Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=O)C(Cl)=O.CN(C=O)C.[CH2:12]([O:14][P:15]([CH2:18][CH2:19][NH:20][C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])(=O)[OH:16])[CH3:13].C[Mg+].[Br-]>C(Cl)Cl.C1COCC1.C1(C)C=CC=CC=1>[CH2:12]([O:14][P:15]([CH2:18][CH2:19][NH:20][C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])([CH3:1])=[O:16])[CH3:13]
Reactant: CCOP(=O)(O)CCNC(=O)OCc1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Agent: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CCOP(C)(=O)CCNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
Oxaloyl chloride (2.88 mL, 33 mmol) was dissolved in CH2Cl2 (42 mL). DMF (284 □L) was added to this solution in a drop-wise manner. After 15 minutes a solution of (2-benzyloxycarbonylamino-ethyl)-phosphonic acid monoethyl ester (4.75 g, 16.5 mmol) in solution with CH2Cl2 (42 mL) was added drop-wise over 20 minutes at room temperature. The reaction was stirred at room temperature for 40 minutes. The reaction was determined to be complete by the absence of starting material in a 31P NMR spectrum of the crude reaction mixture. The reaction was concentrated in vacuo to yield an orange-brown oil that was placed under high vacuum overnight. The oil was then dissolved in THF (80 mL) and cooled to −30° C., as determined by an internal thermometer. A 1M solution of MeMgBr in a mixture of toluene and THF was then slowly added to the reaction while keeping the internal temperature at about −30° C. The mixture was stirred at −30° C. for 45 minutes and then another 1 equivalent of MeMgBr was added. After stirring at −30° C. for another 45 minutes the reaction was quenched by the addition of saturated NH4Cl. The reaction was warmed to room temperature and then partitioned between EtOAc and H2O. The layers were separated and the organic layer was washed with brine and dried over Na2SO4. (2-Benzyloxycarbonylamino-ethyl)-methyl-phosphinic acid ethyl ester was isolated from the concentrated filtrate (1.33 g, 28%) by silica gel column chromatography (EtOAc/hexanes then MeOH/CH2Cl2) as a yellow crystalline solid.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2.[OH:17][CH2:18][CH2:19][NH:20][S:21]([C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1)(=[O:23])=[O:22].COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.O.CCOC(C)=O.CC([O-])=O.CC([O-])=O.[Pd+2]>[OH:17][CH2:18][CH2:19][NH:20][S:21]([C:24]1[CH:29]=[CH:28][C:27]([C:2]2[CH:11]=[CH:10][N:9]=[C:8]3[C:3]=2[C:4]2[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=2[C:6](=[O:12])[NH:7]3)=[CH:26][CH:25]=1)(=[O:23])=[O:22]
Reactant: O=c1[nH]c2nccc(Cl)c2c2ccccc12
Reactant: O=S(=O)(NCCO)c1ccc(B(O)O)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: O=c1[nH]c2nccc(-c3ccc(S(=O)(=O)NCCO)cc3)c2c2ccccc12
Temperature: 100 °C
Reaction time: 8 h
Yield: 3.5 %

Procedure:
Compound 83 (100 mg, 0.43 mmol), 4-(2-hydroxyethylsulfamoyl)phenylboronic acid (212 mg, 0.87 mmol), Pd(OAc)2 (5 mg, 0.02 mmol), S-Phos (18 mg, 0.04 mmol), and K2CO3 (299 mg, 2.17 mmol) were dissolved in dioxane/H2O (2.2 mL, 10/1, v/v), and stirred overnight at 100° C. The reaction mixture was diluted with H2O/EtOAc, and filtered through an Extrelut column. The column was washed with EtOAc, and the filtrate was concentrated. The crude product was purified via Biotage eluting with a gradient of 0 to 10% MeOH in CH2Cl2. The resulting material was triturated with MeOH, filtered, and dried under vacuum to provide 174 (6 mg, 4% yield) as a light-yellow solid. LC-MS (M+H=396, obsd.=396).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:35])[CH:5]=[C:6]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[Cl:34])[C:7]1[N:19]([C:20]2[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:21]=2[F:27])[C:10]2[N:11]=[C:12](S(C)(=O)=O)[N:13]=[CH:14][C:9]=2[CH:8]=1)[CH3:2].C(N(C(C)C)CC)(C)C.Cl.[NH2:46][CH:47]([CH3:52])[C:48]([CH3:51])([OH:50])[CH3:49]>CN1CCCC1=O.[NH4+].[Cl-]>[CH2:1]([O:3][C:4](=[O:35])[CH:5]=[C:6]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[Cl:34])[C:7]1[N:19]([C:20]2[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:21]=2[F:27])[C:10]2[N:11]=[C:12]([NH:46][CH:47]([CH3:52])[C:48]([OH:50])([CH3:51])[CH3:49])[N:13]=[CH:14][C:9]=2[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C=C(c1ccccc1Cl)c1cc2cnc(S(C)(=O)=O)nc2n1-c1c(F)cccc1F
Reactant: CC(N)C(C)(C)O
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CCOC(=O)C=C(c1ccccc1Cl)c1cc2cnc(NC(C)C(C)(C)O)nc2n1-c1c(F)cccc1F
Temperature: 120 °C

Procedure:
To a solution of 3-(2-chloro-phenyl)-3-[7-(2,6-difluoro-phenyl)-2-methanesulfonyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-acrylic acid ethyl ester, 14, (0.30 g, 0.59 mmol)) in N-methylpyrrolidinone (4 mL) is added diisopropylethylamine (0.41 mL, 2.36 mmol) and 3-amino-2-methyl-butan-2-ol hydrochloride salt (0.10 g, 0.71 mmol). After heating the reaction at 90° C. for 21 hours, an additional equivalent of 3-amino-2-methyl-butan-2-ol hydrochloride salt (0.08 g, 0.59 mmol) is added and the mixture heated at 120° C. for 4 hours. The reaction is cooled to room temp and then diluted with aqueous saturated NH4Cl solution. The aqueous phase is twice extracted with CHCl3 and the organic phase is then washed with aqueous saturated NaHCO3 solution. The organic phase is dried (MgSO4), filtered, concentrated in vacuo and the resulting residue is purified by preparative HPLC to afford the desired product as a yellowish solid: 1H NMR (300 MHz, d3-DMSO) δ 8.64 (s, 1H), 7.64-7.52 (m, 1H), 7.38-7.24 (m, 5H), 7.14-7.08 (m, 1H), 6.57 (s, 1H), 5.95 (s, 1H), 4.31 (bd s, NH), 3.85 (q, J=7.2 Hz, 2H), 3.34 (m, 1H), 1.04 (s, 9H), 0.93 (t, J=7.2 Hz); ESI+ MS: m/z (rel intensity) 541.0 (100, M++H).
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O1CCCC1.CS([C:18]1[CH:23]=[C:22]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][N:25]=2)[N:21]2[N:34]=[CH:35][N:36]=[C:20]2[N:19]=1)(=O)=O>O>[C:1]1([C:18]2[CH:23]=[C:22]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:31])([F:32])[F:33])=[CH:26][N:25]=3)[N:21]3[N:34]=[CH:35][N:36]=[C:20]3[N:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CS(=O)(=O)c1cc(-c2ccc(C(F)(F)F)cn2)n2ncnc2n1
Reactant: Br[Mg]c1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: FC(F)(F)c1ccc(-c2cc(-c3ccccc3)nc3ncnn23)nc1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
0.2 mL of a phenyl magnesium bromide 3.0 M tetrahydrofuran solution was added at 0° C. to a tetrahydrofuran (dehydrated) 3 mL solution of 200 mg of 5-(methylsulfonyl)-7-(5-(trifluoromethyl)pyridin-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidine, followed by stirring at 0° C. for 5 minutes. After completion of the reaction, water was added to the reaction liquid, followed by extraction with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=4/1) to obtain 93 mg of the desired product.
Reaction SMILES: [CH3:1][CH:2]([CH3:21])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[S:12][C:11]([N:13]2[CH2:20][C:19]3[CH2:18][NH:17][CH2:16][C:15]=3[CH2:14]2)=[N:10][CH:9]=1)=[O:7].FC(F)(F)C([O-])=O.C(N(CC)CC)C.[F:36][C:37]([F:48])([F:47])[C:38]1[CH:46]=[CH:45][CH:44]=[CH:43][C:39]=1[C:40](Cl)=[O:41]>CN(C=O)C>[CH3:1][CH:2]([CH3:21])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[S:12][C:11]([N:13]2[CH2:14][C:15]3[CH2:16][N:17]([C:40](=[O:41])[C:39]4[CH:43]=[CH:44][CH:45]=[CH:46][C:38]=4[C:37]([F:36])([F:47])[F:48])[CH2:18][C:19]=3[CH2:20]2)=[N:10][CH:9]=1)=[O:7]
Reactant: CC(C)CCNC(=O)c1cnc(N2CC3=C(CNC3)C2)s1
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Agent: O=C([O-])C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)CCNC(=O)c1cnc(N2CC3=C(CN(C(=O)c4ccccc4C(F)(F)F)C3)C2)s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N-(3-Methylbutyl)-2-(3,4,5,6-tetrahydro-1H-pyrrolo[3,4-c]pyrrol-2-yl)thiazole-5-carboxamide, trifluoroacetate (220 mg, 0.52 mmol) and triethylamine (0.22 ml, 1.57 mmol) were dissolved in 10 ml of DMF and admixed in an ice bath with 2-trifluoromethylbenzoyl chloride (218 mg, 1.04 mmol). The mixture was stirred further for 1 h and allowed to warm to room temperature, and concentrated, water and ethyl acetate were added and the organic phase was removed, concentrated and purified by preparative HPLC (PR18, acetonitrile/water 0.1% TFA). Yield: 25 mg (10%), M+H+: 479.06.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([N:8]=[C:9]([O:16][CH3:17])[C:10]([O:14][CH3:15])=[N:11]2)=[C:6]([CH2:18][NH:19][CH:20]([P:22](=[O:27])([O:25][CH3:26])[O:23][CH3:24])[CH3:21])[CH:5]=1)([O-:3])=[O:2].[CH2:28](I)[CH3:29].C(N(C(C)C)CC)(C)C>C(#N)C>[N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([N:8]=[C:9]([O:16][CH3:17])[C:10]([O:14][CH3:15])=[N:11]2)=[C:6]([CH2:18][N:19]([CH2:28][CH3:29])[CH:20]([P:22](=[O:27])([O:23][CH3:24])[O:25][CH3:26])[CH3:21])[CH:5]=1)([O-:3])=[O:2]
Reactant: COc1nc2cc([N+](=O)[O-])cc(CNC(C)P(=O)(OC)OC)c2nc1OC
Reactant: CCI
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCN(Cc1cc([N+](=O)[O-])cc2nc(OC)c(OC)nc12)C(C)P(=O)(OC)OC

Procedure:
300 mg (0.75 mmol) of dimethyl N-(7-nitro-2,3-dimethoxyquinoxalin-5-ylmethyl)-α-aminoethylphosphonate, 0.482 ml (8 eq.) of ethyl iodide and 1.4 ml (11 eq.) of diisopropylethylamine are stirred at 700 for 24 hours in 10 ml of acetonitrile. The reaction mixture is evaporated and the residue is stirred in diethyl ether. The solid is filtered off, washed with diethyl ether and the filtrate is evaporated. The title compound is obtained as a brownish oil.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1)#[N:2].[CH3:11][C:12]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:16](=[O:17])[CH:15]=[C:14]([CH3:18])[O:13]1.[OH-].[Na+].[Cl-].[Na+]>C(O)C>[CH3:11][C:12]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:16](=[O:17])[CH:15]=[C:14]([CH:18]=[CH:7][C:6]2[CH:9]=[CH:10][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[O:13]1
Reactant: N#Cc1ccc(C=O)cc1
Reactant: CC1=CC(=O)C(C)(c2ccccc2)O1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC1(c2ccccc2)OC(C=Cc2ccc(C#N)cc2)=CC1=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 41.9 %

Procedure:
To a solution of p-cyanobenzaldehyde (0.84 g, 6.4 mM) and 2,5-dimethyl-2-phenyl-3(2H)-furanone (1.0 g, 5.3 mM) in ethanol (50 mL), was added 1N aqueous sodium hydroxide (0.5 mL, 0.5 mm). The reaction solution was stirred at room temperature for two days. Then, saturated aqueous sodium chloride (200 mL) was added. The aqueous layer was extracted with diethyl ether (3×100 mL). The combined ethereal extracts were washed with saturated aqueous sodium chloride (50 mL), dried over MgSO4, filtered and concentrated to give a beige solid. The crude product was recrystallized from ethanol to afford a yellow solid (671 mg, 42% yield), m.p. 187°-188° C.
Reaction SMILES: ClCC([NH:5][C:6](C)(C)[CH2:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)=O.NC(N)=S.[C:20](O)(=O)[CH3:21]>CCO>[CH3:10][C:9]1[C:20]([CH3:21])=[N:5][CH:6]=[CH:7][C:8]=1[CH2:13][CH2:12][NH2:11]
Reactant: CC(=O)O
Reactant: CC(C)(Cc1ccncc1)NC(=O)CCl
Agent: NC(N)=S
Solvent: CCO
Product: Cc1nccc(CCN)c1C
Temperature: 25 °C
Yield: 45 %

Procedure:
A mixture of 260B (1.30 g, 5.75 mmol), thiourea (524 mg, 6.90 mmol), acetic acid (2 ml) and EtOH (10 ml) was refluxed overnight. The reaction mixture was cooled to room temperature and the solid that separated out was filtered. The filtrate was concentrated and made acidic using 1N HCl. The aqueous solution was washed with EtOAc (2×25 mL), cooled to 0° C. and basified with 2N NaOH. The sodium hydroxide layer was re-extracted with EtOAc (2×25 mL), washed with water (25 mL), dried over Na2SO4 and concentrated under reduced pressure to give 260C (390 mg, 45%) 1NMR (CDCl3) δ 8.45 (d, 2H), 7.06 (d, 2H), 2.58 (s, 2H), 1.06 (s, 6H)
Reaction SMILES: [O:1]=[C:2]1[C@H:8]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:7][CH2:6][CH2:5][CH2:4][NH:3]1.[CH3:17]I>C1COCC1>[CH3:17][N:3]1[CH2:4][CH2:5][CH2:6][CH2:7][C@@H:8]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:15])[CH3:14])[C:2]1=[O:1]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCCNC1=O
Reactant: CI
Solvent: C1CCOC1
Product: CN1CCCC[C@@H](NC(=O)OC(C)(C)C)C1=O
Reaction time: 0.5 h

Procedure:
To a stirred solution of [(3R)-hexahydro-2-oxo-1H-azepin-3-yl]-carbamic acid, 1,1-dimethylethyl ester (500 mg) in THF (5 mL) at rt, KHDMS (5.26 mL, 1.0 M in THF) was added. After 30 min, CH3I (0.26 mL) was introduced. The reaction was kept at rt overnight, and then quenched with brine. The reaction mixture was extracted with EtOAc, washed with brine, and dried over Na2SO4. Concentration in vacuo afforded the crude product which was used directly for the next step reaction without further purification.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH2:9])[N:3]=1.[NH:10]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.C(N(CC)CC)C>CO>[Cl:8][C:6]1[CH:7]=[C:2]([N:10]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[N:3]=[C:4]([NH2:9])[N:5]=1
Reactant: C1CCCNCC1
Reactant: Nc1nc(Cl)cc(Cl)n1
Solvent: CCN(CC)CC
Solvent: CO
Product: Nc1nc(Cl)cc(N2CCCCCC2)n1
Temperature: 50 °C
Reaction time: 5 h
Yield: 86.8 %

Procedure:
In a 25 mL sealable tube under nitrogen were combined 4,6-dichloro-2-pyrimidinamine (0.50 g, 3.05 mmol) and hexahydro-1H-azepine (0.34 mL, 3.05 mmol) in CH3OH (10 mL). Triethylamine (0.47 mL, 3.35 mmol) was added, the vial was sealed, and the reaction mixture was stirred for 5 hours at 50° C. The reaction was cooled to room temperature and concentrated. The resulting yellow solid was partitioned between EtOAc and water. The organic layer was separated, dried (MgSO4), filtered and concentrated to afford the title compound (600 mg, 82%) as a yellow solid. LC-MS (ES) m/z=227 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH:9][C:10]([C@:12]2([CH2:18][O:19][Si:20]([CH:27]([CH3:29])[CH3:28])([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:23])[CH3:22])[CH2:16][CH2:15][CH2:14][N:13]2[CH3:17])=O)=[N:6][CH:7]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCN(CC)CC.ClC(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1.C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:10]([C@:12]3([CH2:18][O:19][Si:20]([CH:27]([CH3:29])[CH3:28])([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:23])[CH3:22])[CH2:16][CH2:15][CH2:14][N:13]3[CH3:17])=[N:9][N:8]=2)[CH:7]=1
Reactant: CC(C)[Si](OC[C@@]1(C(=O)NNc2ccc(F)cn2)CCCN1C)(C(C)C)C(C)C
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)[Si](OC[C@@]1(c2nnc3ccc(F)cn23)CCCN1C)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 20 h
Yield: 41.4 %

Procedure:
To a solution of Intermediate 85h (1.37 g, 2.08 mmol), Ph3P (1.09 g, 4.16 mmol) and Et3N (840 mg, 8.32 mmol) in THF (60 mL) was added hexachloroethane (980 mg, 4.16 mmol) and the mixture stirred at RT for 20 h. The mixture was diluted with DCM, washed with 10% aq. K2CO3 solution, brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by FCC, using 0-100% EtOAc in cyclohexane, to give the title compound as a clear oil (350 mg, 41%). LCMS (Method 4): Rt 3.07 min, m/z 407 [MH+].
Reaction SMILES: [S:1]([C:5]1[CH:23]=[CH:22][C:8]([CH2:9][N:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17](OCC)=[O:18])[CH2:12][CH2:11]2)=[CH:7][CH:6]=1)(=[O:4])(=[O:3])[NH2:2].C(O)C.CO.[NH2:29][NH2:30]>CO.CCOC(C)=O>[NH:29]([C:17](=[O:18])[CH2:16][N:13]1[CH2:14][CH2:15][N:10]([CH2:9][C:8]2[CH:22]=[CH:23][C:5]([S:1]([NH2:2])(=[O:4])=[O:3])=[CH:6][CH:7]=2)[CH2:11][CH2:12]1)[NH2:30]
Reactant: NN
Reactant: CCOC(=O)CN1CCN(Cc2ccc(S(N)(=O)=O)cc2)CC1
Solvent: CCO
Solvent: CO
Solvent: CCOC(C)=O
Product: NNC(=O)CN1CCN(Cc2ccc(S(N)(=O)=O)cc2)CC1
Yield: 90.6 %

Procedure:
To a stirred solution of 3 (110.9 g, 324.8 mmol, 1 equiv.) in 2:1 ethanol/methanol (650 mL in total, 0.5 M) was added anhydrous hydrazine (30.6 mL, 974.5 mmol, 3 equiv.). The reaction was refluxed for 16 h monitoring by TLC (1:1 MeOH/EtOAc). The reaction mixture was concentrated in vacuo. The residue was dissolved in CH2Cl2 and washed with water (100 mL) and brine (100 mL). The aqueous layer was extracted with CH2Cl2 (3×80 mL) and EtOAc (80 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated in vacuo. Purification with recrystallization in methanol gave 4 (96.3 g, 91%) as white solid. On the milligram-scale, the reaction was run in ethanol (0.06 M). 1H NMR (500 MHz, CD3OD): δ 7.85 (d, J=8.2 Hz, 2H), 7.51 (d, J=8.2 Hz, 2H), 3.61 (s, 2H), 3.04 (s, 2H), 2.54 (broad s, 8H). 13C NMR (126 MHz, CD3OD): δ 170.2, 142.8, 142.4, 129.7, 126.0, 61.9, 59.8, 53.0, 52.6. HRMS (ESI): found 328.1436 (M+1). calcd for C13H22N5O3S: 328.1443. m.p.: 194.5-196.0. IR (neat): 3320, 1670, 1158 cm−1.
Reaction SMILES: [Br:1][C:2]1[C:15]2[O:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:16])[C:6]=2[CH:5]=[C:4]([OH:17])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][C:26]([O:28]CC)=[O:27].[OH-].[Na+].Cl>O.CN(C=O)C>[Br:1][C:2]1[C:15]2[O:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:16])[C:6]=2[CH:5]=[C:4]([O:17][CH2:25][C:26]([OH:28])=[O:27])[CH:3]=1
Reactant: CCOC(=O)CBr
Reactant: O=c1c2ccccc2oc2c(Br)cc(O)cc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)COc1cc(Br)c2oc3ccccc3c(=O)c2c1
Reaction time: 1.5 h
Yield: 75 %

Procedure:
A mixture of 4-bromo-2-hydroxy-9-oxo-9H-xanthene (2.0 g), potassium carbonate (1.9 g), ethyl bromoacetate (2.3 g) and DMF (20 ml) was stirred at 60°-70° C/ for 1.5 hours. After cooling the mixture, sodium hydroxide (4 g) and water (40 ml) were added and the resulting mixture was stirred at 90°-100° C. for 30 minutes. After cooling, the mixture was rendered acidic with hydrochloric acid and the solid crystal was recovered by filtration, washed with water and dried. Recrystallization from ethanol gave 1.8 g of 4-bromo-9-oxo-9H-xanthene-2-yloxyacetic acid. m.p. 219°-221° C. This compound exhibited a mass spectrum having a molecular ion peak at m/e 348.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[C:13]3[NH:12][C@H:11]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[C@@H:10]([OH:20])[C:9](=[O:21])[C:8]=3[CH:7]=[CH:6][N:5]2[C:22]=1[CH3:23].C(N(CC)CC)C.[C:31](Cl)(=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33]>ClCCl>[CH3:1][C:2]1[N:3]=[C:4]2[C:13]3[NH:12][C@H:11]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[C@@H:10]([O:20][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[C:9](=[O:21])[C:8]=3[CH:7]=[CH:6][N:5]2[C:22]=1[CH3:23]
Reactant: Cc1nc2c3c(ccn2c1C)C(=O)[C@H](O)[C@@H](c1ccccc1)N3
Reactant: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nc2c3c(ccn2c1C)C(=O)[C@H](OC(=O)C(C)(C)C)[C@@H](c1ccccc1)N3
Temperature: 0 °C
Reaction time: 8 h

Procedure:
140 g of (8R,9R)-2,3-dimethyl-8-hydroxy-9-phenyl-7,8,9,10-tetrahydroimidazo[1,2-h][1,7]naphthyridin-7-one (WO 00/17200, example B1) are suspended in 1100 ml of dichloromethane under argon and with exclusion of moisture. After addition of 70 ml of triethylamine and 2.5 g of 4-dimethyl-aminopyridine, a solution of 62 ml of pivaloyl chloride in 70 ml of dichloromethane is added dropwise such that the temperature of the reaction mixture does not rise above 30° C. (cooling with a water bath). After stirring overnight, the mixture is added to 1 l of ice water and stirred in the cold for a further 10 min. The organic phase is separated off and the aqueous phase is extracted with dichloromethane (2×200 ml). The combined organic phases are washed with water (3×300 ml) until neutral, dried over sodium sulfate and evaporated. 220 g of yellowish oil are obtained, which is crystallized using 600 ml of tert-butyl methyl ether. After stirring in the cold for 2 h, the solid is filtered off, washed with 200 ml of tert-butyl methyl ether and the filter residue is dried to constant weight in a vacuum drying oven. 175 g (97%) of the title compound are obtained as a slightly yellowish solid of m.p. 185-187° C.
Reaction SMILES: [ClH:1].Cl.[NH2:3][C:4]1[NH:5][C:6](=[CH:10][CH2:11][CH2:12][NH2:13])[C:7](=[O:9])[N:8]=1.Cl.NC1NC=C(CCCN[C:25]([C:27]2[N:28]([CH3:34])[C:29]([Br:33])=[C:30]([Br:32])[CH:31]=2)=[O:26])N=1>>[ClH:1].[NH2:3][C:4]1[NH:5][C:6](=[CH:10][CH2:11][CH2:12][NH:13][C:25]([C:27]2[N:28]([CH3:34])[C:29]([Br:33])=[C:30]([Br:32])[CH:31]=2)=[O:26])[C:7](=[O:9])[N:8]=1
Reactant: Cn1c(C(=O)NCCCc2c[nH]c(N)n2)cc(Br)c1Br
Reactant: NCCC=C1NC(N)=NC1=O
Agent: Cl
Product: Cn1c(C(=O)NCCC=C2NC(N)=NC2=O)cc(Br)c1Br
Yield: 47 %

Procedure:
Using the same general procedure as used for 2-amino-5-(3-amino-propylidene)-1,5-dihydro-imidazol-4 -one dihydrochloride, 0.100 g of dihydrosventrin hydrochloride 23 gave 0.048 g (47%) of the title compound 32 as a tan solid ((Z)-isomer exclusively). 1H NMR (300 MHz, CD3OD) δ 6.84 (s, 1H), 6.16 (t, 1H, J=7.8 Hz), 3.91 (s, 3H), 3.46 (t, 2H, J=6.9 Hz), 2.59 (dt, 2H, J=6.9, 14.7 Hz); 13C NMR (100 MHz, DMSO-d6) δ 163.80, 163.00, 157.19, 130.63, 129.04, 119.42, 115.92, 112.67, 99.09, 39.06, 36.28, 28.73; HRMS (ESI) calcd for C12H14Br2N5O2 (MH+) 417.9509, found 417.9511.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]=[C:10]([CH2:12][O:13][CH3:14])[CH3:11].[H][H]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1.ClCCl.O1CCCC1>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[NH:9][CH:10]([CH2:12][O:13][CH3:14])[CH3:11]
Reactant: [H][H]
Reactant: COCC(C)=Nc1c(C)cccc1C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: COCC(C)Nc1c(C)cccc1C
Reaction time: 91 h

Procedure:
The general procedure described in Example B1 is repeated, with the following modifications to the reaction conditions: A catalyst solution is prepared consisting of 5.3 mg of [Ir((1,5-cyclooctadien)Cl]2 (0.0079 mmol), 10.2 mg of A (0.017 mmol) and 11.9 mg of tetrabutylammonium iodide (0.032 mmol) in 5 ml of tetrahydrofuran/dichloromethane (1:1). A substrate solution consisting of 1.5 g of N-(2',6'-dimethylphenyl)-1-methoxymethyl-ethylideneamine (7.8 mmol) in 5 ml of tetrahydrofuran is also used. Hydrogenation is carried out with hydrogen under a pressure of 40 bar. The reaction temperature is 30° C. After 91 hours the conversion is 90%, the ee is 59% (R).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:14]=[CH:15][CH:16]=1)[NH:7][C:8](=[O:13])[CH2:9][CH2:10][CH2:11][CH3:12])([O-])=O.O>[Fe].C(O)C>[NH2:1][C:4]1[CH:5]=[C:6]([CH:14]=[CH:15][CH:16]=1)[NH:7][C:8](=[O:13])[CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCC(=O)Nc1cccc([N+](=O)[O-])c1
Agent: [Fe]
Solvent: CCO
Solvent: O
Product: CCCCC(=O)Nc1cccc(N)c1
Reaction time: 0.5 h
Yield: 98.3 %

Procedure:
A mixture of 177.6 g of m-nitrovaleranilide, 160 ml of water, 8 ml of 22° Be hydrochloric acid and 640 ml of 95% ethanol was refluxed and 480 g of iron powder were added with stirring over 30 minutes. Reflux was continued for 30 minutes with stirring and the mixture was filtered. The filtrate was concentrated to dryness under reduced pressure and the residue was chromatographed over silica gel. Elution with an 8- 2 methylene chloride-acetone mixture gave 151 g of m-aminovaleranilide with a specific rotation nD20 = 1.541.
Reaction SMILES: [CH2:1]=O.[OH:3][CH2:4][CH2:5][NH:6][CH2:7][CH2:8][O:9][CH2:10][CH:11]([OH:22])[CH2:12][CH2:13][CH2:14][CH:15]([CH2:19][CH2:20][CH3:21])[CH2:16][CH2:17][CH3:18]>C1(C)C=CC=CC=1.C(O)(C)C>[O:3]1[CH2:4][CH2:5][N:6]([CH2:7][CH2:8][O:9][CH2:10][CH:11]([OH:22])[CH2:12][CH2:13][CH2:14][CH:15]([CH2:19][CH2:20][CH3:21])[CH2:16][CH2:17][CH3:18])[CH2:1]1
Reactant: C=O
Reactant: CCCC(CCC)CCCC(O)COCCNCCO
Solvent: CC(C)O
Solvent: Cc1ccccc1
Product: CCCC(CCC)CCCC(O)COCCN1CCOC1
Temperature: 25 °C

Procedure:
To a 10 mL flask containing paraformaldehyde (52 mg, 1,73 mmol, 1 eq.) in toluene (1 mL), was added 1-[2-(2-hydroxy-ethylamino)-ethoxy]-6-propyl-nonan-2-ol (500 mg 1,73 mmol) diluted with isopropanol (1mL) before heating to reflux with a Dean-Stark trap for 17 h. The reaction was cooled to room temperature and, after evaporation, 520 mg of a mixture of products was obtained with the title compound as the major component (100% crude yield). 1H NMR (CDCl3, 400 MHz) d?(ppm); 4,33 (s, 2H); 3,78 (t, J=6,8 Hz, 2H); 3,83-3,74 (m, H); 3,70-3,57 (m, 2H); 3,55 (dd, J=2,7 Hz, J=10,0 Hz, H); 3,29 (dd, J=8,2 Hz, J=10,0 Hz, H); 3,02 (t, J=6,8 Hz, 2H); 2,81-2,74 (m, 2H); 1,50-1,12 (m, 15H); 0,87 (t, J=7,0 Hz, 6H′). 13C NMR (CDCl3, 129,9 MHz) d?(ppm): 87,0; 76,0; 70,5; 70,3; 63,3; 54,3; 52,7; 36,9; 36,0 (2C); 33,7; 33,5; 22,7; 19,8 (2C); 14,5 (2C)