[C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:30])[CH3:31])[CH:15]=3)=[O:22])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(Br)ncc1Cl
Reactant: C#CCN(CCCOC1CCCCO1)C(=O)OC(C)(C)C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N(CC#Cc1cc(C(=O)NCC23CC4CC(CC(C4)C2)C3)c(Cl)cn1)CCCOC1CCCCO1
Reaction time: 2 h
Yield: 58 %

Procedure:
A suspension of N-(1-adamantylmethyl)-2-bromo-5-chloroisonicotinamide (Example 2(i)) (0.43 g) and tert-butyl prop-2-ynyl[3-(tetrahydro-2H-pyran-2-yloxy)propyl]carbamate (Example 2(ii)) (0.60 g) in anhydrous acetonitrile (6 ml) and triethylamine (6 ml) was purged with nitrogen for 5 minutes and then copper (I) iodide (0.004 g) and bis-triphenyphosphine palladium dichloride (0.014 g) were added. The mixture was stirred under nitrogen for 2 hours. The mixture was concentrated and the residue was purified by chromatography on silica gel eluting with iso-hexane:ethyl acetate (19:1 to 7:3) to afford the sub-titled compound (0.39 g) as a yellow gum.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[NH2:13].[C:14](Cl)(=[O:20])[CH2:15][CH2:16][CH2:17][CH:18]=[CH2:19]>C(Cl)Cl>[CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[NH:13][C:14](=[O:20])[CH2:15][CH2:16][CH2:17][CH:18]=[CH2:19]
Reactant: C=CCCCC(=O)Cl
Reactant: COc1ccc2nccc(N)c2n1
Solvent: ClCCl
Product: C=CCCCC(=O)Nc1ccnc2ccc(OC)nc12
Temperature: 25 °C
Reaction time: 20 h
Yield: 71.5 %

Procedure:
To a suspension of 6-methoxy-[1,5]naphthyridin-4-ylamine (1.5 g, 8.56 mmol) and TEA (1.55 mL, 1.3 eq.) in DCM (8.5 mL) was added 5-hexenoyl chloride (1.36 g, 1.2 eq.) in DCM (1.5 mL) at rt. The resulting suspension was vigorously stirred at rt for 20 h. The mixture was then washed with water. The org. layer was dried over Na2SO4 and concentrated. The residue was chromatographed on SiO2 (DCM-MeOH—NH4OH: 1000:50:4) to afford the title intermediate as a yellow solid (1.66 g, 71% yield).
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].C([Li])CCC.[CH3:13][C:14]([CH3:24])([CH2:20][CH2:21][CH2:22][CH3:23])[C:15](OCC)=[O:16].C(O)(=O)C>C1COCC1>[CH3:13][C:14]([CH3:24])([CH2:20][CH2:21][CH2:22][CH3:23])[C:15](=[O:16])[CH2:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4]
Reactant: COP(C)(=O)OC
Reactant: CCCCC(C)(C)C(=O)OCC
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCCCC(C)(C)C(=O)CP(=O)(OC)OC
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution of dimethyl methylphosphonate (35.0 ml) in THF (300 ml) was cooled to -78° C., to which n-butyllithium (1.6 -M, 196 ml) was added dropwise. After stirring at -78° C. for one hour, a solution of ethyl 2,2-dimethylcaproate (27 g) in dry THF was added. The reaction solution was stirred at -78° C. for one hour, and then at room temperature for additional 2 hours. The reaction solution was cooled to 0° C. and acetic acid (18 ml) was added thereto. The crude product obtained after the conventional work-up was distilled under reduced pressure and the resulting fraction (>130° C.) was chromatographed to give dimethyl (3,3-dimethyl-2-oxoheptyl)phosphonate. Yield, 9.72 g (26%)
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]([O:25][C:26](=[O:28])[CH3:27])[C:7](=[O:24])[NH:8][C:9]1[C:14]([I:15])=[C:13]([C:16](Cl)=[O:17])[C:12]([I:19])=[C:11]([C:20]([Cl:22])=[O:21])[C:10]=1[I:23])(=[O:3])[CH3:2].[CH3:29][C:30]1([CH3:40])[O:34][CH:33]([CH2:35][NH:36][CH2:37][CH2:38][OH:39])[CH2:32][O:31]1.C(N(CC)CC)C>CC(N(C)C)=O>[C:1]([O:4][CH2:5][CH:6]([O:25][C:26](=[O:28])[CH3:27])[C:7](=[O:24])[NH:8][C:9]1[C:14]([I:15])=[C:13]([C:16](=[O:17])[N:36]([CH2:35][CH:33]2[CH2:32][O:31][C:30]([CH3:40])([CH3:29])[O:34]2)[CH2:37][CH2:38][OH:39])[C:12]([I:19])=[C:11]([C:20]([Cl:22])=[O:21])[C:10]=1[I:23])(=[O:3])[CH3:2]
Reactant: CC1(C)OCC(CNCCO)O1
Reactant: CC(=O)OCC(OC(C)=O)C(=O)Nc1c(I)c(C(=O)Cl)c(I)c(C(=O)Cl)c1I
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: CC(=O)OCC(OC(C)=O)C(=O)Nc1c(I)c(C(=O)Cl)c(I)c(C(=O)N(CCO)CC2COC(C)(C)O2)c1I
Temperature: 25 °C
Reaction time: 24 h
Yield: 38.5 %

Procedure:
To a ice cooled solution of acetic acid 2-acetoxy-1-(3,5-bis-chlorocarbonyl-2,4,6-triiodo-phenylcarbamoyl)-ethyl ester (20 g, 0.026 mol) in anhydrous DMAC (20 ml) were added dropwise a solution of 2-[(2,2-Dimethyl-[1,3]dioxolan-4-yl-methyl)-amino]-ethanol (4.6 g, 0.026 mol) in DMAC (20 mL) followed by triethylamine (˜3 g). The mixture was stirred at room temperature for 24 h and then poured over icewater (0.75 litre). A white precipitate formed. This was collected and washed with cold water. The filter cake was then dissolved in ethyl acetate and washed with brine. The organics were collected, dried over MgSO4, filtered and evaporated to dryness. The product was purified by silica column chromatography eluting with Petroleum ether/ethyl acetate. Two peaks closely eluting at 80% ethyl acetate were analysed by NMR and mass spec, and show to both contain the desired material. These were combined post analysis to give the desired product (10 mmol, Yield=38%). The structure was confirmed by Mass Spec (ESI) m/z: Calculated for C23H26Cl I3N2O10 [M+H]+906.64. Found 906.93. 1H NMR (CDCl3; 300 MHz) δ=1.33 (2s, 3H) 1.45 (2s, 3H) 2.02 (s, 3H) 2.26 (s, 3H) 3-3.5 (m, 4H) 3.5-3.9 (m, 3H) 3.9-4.3 (m, 2H) 4.5 (m, 1H) 4.6-4.8 (m, 2H) 5.62 (NH singlet, 1H)
Reaction SMILES: [C:1](=[O:4])([O-:3])[NH2:2].[NH4+:5].[NH2:6][C:7]([NH2:9])=[O:8].N.C(=O)=[O:12].C(=O)([O-])[NH2:15]>>[NH2:6][C:7]([NH2:9])=[O:8].[NH3:2].[C:1](=[O:4])([O-:12])[O-:3].[NH4+:15].[NH4+:5]
Reactant: NC(=O)[O-]
Reactant: O=C=O
Agent: N
Agent: NC(N)=O
Agent: [NH4+]
Product: O=C([O-])[O-]

Procedure:
In a method for the concurrent production of ammonia and urea comprising the steps of producing ammonia in an ammonia-synthesis apparatus, absorbing ammonia at the exit of the ammonia-synthesis reactor with water, thus obtaining a concentrated aqueous solution of ammonia, utilizing the concentrated solution of ammonia for the absorption of the CO2 contained in the raw gases for the synthesis of ammonia, obtaining ammonium carbamate, converting the ammonium carbamate partially into urea in a urea-synthesis reactor, thermally decomposing the carbamate which has not been converted into urea and stripping the decomposition products with a gas selected from the group consisting of ammonia, CO2 and inerts, discharging from the stripping zone a solution of urea which still contains carbamate, recycling the products of decomposition of the carbamate to the urea-synthesis reactor, distilling under a pressure of from 3 to 30 atm, in at least one stage, the solution of urea to obtain liquid ammonia and one or more ammoniacal solutions of ammonium carbonate, and an aqueous solution of urea deprived of ammonium carbamate the improvement which comprises introducing the CO2 -containing gas at the bottom, or near the bottom, of an absorber which is split into two sections, the lower section being a film-absorber and the upper section being a plate-absorber, the absorbing solution in the upper section being the concentrated aqueous solution of ammonia aforesaid, the absorbing solution in the lower section being one or more of the aqueous ammoniacal solutions of ammonium carbonate as obtained by distillation of the solution of urea under a pressure of from 3 to 30 atm. with addition of liquid ammonia.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].I[CH2:8][CH2:9][CH3:10].[C:11]([C:14]1[C:15]([CH2:19][C:20]([O:22][CH3:23])=[O:21])=[CH:16][S:17][CH:18]=1)([OH:13])=[O:12]>CN(C=O)C.O>[CH2:8]([O:13][C:11]([C:14]1[C:15]([CH2:19][C:20]([O:22][CH3:23])=[O:21])=[CH:16][S:17][CH:18]=1)=[O:12])[CH2:9][CH3:10]
Reactant: COC(=O)Cc1cscc1C(=O)O
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCOC(=O)c1cscc1CC(=O)OC
Reaction time: 3 h

Procedure:
Potassium carbonate (670 mg) and, after 15 minutes, 1-iodopropane (0.26 ml) were added successively to a stirred solution of methyl (4-carboxy-3-thienyl)acetate (490 mg) in DMF (10 ml). After 3 h, the resulting mixture was diluted with water and extracted with ether. The extracts were washed with water, dried, and concentrated to give methyl [4-(prop-1-yloxycarbonyl)-3-thienyl]acetate (600 mg, quantitative yield) as a yellow liquid, pure by GC, IR (film): 1735, 1710 cm-1, 1H nmr: delta 1.00 (3H, t), 1.75 (2H, q), 3.69 (3H, s), 3.92 (2H, s), 4.20 (2H, t), 7.13 (1H, d J 3.5 Hz), 8.12 (1H, d J 3.5 Hz) Ppm.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:34][CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.[CH3:35][O:36][CH2:37][C:38](Cl)=[O:39]>>[CH3:35][O:36][CH2:37][C:38]([N:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:32][CH2:33][CH2:34]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1)=[O:39]
Reactant: O=C(NC1CCNCC1)c1c[nH]c2c(-c3c(OCC4CCC4)ccc4c3OCO4)ncnc12
Reactant: COCC(=O)Cl
Agent: Cl
Product: COCC(=O)N1CCC(NC(=O)c2c[nH]c3c(-c4c(OCC5CCC5)ccc5c4OCO5)ncnc23)CC1

Procedure:
Starting from 4-(5-cyclobutylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide hydrochloride (example A174) and methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]([NH:5][CH2:6][CH2:7][NH:8][CH2:9][CH3:10])=[O:4].CCN(C(C)C)C(C)C.[CH2:22]([O:29][C:30](N1C(=O)CCC1=O)=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1COCC1>[CH2:22]([O:29][C:30](=[O:31])[N:8]([CH2:9][CH3:10])[CH2:7][CH2:6][NH:5][C:3](=[O:4])[C:2]([F:11])([F:12])[F:1])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCNCCNC(=O)C(F)(F)F
Reactant: O=C1CCC(=O)N1C(=O)OCc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CCNC(=O)C(F)(F)F)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.8 %

Procedure:
A solution of compound M (24.6 g, 82.4 mmol) and DIEA (14.3 ml, 82.4 mmol) in THF (100 ml) was cooled to ˜5° C., followed by the addition of a solution of N-(benzyloxycarbonyl)succinimide (20.3 g, 81.6 mmol) in THF (75 ml) dropwise over 20 min The temperature of the reaction mixture was raised to room temperature and stirring was continued for an additional 30 min. Solvents were evaporated and the residue was dissolved in EtOAc (500 ml). The organic layer was extracted with 5% aqueous NaHCO3 (2×100 ml) and brine (100 ml). The organic layer was evaporated to provide compound N (24.9 g, 78.2 mmol) as yellowish oil. LC-MS [M+H] 319.0 (C14H17F3N2O3+H, calc: 319.2). Compound N was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:31])([C@H:16]([S:18][C@@H:19]1[CH2:24][O:23][C@@H](C2C=CC=CC=2)[O:21][CH2:20]1)[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.Cl.O1CCOCC1.C([O-])(O)=O.[Na+]>CO>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:31])([C@H:16]([S:18][CH:19]([CH2:20][OH:21])[CH2:24][OH:23])[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: C[C@@H](S[C@H]1CO[C@H](c2ccccc2)OC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Product: C[C@@H](SC(CO)CO)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.1 %

Procedure:
In 3.5 ml of methanol were dissolved 253 mg of (2R,3R)-2-(2,4-difluorophenyl)-3-[[trans-2-phenyl-1,3-dioxan-5-yl]thio]-1-(1H-1,2,4-triazol-1-yl)-2-butanol as described in Example 40, and 0.35 ml of a 4N HCl-dioxane solution were added to the solution, followed by stirring of the resulting mixture at room temperature for 30 minutes. To the reaction mixture were added 250 mg of a NaHCO3 powder, and the mixture was stirred for 10 minutes, followed by filtration of the reaction mixture and concentration of the filtrate under reduced pressure. The thus obtained oil was subjected to column chromatography using 5 g of silica gel and eluted with 10% methanol-ethyl acetate to obtain 179 mg (yield: 88%) of the title compound as a viscous oil.