Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@@H:18]([C:36]([O:38][CH3:39])=[O:37])[CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26]COCC[Si](C)(C)C)=[C:22]([Br:35])[CH:21]=3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:40]=[CH:41][CH:42]=[CH:43][C:4]=2[NH:3]1.S(=O)(=O)(O)O>>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@@H:18]([C:36]([O:38][CH3:39])=[O:37])[CH2:19][C:20]3[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([Br:35])[CH:21]=3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:40]=[CH:41][CH:42]=[CH:43][C:4]=2[NH:3]1
Reactant: COC(=O)[C@@H](Cc1ccc(OCOCC[Si](C)(C)C)c(Br)c1)OC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1
Agent: O=S(=O)(O)O
Product: COC(=O)[C@@H](Cc1ccc(O)c(Br)c1)OC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1

Procedure:
Prepared analogously to Example 24g from 5.40 g (7.98 mmol) (R)-2-[3-bromo-4-(2-trimethylsilanyl-ethoxy-methoxy)-phenyl]-1-methoxycarbonyl-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate and 7.7 mL (4.2 mmol) methanolic sulphuric acid (0.5 M). The crude product (5.44 g) was further reacted without purification.
Reaction SMILES: [CH3:1][S:2]([NH2:5])(=[O:4])=[O:3].[H-].[Na+].CS(N)(=O)=O.[Na].[CH3:14][O:15][C:16](=[O:29])[C:17]1[CH:22]=[C:21]([N:23]([CH3:27])[CH2:24][CH2:25][CH3:26])[N:20]=[C:19](Cl)[CH:18]=1.C1(C2C=CC=CC=2)C=CC=CC=1P(C(C)(C)C)C(C)(C)C>C1COCC1.C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:14][O:15][C:16](=[O:29])[C:17]1[CH:22]=[C:21]([N:23]([CH3:27])[CH2:24][CH2:25][CH3:26])[N:20]=[C:19]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])[CH:18]=1
Reactant: CS(N)(=O)=O
Reactant: CCCN(C)c1cc(C(=O)OC)cc(Cl)n1
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCCN(C)c1cc(C(=O)OC)cc(NS(C)(=O)=O)n1
Temperature: 25 °C
Yield: 88.3 %

Procedure:
Dissolve methane sulfonamide (951 mg, 10 mmol) in THF (30 mL). Add sodium hydride (380 mg, 9.5 mmol, 60% dispersion in mineral oil) and reflux for 3 h, cool to room temperature and concentrate. Charge a sealed flask with sodium methansulfonamide (478 mg, 4.09 mmol), 2-chloro-6-(methylpropylamino)-isonicotinic acid methyl ester (79 mg, 3.27 mmol), biphenyl-2-yl-di-tert-butylphosphane (98 mg, 0.33 mmol), and tris(dibenzylideneacetone)dipalladium (0) (150 mg, 0.16 mmol) in toluene (7 mL). Degas with argon, seal the vessel and heat at 100° C. for 16 h. Cool to room temperature, dilute with ethyl acetate, wash with water, aqueous sodium chloride, concentrate and purify (silica gel chromatography, eluting with 0:100 to 50:50 ethyl acetate:hexanes) to give the title compound as an oil (870 mg, 88%).
Reaction SMILES: C([Li])CCC.CCCCCC.Br[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1.[CH3:19][O:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][C:22]1=[O:27]>C(OCC)C.O>[CH3:19][O:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][C:22]1([C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)[OH:27]
Reactant: COC1CCCCC1=O
Reactant: Brc1ccncc1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Solvent: CCCCCC
Product: COC1CCCCC1(O)c1ccncc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 38.5 %

Procedure:
A stirred solution of 2.5M n-butyllithium in hexane (30.8ml, 0.77mol) at -78° C. was mixed with diethyl ether (310ml) and a solution of 4-bromopyridine (60.9g, 0.39mol) in diethyl ether (1200 ml) was added dropwise over 3 hours. Stirring was continued for 2 hours and a solution of 2-methoxycyclohexanone (54.3g, 0.42mol) in diethyl ether (total volume 100ml) was added dropwise over 1 hour. The stirred solution was allowed to warm to room temperature and stirring was continued overnight. Water (250ml) was then added to the reaction mixture, keeping the temperature below 20° C. and the mixture stirred for a further 30 minutes. The organic layer was separated and the aqueous layer was extracted with diethyl ether (3×50ml). The combined organic layers were extracted with hydrochloric acid (2N, 2×250ml+100ml) and the combined acidic extracts brought to pH 11 with 5N aqueous sodium hydroxide and extracted with ethyl acetate (3×250ml). The combined ethyl acetate extracts were dried (MgSO4) and evaporated in vacuo. The residue was recrystallized from petroleum ether (60°-80° C.) to give (±)-2-methoxy-l-(pyrid-4-yl)cyclohexanol (32.0g, 0.15mol) as a mixture of cis and trans isomers, m.p. 98°-101° C.
Reaction SMILES: Cl.[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[CH:4]([NH:10][C:11](=[O:14])[CH2:12][Cl:13])[CH2:3]2.[CH3:15][C:16]([C:19]1[CH:24]=[C:23]([SH:25])[CH:22]=[C:21]([C:26]([CH3:29])([CH3:28])[CH3:27])[C:20]=1[OH:30])([CH3:18])[CH3:17].C(N(CC)CC)C>C(#N)C>[ClH:13].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[CH:4]([NH:10][C:11](=[O:14])[CH2:12][S:25][C:23]1[CH:22]=[C:21]([C:26]([CH3:27])([CH3:28])[CH3:29])[C:20]([OH:30])=[C:19]([C:16]([CH3:18])([CH3:17])[CH3:15])[CH:24]=1)[CH2:3]2
Reactant: O=C(CCl)NC1CN2CCC1CC2
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)c1cc(SCC(=O)NC2CN3CCC2CC3)cc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
The title compound was prepared by dissolving the product of Example 17 (2.0 g, 0.0084 mole) and 2,6-bis (1,1-dimethylethyl)-4-mercaptophenol (1.99 g, 0.0084 mole) in acetonitrile (25 ml). Triethylamine (5 ml) was added to the mixture and the mixture stirred at room temperature for 12 hours then refluxed for 72 hours. The hot mixture was filtered and the solvent removed on a rotary evaporator. The residue was triturated with hexane and dissolved in hot ethyl acetate and allowed to cool. After filtering, the solvent was removed by a rotary evaporator and the residue recrystallized from ethyl acetate-methanol-ethyl ether to give a tan solid. The structure was confirmed by mass spectroscopy M+ 404.
Reaction SMILES: [C:1]([O:5][C:6](=[O:43])[C:7]1[CH:12]=[C:11]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:21]=2[CH2:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH:10]=[C:9](Br)[CH:8]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].[CH3:50][C:51]1[C:52](B(O)O)=[CH:53][S:54][CH:55]=1>COCCOC.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>[C:1]([O:5][C:6](=[O:43])[C:7]1[CH:8]=[C:9]([C:52]2[C:51]([CH3:50])=[CH:55][S:54][CH:53]=2)[CH:10]=[C:11]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:21]=2[CH2:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH:12]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cscc1B(O)O
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(Br)cc(C(=O)OC(C)(C)C)c2)c1CCC(=O)OCC
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: COCCOC
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(C(=O)OC(C)(C)C)cc(-c3cscc3C)c2)c1CCC(=O)OCC
Temperature: 85 °C
Reaction time: 2 h
Yield: 87.7 %

Procedure:
3-Bromo-5-{6-[2-(2-ethoxycarbonyl-ethyl)-3-(3-ethoxycarbonyl-propoxy)-phenyl]-hexyloxy}-benzoic acid tert-butyl ester (2.0 g) was dissolved in 1,2-dimethoxyethane (40 mL), followed by addition of Pd(PPh3)4 (80 mg), 2 M solution of sodium carbonate (6 mL) and 4-methyl-3-thiopheneboronic acid (641 mg). The resulting reaction mixture was stirred at 85° C. for 2 h. After cooling the reaction mixture was filtered through Celite™, diluted with ethyl acetate and washed with water and brine. The organic extract was dried over anhydrous sodium sulfate, concentrated under reduced pressure and purified on a silica gel column using ethyl acetate and hexanes to the title compound (1.8 g, 88% yield).
Reaction SMILES: C([O:3][P:4]([O:8][CH2:9][CH3:10])[O:5][CH2:6][CH3:7])C.Br[CH2:12][CH2:13][CH2:14][N:15]1[C:27]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:21]2[C:16]1=[CH:17][CH:18]=[CH:19][CH:20]=2>>[CH:17]1[C:16]2[N:15]([CH2:14][CH2:13][CH2:12][P:4](=[O:3])([O:5][CH2:6][CH3:7])[O:8][CH2:9][CH3:10])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]=2[CH:20]=[CH:19][CH:18]=1
Reactant: BrCCCn1c2ccccc2c2ccccc21
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(CCCn1c2ccccc2c2ccccc21)OCC
Temperature: 130 °C
Reaction time: 18 h
Yield: 92.2 %

Procedure:
Triethylphosphite (13.4 mL, 80.1 mmol) was added via syringe to 9-(3-bromopropyl)-9H-carbazole (7.70 g, 26.7 mmol) in a 50 mL rbf. The reaction was heated and stirred under Argon at 130° C. for 18 hours. Excess triethylphosphite and side-products were removed under vacuum at ˜100° C. to yield a thick yellow oil (8.50 g, 92% yield). 1H NMR (400.14 MHz, CD2Cl2) δ 8.10 (dt, J=7.73, 2.00 Hz, 2H), 7.50-7.44 (m, 4H), 7.27-7.19, m, 2H), 4.43 (t, J=7.00 Hz, 2H), 4.10-3.95 (m, 4H), 2.23-2.09 (m, 2H), 1.74 (dt, J=18.41, 7.80 Hz, 2H), 1.26 (t, J=7.00 Hz, 6H). 13C{1H} NMR (100.62 MHz, CD2Cl2) δ 139.99 (2C), 125.36 (2C), 122.42 (2C), 119.88 (2C), 118.56 (2C), 108.37 (2C), 61.18 (d, J=6.44 Hz), 42.52 (d, J=15.39 Hz), 22.59 (d, J=141.97 Hz), 21.75 (J=4.83 Hz), 15.91 (d, J=5.84 Hz). 31P{1H} NMR (161.97 MHz, CD2Cl2): δ 31.22. Analysis found (calculated) %: C, 65.67 (66.07); H, 7.01 (7.00); N, 4.05 (4.06). MS (EI, m/z): 290 ([M], 100%). Exact mass found (calculated for [M], m/z): 345.14264 (345.14938).
Reaction SMILES: I[C:2]1[N:22]=[CH:21][C:5]2[N:6]=[CH:7][N:8]([CH2:11][C:12]3[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=3)[C:9](=[O:10])[C:4]=2[CH:3]=1.C(N(C(C)C)CC)(C)C.[C:32]1([CH2:38][C:39]#[CH:40])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CN(C=O)C.CCOC(C)=O.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:32]1([CH2:38][C:39]#[C:40][C:2]2[N:22]=[CH:21][C:5]3[N:6]=[CH:7][N:8]([CH2:11][C:12]4[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=4)[C:9](=[O:10])[C:4]=3[CH:3]=2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C(O)c1ccc(Cn2cnc3cnc(I)cc3c2=O)cc1
Reactant: C#CCc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)c1ccc(Cn2cnc3cnc(C#CCc4ccccc4)cc3c2=O)cc1
Temperature: 50 °C

Procedure:
To a solution of the compound obtained in Step 1 (0.739 mmol) in 6.5 ml of DMF, is added diisopropylethylamine (0.381 g, 2.96 mmol), CuI (catalytic amount), 3-phenyl-1-propyne (0.120 g, 1.03 mmol), and Pd(PPh3)2Cl2 (catalytic amount). The reaction mixture is warmed to 50° C. for 4 hours. The mixture is then diluted with 150 ml of EtOAc, and washed with 3×100 ml of water, 1×100 ml of brine. The organic layer is then dried over MgSO4 and filtered. The filtrate is concentrated in vacuo. The crude product is triturated with 8/1: hexane/EtOAc to yield the desired compound.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([S:22][CH3:23])[C:10]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)(=[O:13])=[O:12])=[C:6]2[N:5]=[C:4]([CH3:24])[CH:3]=1.[NH3:25]>CO>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([S:11]([C:10]2[C:9]([S:22][CH3:23])=[N:8][N:7]3[C:2]([NH2:25])=[CH:3][C:4]([CH3:24])=[N:5][C:6]=23)(=[O:13])=[O:12])=[CH:15][CH:16]=1
Reactant: N
Reactant: COc1ccc(S(=O)(=O)c2c(SC)nn3c(Cl)cc(C)nc23)cc1
Solvent: CO
Product: COc1ccc(S(=O)(=O)c2c(SC)nn3c(N)cc(C)nc23)cc1

Procedure:
In an analogous manner to that described in Example 4, from 7-chloro-3-(4-methoxy-benzenesulphonyl)-5-methyl-2-methylsulphanyl-pyrazolo[1,5-a]pyrimidine and NH3 in MeOH there was obtained 3-(4-methoxy-benzenesulphonyl)-5-methyl-2-methylsulphanyl-pyrazolo[1,5-a]pyrimidin-7-ylamine as colorless crystals, m.p.>230°.
Reaction SMILES: [CH3:1][O:2][C:3]([O:6][CH3:7])([CH3:5])[CH3:4].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[I:25][C:26](=[CH2:32])[CH2:27][C@H](O)CO>ClCCl>[I:25][C:26](=[CH2:27])[CH2:32][C@H:1]1[CH2:7][O:6][C:3]([CH3:5])([CH3:4])[O:2]1
Reactant: COC(C)(C)OC
Reactant: C=C(I)C[C@H](O)CO
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: C=C(I)C[C@H]1COC(C)(C)O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2,2-Dimethoxypropane and pyridinium p-toluenesulfonate (PPTS) are added to a solution of (S)-4-iodopent-4-ene-1,2-diol in dichloromethane and the mixture stirred at room temperature for 2 hours. Solvents are removed under reduced pressure and the crude product purified by flash chromatography using ethyl acetate/hexane (1:10) eluant.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([N+:9]([O-])=O)[CH:5]=[C:6]([I:8])[CH:7]=1.[Cl-]>C(O)C>[I:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([I:8])[CH:7]=1)[NH2:9]
Reactant: O=[N+]([O-])c1cc(I)cc(I)c1
Agent: [Cl-]
Solvent: CCO
Product: Nc1cc(I)cc(I)c1
Yield: 61.9 %

Procedure:
A mixture of 61.5 g (0.164 M) of 3,5-diiodonitrobenzene and 111.1 g (0.4924 M) of etannous chloride in 900 mL of ethanol was heated to reflux 1.5 hrs under nitrogen. The reaction mixture was cooled and most of the solvent was removed in vacuo. The residue was partitioned between ethyl acetate and excess ice-cold 5 N sodium hydroxide and ice. The organic phase was separated, washed with sat'd sodium chloride solution, and dried over anhyd. magnesium sulfate. Solvent removal afforded a crude oil which was purified on silica gel using 8:1:1 mixture of hexane:methylene chloride:ethyl acetate to give 35 g of 3,5-diiodoaniline as a light tan colored solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=O.[CH:19]1([NH2:25])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>>[CH:19]1([NH:25][C:12](=[O:14])[C:11]2[CH:15]=[CH:16][N:17]=[CH:18][C:10]=2[NH:9][C:3]2[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=2[F:1])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: NC1CCCCC1
Reactant: O=C(O)c1ccncc1Nc1ccc(I)cc1F
Product: O=C(NC1CCCCC1)c1ccncc1Nc1ccc(I)cc1F

Procedure:
N-cyclohexyl-3-[(2-fluoro-4-iodophenyl)amino]isonicotinamide was synthesized according to the procedure for General Method 1, outlined above, starting with 0.33 mmol of 3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and 0.42 mmol of cyclohexylamine. LC/MS [10.52 min; 440 (M+1)]
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]([C:14]([OH:16])=O)=[CH:12][O:11][N:10]=2)=[CH:5][CH:4]=1.C(N(C(C)C)C(C)C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.Cl.[Cl:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=1[C:56]1([OH:61])[CH2:60][CH2:59][NH:58][CH2:57]1>CN(C=O)C>[Cl:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=1[C:56]1([OH:61])[CH2:60][CH2:59][N:58]([C:14]([C:13]2[C:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)=[N:10][O:11][CH:12]=2)=[O:16])[CH2:57]1
Reactant: COc1ccc(-c2nocc2C(=O)O)cc1
Reactant: OC1(c2ccccc2Cl)CCNC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2nocc2C(=O)N2CCC(O)(c3ccccc3Cl)C2)cc1
Yield: 75.2 %

Procedure:
A solution of 3-(4-methoxyphenyl)isoxazole-4-carboxylic acid (7 mg, 0.03 mmol), N-ethyl-N-isopropylpropan-2-amine (16 μL, 0.09 mmol, 3 equ.) and TBTU (12 mg, 0.036 mmol, 1.2 equ.) in DMF (0.3 mL) was added to 3-(2-chlorophenyl)pyrrolidin-3-ol hydrochloride (7 mg, 0.03 mmol). After 1 h at rt the crude product was purified by RP-HPLC. The pure fractions were basified (NaHCO3) and extracted with ethyl acetate, dried (Na2SO4), evaporated and dried in vacuum to yield the title compound (9 mg). MS (ESI, pos. ion) m/z: calcd for C21H19ClN2O4: 398.1033, found 398.1036.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][N:3]=1.[OH-].[K+].[N+:12]([CH2:14][C:15]([N:17]1[CH2:21][CH:20]=[CH:19][CH2:18]1)=[O:16])#[C-:13]>CO>[Cl:1][C:2]1[CH:7]=[C:6]([C@@H:8]2[O:9][CH:13]=[N:12][C@H:14]2[C:15]([N:17]2[CH2:21][CH:20]=[CH:19][CH2:18]2)=[O:16])[CH:5]=[CH:4][N:3]=1
Reactant: O=Cc1ccnc(Cl)c1
Reactant: [C-]#[N+]CC(=O)N1CC=CC1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C([C@@H]1N=CO[C@H]1c1ccnc(Cl)c1)N1CC=CC1
Reaction time: 2 h
Yield: 84 %

Procedure:
SLA 07158 was prepared in accordance with method D using 2-chloropyridine-4-carbaldehyde SLA 07156 (0.47 g, 3.31 mmol), KOH (0.184 g, 3.33 mmol) in methanol (10 mL) and 2-Isocyano-1-(2H-pyrrol-1(5H)-yl)ethanone SLA 07178 (0.410 g, 3.01 mmol). The solution was stirred 2 h with continued cooling. After work-up and column chromatography on florisil (EtOAc), trans-(5-(2-chloropyridin-4-yl)-4,5-dihydrooxazol-4-yl)(2H-pyrrol-1(5H)-yl)methanone SLA 07158 was obtained as a yellow solid (0.597 g, 84
Reaction SMILES: [C:1]1([NH2:9])[N:6]=[C:5]([NH2:7])[N:4]=[C:3]([NH2:8])[N:2]=1.O[P:11](O)(O)=O>O>[N:2]1[C:3]([NH2:8])=[N:4][C:5]([NH2:7])=[N:6][C:1]=1[NH2:9].[P:11]
Reactant: O=P(O)(O)O
Agent: Nc1nc(N)nc(N)n1
Solvent: O
Product: [P]

Procedure:
Melamine polyphosphate and a process for preparing this salt are described, inter alia, in WO 97/44377. According to this reference, melamine polyphosphate having a solubility of 0.01 to 0.10 g per 100 ml water at 25° C., a pH between 2.5 and 4.5, and a melamine/phosphorus molar ratio of between 1.0 and 1.1, may be obtained at 25° C. as an aqueous slurry of 10.0 wt %.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH:27]=[N:28][CH2:29][CH2:30][OH:31])=[C:5]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-:21])=[O:20])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[BH4-].[Na+].Cl>C(O)C>[CH3:1][C:2]1[NH:3][C:4]([CH2:27][NH:28][CH2:29][CH2:30][OH:31])=[C:5]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-:21])=[O:20])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C1=C(C)NC(C=NCCO)=C(C(=O)OCC)C1c1ccccc1[N+](=O)[O-]
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C1=C(C)NC(CNCCO)=C(C(=O)OCC)C1c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of diethyl 2-methyl-4-(2-nitrophenyl)-6-(2-hydroxyethyl)iminomethyl-1,4-dihydropyridine-3,5-dicarboxylate (1.2 g) in 95% ethanol (15 ml) was added sodium borohydride (115 mg) and stirred overnight at room temperature. The resultant mixture was weakly acidified with dilute hydrochloric acid and the ethanol was removed from the mixture. The residue was basified with an aqueous solution of sodium bicarbonate and then extracted with ethyl acetate. The extract was washed with water and dried over magnesium sulfate. The solvent was distilled off to give an oil of diethyl 2-methyl-4-(2-nitrophenyl)-6-(2-hydroxyethyl)aminomethyl-1,4-dihydropyridine-3,5-dicarboxylate. This oil was dissolved in 95% ethanol (15 ml) and the solution was refluxed for 3 hours. Ethanol was removed from the solution to give a red oil. The oil was pulverized and recrystallized from a mixture of ethanol and diethyl ether to give an orange crystals (0.5998 g) of ethyl 2-methyl-4-(2-nitrophenyl)-5-oxo-6-(2-hydroxyethyl)-1,4,5,7-tetrahydropyrrolo-[3,4-b]pyridine-3-carboxylate. The product was further recrystallized from a mixture of ethanol and diethyl ether to give pure pale orange granules, m.p. 210° to 211° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[C:12]([C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1)([CH3:15])([CH3:14])[CH3:13].S(OS([O-])=O)([O-])=O.[Na+].[Na+]>CN(C)C(=O)C>[C:12]([C:16]1[CH:17]=[CH:18][C:19]([C:20]2[NH:6][C:4](=[O:5])[C:3]3[C:2](=[CH:10][CH:9]=[C:8]([F:11])[CH:7]=3)[N:1]=2)=[CH:22][CH:23]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)c1ccc(C=O)cc1
Reactant: NC(=O)c1cc(F)ccc1N
Agent: O=S([O-])OS(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CC(C)(C)c1ccc(-c2nc3ccc(F)cc3c(=O)[nH]2)cc1
Temperature: 150 °C
Reaction time: 3 h

Procedure:
A suspension of 2-amino-5-fluorobenzamide (154 mg, 1.0 mmol), 4-tert-butylbenzaldehyde (162 mg, 1.0 mmol) and sodium disulfite (194 mg, 1.02 mmol) in N,N-dimethylacetamide (2 ml) is heated to 150° C. and stirred at this temperature for 3 hours. The reaction mixture is allowed to reach room temperature and poured into ice water. The resulting precipitate is collected by filtration, washed with water and dried under vacuum to afford 2-(4-tert-butyl-phenyl)-6-fluoro-3H-quinazolin-4-one as light grey solid;
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][NH:10][C:9]2=[O:13])[CH:5]=[CH:4][N:3]=1.Br[C:15]1[CH:16]=[N:17][CH:18]=[CH:19][C:20]=1[CH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1.CN[C@@H]1CCCC[C@H]1NC.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][N:10]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][C:20]=3[CH:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[C:9]2=[O:13])[CH:5]=[CH:4][N:3]=1
Reactant: Brc1cnccc1C1CCCC1
Reactant: O=C1NCCN1c1ccnc(Cl)c1
Agent: I[Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: O=C1N(c2ccnc(Cl)c2)CCN1c1cnccc1C1CCCC1
Yield: 1.9 %

Procedure:
Using analogous reagents and reaction conditions as described in Example 1 above, 1-(2-chloro-pyridin-4-yl)imidazolidin-2-one (I-33b: 75 mg, 0.38 mmol) was reacted with and 3-bromo-4-cyclopentyl-pyridine (I-34c: 95 mg, 0.418 mmol) copper iodide (7.22 mg, 0.38 mmol), trans-N,N′-dimethylcyclohexane-1,2-diamine (16.21 mg, 0.114 mmol), potassium phosphate (241.9 mg, 1.15 mmol) and 1,4-dioxane (5 mL) to yield the crude product. Purified by preparative HPLC afforded 2.50 mg of the product (2% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([N:8]([CH3:23])[CH2:9][CH2:10][C@H:11]2[CH2:16][CH2:15][C@H:14]([CH2:17][NH:18][CH2:19][CH2:20][CH2:21][OH:22])[CH2:13][CH2:12]2)=[N:6][CH:7]=1.[CH2:24]=O.P(O)(O)O>O1CCOCC1>[Br:1][C:2]1[CH:7]=[N:6][C:5]([N:8]([CH3:23])[CH2:9][CH2:10][C@H:11]2[CH2:16][CH2:15][C@H:14]([CH2:17][N:18]([CH3:24])[CH2:19][CH2:20][CH2:21][OH:22])[CH2:13][CH2:12]2)=[N:4][CH:3]=1
Reactant: CN(CC[C@H]1CC[C@H](CNCCCO)CC1)c1ncc(Br)cn1
Reactant: C=O
Agent: OP(O)O
Solvent: C1COCCO1
Product: CN(CCCO)C[C@H]1CC[C@H](CCN(C)c2ncc(Br)cn2)CC1
Temperature: 60 °C

Procedure:
A solution of 0.21 g (0.6 mmol) trans-3-[(4-{2-[(5-Bromo-pyrimidin-2-yl)-methyl-amino]-ethyl}-cyclohexylmethyl)-amino]-propan-1-ol was taken up in 3 ml of dioxan, treated with 3 ml of a aqueous 1N NaH2PO3 solution and 3 ml of a 36% aqueous formaldehyde solution (Loibner, H., A. Pruckner, et al. (1984). “Reductive methylation of primary and secondary amines with formaldehyde and phosphorous acid salts.” Tetrahedron Lett. 25(24): 2535–6). The mixture was heated to 60° C. for 30 min. The mixture was cooled and extracted with 2N NaOH/ether (3×). The organic phase was washed with aqueous 10% NaCl, dried (NaSO4) and evaporated. Purification by flash silica gel column (CH2Cl2/MeOH 98:2 to 9:1) gave 0.17 g (76%) of trans-3-[(4-{2-[(5-Bromo-pyrimidin-2-yl)-methyl-amino]-ethyl}-cyclohexylmethyl)-methyl-amino]-propan-1-ol, MS: 399 (MH+, 1Br).