Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]([C@@H:16]([CH3:19])[CH:17]=[O:18])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>>[CH2:9]([N:8]([C@H:16]([C@H:17]([OH:18])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH3:21])[CH3:19])[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCCCCCCCCCCCCBr
Reactant: C[C@@H](C=O)N(Cc1ccccc1)Cc1ccccc1
Product: CCCCCCCCCCCCC[C@@H](O)[C@H](C)N(Cc1ccccc1)Cc1ccccc1

Procedure:
According to the method of Example 26, from aldehyde 4 (332 mg, 1.31 mmol) and 1-bromotridecane (863 mg, 3.28 mmol), alcohol 33 was obtained as a colorless oil (172 mg, 30% yield).
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:10][C@H:9]1[OH:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:27][CH2:28][C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=1)[C:32](Cl)=[O:33]>>[CH2:1]([C@H:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][C:32](=[O:33])[C:31]3[CH:35]=[CH:36][CH:37]=[C:29]([CH2:28][Cl:27])[CH:30]=3)=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:10][C@H:9]1[OH:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1cccc(CCl)c1
Reactant: O=S(=O)(CCN1CC[C@H](Cc2ccccc2)[C@H](O)C1)c1ccc(O)cc1
Product: O=C(Oc1ccc(S(=O)(=O)CCN2CC[C@H](Cc3ccccc3)[C@H](O)C2)cc1)c1cccc(CCl)c1
Yield: 80 %

Procedure:
The title compound was prepared from (3S,4S)-4-[2-(4-benzyl-3-hydroxy-piperidin-1-yl)-ethanesulfonyl]-phenol and 3-chlormethylbenzoylchloride in 80% yield as a colorless solid.
Reaction SMILES: I.[NH:2]1[CH2:8][CH2:7][CH2:6][CH2:5][NH:4][C:3]1=[N:9][NH2:10].Cl.[C:12](Cl)(=O)[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1>>[N:16]1[CH:17]=[CH:18][C:13]([C:12]2[N:2]3[CH2:8][CH2:7][CH2:6][CH2:5][NH:4][C:3]3=[N:9][N:10]=2)=[CH:14][CH:15]=1
Reactant: NN=C1NCCCCN1
Reactant: O=C(Cl)c1ccncc1
Agent: Cl
Agent: I
Product: c1cc(-c2nnc3n2CCCCN3)ccn1
Temperature: 160 °C
Yield: 207.3 %

Procedure:
A mixture of 1,3-diazepan-2-one hydrazone hydroiodide (1.00 g, 3.9 mmol) and isonicotinoyl chloride hydrochloride (695 mg, 3.9 mmol) was heated in a microwave reactor at 160° C. for 10 min. The reaction mixture was poured into NaaCO3 solution, sat., and extracted with DCM. The organic phase was dried and concentrated. Flash chromatography (DCM/MeOH 20:1) gave 1.74 g crude title compound which was used directly in the next step. 1H NMR: 1.89 (s, 4H) 3.15 (m, 2H) 3.86 (m, 2H) 7.44 (d, 2H) 8.66 (d, 2H).
Reaction SMILES: C(OC(=O)C(=C[NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[N:14]=1)C(OCC)=O)C.Cl.NO.[OH-].[Na+].[CH2:26](Cl)Cl>CCO.O>[CH2:19]([C:15]1[N:14]=[C:13]([NH2:12])[CH:18]=[CH:17][CH:16]=1)[CH3:26]
Reactant: CCOC(=O)C(=CNc1cccc(C)n1)C(=O)OCC
Reactant: ClCCl
Agent: Cl
Agent: NO
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCc1cccc(N)n1
Temperature: 100 °C

Procedure:
The product from Example 1a (4.93 g, 0.025 mol) was dissolved in a mixture of EtOH (80 mL) and water (30 mL). To this was added hydroxylamine hydrochloride (8.6 g, 0.123 mol) and the resulting mixture heated to 100° C. for 8 h. The reaction mixture was poured into dilute sodium hydroxide solution and the crude product isolated by extraction with CH2Cl2 and dried over MgSO4 filtered and concentrated under vacuum giving the title compound. The material was used as isolated.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].CCN(CC)CC.[CH2:19]([NH2:23])[CH2:20][CH2:21][CH3:22]>CN(C=O)C>[CH2:19]([NH:23][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10])[CH2:20][CH2:21][CH3:22]
Reactant: CCCCN
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCNc1cc(F)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a stirred solution of 2,4-difluoronitrobenzene (50 mmol), Et3N (100 mmol) and DMF (80 mL) was added dropwise a solution of n-butylamine (51 mmol) in DMF (20 mL) at rt, and the mixture was stirred at rt for 5 h. The reaction was quenched by cold H2O (100 mL), and the resulting mixture was extracted with EtOAc (4×100 mL). The combined EtOAc extracts were washed with brine (3×60 mL) and dried (anhydrous Na2SO4). The solvent was removed in vacuo to afford the desired 2-n-butylamino-4-fluoronitrobenzene which was used for further transformation.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:16])[CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.CO[CH:19](OC)[N:20]([CH3:22])[CH3:21]>>[CH3:19][N:20]([CH3:22])[CH:21]=[C:9]([C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1)[C:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)=[O:16]
Reactant: O=C(Cc1ccncc1)c1ccc(F)cc1
Reactant: COC(OC)N(C)C
Product: CN(C)C=C(C(=O)c1ccc(F)cc1)c1ccncc1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
A mixture of 1-(4-fluorophenyl)-2-(pyridin-4-yl)-ethan-1-one (5.12 g) and N,N-dimethylformamide dimethyl acetal (16 ml) was stirred at 100° C. for 3 hours under nitrogen. The cooled mixture was concentrated in vacuo. The residue was crystallized from isopropyl ether to yield 3-dimethylamino-1-(4-fluorophenyl)-2-(pyridin-4-yl)-2-propen-1-one (6.15 g).
Reaction SMILES: [ClH:1].Cl.[N:3]1([C:9]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][OH:22])=[CH:17][CH:16]=3)=[N:13][CH:12]=[CH:11][N:10]=2)[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.[CH2:23]([N:25]1[CH:29]=[C:28]([CH:30]=O)[CH:27]=[N:26]1)[CH3:24].C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl-].[NH4+]>ClC(Cl)C.C(=O)(O)[O-].[Na+].CO.C(O)(=O)C>[ClH:1].[CH2:23]([N:25]1[CH:29]=[C:28]([CH2:30][N:6]2[CH2:7][CH2:8][N:3]([C:9]3[C:14]([C:15]4[CH:16]=[CH:17][C:18]([CH2:21][OH:22])=[CH:19][CH:20]=4)=[N:13][CH:12]=[CH:11][N:10]=3)[CH2:4][CH2:5]2)[CH:27]=[N:26]1)[CH3:24]
Reactant: CCn1cc(C=O)cn1
Reactant: OCc1ccc(-c2nccnc2N2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Solvent: CO
Product: CCn1cc(CN2CCN(c3nccnc3-c3ccc(CO)cc3)CC2)cn1
Temperature: 25 °C
Reaction time: 20 h
Yield: 83.1 %

Procedure:
Combine [4-(3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-3′-yl)-phenyl]-methanol dihydrochloride (0.177 g, 0.516 mmol), 1-ethyl-1H-pyrazole-4-carbaldehyde (0.064 g, 0.516 mmol) and triethylamine (0.144 mL, 1.03 mmol) in dichloroethane (4 mL). Add glacial acetic acid (42 mL) followed by sodium triacetoxyborohydride (0.153 g, 0.722 mmol). Stir at room temperature for 20 hr. Dilute with saturated aq. sodium bicarbonate then extract three times using DCM. Dry (sodium sulfate), filter, concentrate and purify (silica gel chromatography, eluting with 4.5:95.5 methanol (with 2 M ammonia):DCM), to give a white solid. Dissolve the solid in methanol and add ammonium chloride (1 equivalent) then sonicate the mixture for 10 min. Evaporate the solution to give the title compound as a white solid (0.178 g, 83%). MS (ES): m/z=379
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]=[CH2:5].[Mg].II.[CH2:9]1[O:19][C:12]2([CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH2:13]2)[O:11][CH2:10]1>O1CCCC1.[Cl-].[NH4+]>[CH2:10]1[O:11][C:12]2([CH2:13][CH2:14][C:15]([CH2:5][CH2:4][CH:3]=[CH2:2])([OH:18])[CH2:16][CH2:17]2)[O:19][CH2:9]1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: C=CCCBr
Agent: II
Agent: [Cl-]
Agent: [Mg]
Solvent: C1CCOC1
Product: C=CCCC1(O)CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 4-bromo-1-butene (1.0 g) and magnesium turnings (1.77 g) in dry tetrahydrofuran (10 mL) was added a crystal of iodine and the mixtures was stirred at room temperature until complete reaction had occurred. To this mixture was added 1,4-cyclohexanedione monoethylene ketal (780 mg) in tetrahydrofuran (1 mL) at 0° C. After 1 h at 0° C. and 1 h at room temperature the reaction mixture was diluted with ammonium chloride solution and the product was extracted with ether. After drying over magnesium sulfate the solvent was removed in vacuo and the residue was subjected to flash chromatography with 25% ethyl actetate /hexane as the eluent to afford 4-(3-Butenyl)-4-hydroxy-cyclohexanone ethylene ketal as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[N:18][C:19]#[N:20])OC2C=CC=CC=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH3:21][CH:22]([CH3:26])[CH2:23][CH2:24][NH2:25].C(N(CC)CC)C>C(#N)C>[C:19]([NH:18][C:10]([NH:9][C:4]1[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=1)=[N:25][CH2:24][CH2:23][CH:22]([CH3:26])[CH3:21])#[N:20]
Reactant: N#CN=C(Nc1cc(Cl)cc(Cl)c1)Oc1ccccc1
Reactant: CC(C)CCN
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)CCN=C(NC#N)Nc1cc(Cl)cc(Cl)c1
Temperature: 85 °C
Reaction time: 16 h
Yield: 54.6 %

Procedure:
To N-(3,5-Dichlorophenyl)-N'-cyano-O-phenylisourea (0.98 mmol, 300 mg) in dry acetonitrile (2 ml), 3-methylbutylamine (2.16 mmol, 0.255 ml) and triethylamine (1.08 mmol, 0.150 ml) were added. The reaction mixture was stirred for 16 h at 85° C. under nitrogen. The precipitated material was filtered off and recrystallized from ethyl acetate to give the title compound (160 mg, 54%) as white crystals. Mp 146.5-1451.5° C.; 1H-NMR (CDCl3): δ 0.94 (d, 6H), 1.43 (q, 2H), 1.6 (m, 1H), 3.31 (q, 2H), 4.9 (br, 1H), 7.18 (br s, 2H), 7.29 (br s, 1H), 7.5 ppm (br, 1H); MA calc for C13H16Cl2N4 : C, 52.19%; H, 5.39%; N, 18.73%. Found: C, 52.23%; H, 5.51%; N, 18.60%.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Br:8])=[CH:6][C:5]([C:9](=[O:15])/[CH:10]=[CH:11]/[C:12]([OH:14])=[O:13])=[CH:4][C:3]=1[Br:16].[CH3:17][Si](C)(C)Cl>CO>[NH2:1][C:2]1[C:3]([Br:16])=[CH:4][C:5]([C:9](=[O:15])/[CH:10]=[CH:11]/[C:12]([O:14][CH3:17])=[O:13])=[CH:6][C:7]=1[Br:8]
Reactant: C[Si](C)(C)Cl
Reactant: Nc1c(Br)cc(C(=O)/C=C/C(=O)O)cc1Br
Solvent: CO
Product: COC(=O)/C=C/C(=O)c1cc(Br)c(N)c(Br)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 5.6 g (0.016 mol) of trans-4-(4-amino-3,5-dibromophenyl)-4-oxobutenoic acid, 50 mL of anhydrous methanol, and 4.0 g (0.0368 mol) of trimethylchlorosilane was stirred for 3 days at ambient temperature. The solvent was removed in vacuo, the residue was divided between ethyl acetate and 10% sodium hydrogen carbonate solution. The organic phase was dried over sodium sulfate, evaporated down once more in vacuo, and yielded 5.8 g (100% of theoretical) of a colorless oil which was used without any further purification. MS: M+=361/363/365 (Br2).
Reaction SMILES: [OH:1][C:2]([CH3:20])([CH3:19])[C:3]#[C:4][C:5]1[CH:14]=[CH:13][C:12]2[NH:11][C:10](=[O:15])[C:9]3[NH:16][CH:17]=[CH:18][C:8]=3[C:7]=2[CH:6]=1.[CH2:21]([C:23]([O-:25])=[O:24])[CH3:22].C([O-])=O.[NH4+]>[Pd].C(O)C>[OH:1][C:2]([CH3:20])([CH3:19])[CH2:3][CH2:4][C:5]1[CH:14]=[CH:13][C:12]2[NH:11][C:10](=[O:15])[C:9]3[NH:16][CH:17]=[CH:18][C:8]=3[C:7]=2[CH:6]=1.[CH2:21]([C:23]([O-:25])=[O:24])[CH3:22]
Reactant: CC(C)(O)C#Cc1ccc2[nH]c(=O)c3[nH]ccc3c2c1
Agent: [Pd]
Agent: CCC(=O)[O-]
Agent: O=C[O-]
Solvent: CCO
Product: CC(C)(O)CCc1ccc2[nH]c(=O)c3[nH]ccc3c2c1
Yield: 10.4 %

Procedure:
A suspension of 47 mg (0.14 mmol) of 8-(3-hydroxy-3-methyl-but-1-ynyl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate, 164 mg (2.6 mmol) of ammonium formate and 5 mg of palladium on charcoal in 10 ml of ethanol is refluxed for 8 hours. The solution is filtered on celite and then evaporated. Water is added and the product is extracted twice with ethyl acetate. The organic phases are dried over magnesium sulfate, filtered and evaporated to give 5 mg (10%) of 8-(3-hydroxy-3-methyl-butyl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate in the form of a colourless oil.
Reaction SMILES: [N+:1]([CH:3]([CH3:11])[C:4]([O:6][CH2:7][CH2:8][CH2:9][CH3:10])=[O:5])#[C-:2].C(C(CCCC)CN(CC(CC)CCCC)CC(CC)CCCC)C>ClC1C=CC=CC=1>[CH3:11][C:3]1[N:1]=[CH:2][O:5][C:4]=1[O:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: [C-]#[N+]C(C)C(=O)OCCCC
Agent: CCCCC(CC)CN(CC(CC)CCCC)CC(CC)CCCC
Solvent: Clc1ccccc1
Product: CCCCOc1ocnc1C

Procedure:
A column according to example 1 but without a dividing wall (see FIG. 1) was continuously charged via inlet (A) with a mixture of 20.6% by weight of chlorobenzene, 5.2% by weight of n-butyl α-isocyanopropionate (R1=n-butyl, R2=methyl) and 72.60% by weight of tris(2-ethylhexyl)amine.
Reaction SMILES: Cl.C([O:4][C:5]([C:7]12[CH2:25][CH:24]1[CH:23]=[CH:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH:16]([NH2:26])[C:15](=[O:27])[N:14]1[CH:10]([CH2:11][CH:12]([O:28][C:29]([N:31]3[CH2:40][CH2:39][C:38]4[C:33](=[C:34](C(F)(F)F)[CH:35]=[CH:36][CH:37]=4)[CH2:32]3)=[O:30])[CH2:13]1)[C:9](=[O:45])[NH:8]2)=[O:6])C.C(N(C(C)C)CC)(C)C.[CH:55]1([N:60]=[C:61]=[O:62])[CH2:59][CH2:58][CH2:57][CH2:56]1>ClCCl>[CH:55]1([NH:60][C:61](=[O:62])[NH:26][C@@H:16]2[C:15](=[O:27])[N:14]3[C@@H:10]([CH2:11][C@@H:12]([O:28][C:29]([N:31]4[CH2:40][CH2:39][C:38]5[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=5)[CH2:32]4)=[O:30])[CH2:13]3)[C:9](=[O:45])[NH:8][C@@:7]3([C:5]([OH:4])=[O:6])[C@@H:24]([CH2:25]3)[CH:23]=[CH:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:59][CH2:58][CH2:57][CH2:56]1
Reactant: O=C=NC1CCCC1
Reactant: CCOC(=O)C12CC1C=CCCCCCC(N)C(=O)N1CC(OC(=O)N3CCc4cccc(C(F)(F)F)c4C3)CC1C(=O)N2
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1CCCC1)N[C@H]1CCCCCC=C[C@@H]2C[C@@]2(C(=O)O)NC(=O)[C@@H]2C[C@@H](OC(=O)N3CCc4ccccc4C3)CN2C1=O
Reaction time: 1 h
Yield: 89.3 %

Procedure:
14-Amino-2,15-dioxo-18-(8-trifluoromethyl-3,4-dihydro-1H-isoquinoline-2-carbonyloxy)-3,16-diaza-tricyclo[14.3.0.04,6]nonadec-7-ene-4-carboxylic acid ethyl ester hydrochloride salt (49 mg, 74 umol), diisopropylethylamine (29 mg, 222 umol), and cyclopentyl isocyanate (25 mg, 222 umol) were taken up in 375 uL dichloromethane and stirred at 19 C for 1 hour. The reaction was loaded directly onto a C18 flash column and eluted with water/acetonitrile (10 to 100%) containing 0.1% TFA to provide the title product as a white solid (42 mg, 77%). MS m/z 732.2 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([CH2:8][C:9]#[N:10])=[O:7])=[CH:4][CH:3]=1.[CH3:13][O:14][C:15](OC)(OC)[CH2:16][CH3:17].C(OC(=O)C)(=O)C>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8](=[C:15]([O:14][CH3:13])[CH2:16][CH3:17])[C:9]#[N:10])=[O:7])=[CH:11][CH:12]=1
Reactant: N#CCC(=O)c1ccc(F)cc1
Reactant: CCC(OC)(OC)OC
Solvent: CC(=O)OC(C)=O
Product: CCC(OC)=C(C#N)C(=O)c1ccc(F)cc1

Procedure:
A solution containing 30 g. of (p-fluorobenzoyl)acetonitrile, 36.4 g. of trimethylorthopropionate and 57 g. of acetic anhydride is heated in an oil bath at 130° for 3 hours. The ethanol and excess acetic anhydride is distilled off and the residue is diluted with chloroform. The chloroform solution is passed quickly through Magnesol® and concentrated, then cooled to produce the title product.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[C:7]([O:27][CH3:28])=[C:8]([C:13]([CH2:16][S:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[OH:26])(=[O:19])=[O:18])=[CH:14][CH:15]=2)[C:9]([O:11][CH3:12])=[O:10])=[CH:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl.Br[CH2:37][CH2:38][N:39]([CH2:42][CH3:43])[CH2:40][CH3:41].O>CN(C=O)C.C(Cl)Cl>[CH2:38]([N:39]([CH2:42][CH3:43])[CH2:40][CH2:41][O:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[S:17]([CH2:16][C:13]1[C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([O:27][CH3:28])[C:6]([C:3]2[CH:4]=[CH:5][O:1][CH:2]=2)=[CH:15][CH:14]=1)(=[O:19])=[O:18])[CH3:37]
Reactant: CCN(CC)CCBr
Reactant: COC(=O)c1c(CS(=O)(=O)c2ccccc2O)ccc(-c2ccoc2)c1OC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: CCN(CC)CCOc1ccccc1S(=O)(=O)Cc1ccc(-c2ccoc2)c(OC)c1C(=O)OC
Yield: 100 %

Procedure:
A solution of methyl 3-(furan-3-yl)-6-(2-hydroxybenzenesulphonylmethyl)-2-methoxybenzoate (Intermediate 137, 0.081 g), cesium carbonate (0.144 g) and N-(2-bromoethyl)-N,N,-diethylamine hydrochloride (0.058 g) in DMF (5 ml) was stirred at room temperature. On completion of the reaction, water and DCM were added and the organic layer was separated, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica eluting with a mixture of methanol and DCM (1:19) to give methyl 6-[2-(2-diethylaminoethoxy)benzenesulphonylmethyl]-3-(furan-3-yl)-2-methoxybenzoate (0.101 g) as a colourless oil.
Reaction SMILES: [CH2:1]([Sn:5](=[O:10])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].[OH:11][CH2:12][C:13](CO)(CO)[CH2:14]O>C1(C)C=CC=CC=1>[CH2:1]([Sn:5]1([CH2:6][CH2:7][CH2:8][CH3:9])[O:11][CH2:12][CH2:13][CH2:14][O:10]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCC[Sn](=O)CCCC
Reactant: OCC(CO)(CO)CO
Solvent: Cc1ccccc1
Product: CCCC[Sn]1(CCCC)OCCCO1
Temperature: 25 °C
Reaction time: 26.5 h
Yield: 87.5 %

Procedure:
49.78 g (0.2 mol) of dibutyltin oxide and 13.615 g (0.1 mol) of pentaerythritol were introduced into a 1000 ml reaction vessel equipped with a Dean-Stark device, and the atmosphere in the reaction vessel was replaced by argon. 500 ml of toluene was added, and the mixture was dehydrated by azeotropic distillation at 130° C. and stirred for 26.5 hours during which it became an uniform solution. After left and cooled to room temperature, the precipitated white solids were filtered. The white solids were heated and dissolved in 300 ml of toluene, and cooled gradually to room temperature, and the precipitated white solids were filtered. The resulting white solids were dried at 60° C. for 5 hours in vaccuo to give 4,4′-spirobi[1,1-dibutylstanna-2,6-dioxacyclohexane, 52.3 g (87.5% yield).
Reaction SMILES: [OH:1][C:2]1[C:33]([CH3:34])=[CH:32][C:5]([CH2:6][C@@H:7]([CH2:11][C:12](=[O:31])[N:13]2[CH2:18][CH2:17][CH:16]([N:19]3[CH2:25][CH2:24][C:23]4[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=4[NH:21][C:20]3=[O:30])[CH2:15][CH2:14]2)[C:8]([OH:10])=O)=[CH:4][C:3]=1[CH3:35].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C.[O:65]1[CH2:70][CH2:69][CH:68]([N:71]2[CH2:76][CH2:75][NH:74][CH2:73][CH2:72]2)[CH2:67][CH2:66]1>CN(C=O)C>[OH:1][C:2]1[C:3]([CH3:35])=[CH:4][C:5]([CH2:6][C@@H:7]([CH2:11][C:12]([N:13]2[CH2:18][CH2:17][CH:16]([N:19]3[CH2:25][CH2:24][C:23]4[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=4[NH:21][C:20]3=[O:30])[CH2:15][CH2:14]2)=[O:31])[C:8]([N:74]2[CH2:73][CH2:72][N:71]([CH:68]3[CH2:69][CH2:70][O:65][CH2:66][CH2:67]3)[CH2:76][CH2:75]2)=[O:10])=[CH:32][C:33]=1[CH3:34]
Reactant: C1CN(C2CCOCC2)CCN1
Reactant: Cc1cc(C[C@@H](CC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc(C)c1O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(C[C@@H](CC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCN(C3CCOCC3)CC2)cc(C)c1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 70 mg (0.15 mmol) (S)-2-(4-hydroxy-3,5-dimethyl-benzyl)-4-oxo-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-butanoic acid, 52 mg (0.15 mmol) TBTU and 25 μL (0.18 mmol) triethylamine in 1 mL DMF was stirred for 1 h at RT. Then 25 mg (0.15 mmol) 1-(tetrahydropyran-4-yl)-piperazine was added to the reaction mixture, which was then stirred for a further 16 h at RT. The reaction mixture was purified by HPLC without any further working up; the fractions containing the product were combined and lyophilised.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])[N:9]=1)[CH3:3].[N+](N[C:19]1[NH:24][C:23](=[O:25])[C:22]([CH2:26][C:27]2[CH:28]=[N:29][C:30]([CH3:33])=[CH:31][CH:32]=2)=[CH:21][N:20]=1)([O-])=O>C(O)C>[CH3:3][N:2]([CH2:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:19]2[NH:24][C:23](=[O:25])[C:22]([CH2:26][C:27]3[CH:28]=[N:29][C:30]([CH3:33])=[CH:31][CH:32]=3)=[CH:21][N:20]=2)[N:9]=1)[CH3:1]
Reactant: CN(C)Cc1nc(CSCCN)cs1
Reactant: Cc1ccc(Cc2cnc(N[N+](=O)[O-])[nH]c2=O)cn1
Solvent: CCO
Product: Cc1ccc(Cc2cnc(NCCSCc3csc(CN(C)C)n3)[nH]c2=O)cn1

Procedure:
Following the procedure of Example 1, 0.75 g. of 2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethylamine and 0.78 g. of 2-nitroamino-5-(6-methyl-3-pyridyl)methyl-4-pyrimidone were dissolved in 5 ml. of anhydrous ethanol and the resulting solution refluxed for about 1 day. The solvents were removed by evaporation and the residue extracted with ethyl acetate. The ethyl acetate extract was washed with water and dried. Evaporation of the ethyl acetate yielded crystals of 2-[2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethyl]amino-5-(6-methyl-3-pyridyl)methyl-4-pyrimidone which melted at about 154°-5° C. after recrystallization from an ethyl acetate-ether solvent mixture; yield=0.56 g.
Reaction SMILES: [CH3:1][C@H:2]1[N:15]2[C:6]([CH2:7][O:8][C:9]3[C:14]2=[CH:13][C:12]([N+:16]([O-])=O)=[CH:11][CH:10]=3)=[N:5][NH:4][C:3]1=[O:19].[Cl-].[NH4+]>CO.C1COCC1.[Zn]>[NH2:16][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][C:6]1[N:15]2[C@H:2]([CH3:1])[C:3](=[O:19])[NH:4][N:5]=1
Reactant: C[C@@H]1C(=O)NN=C2COc3ccc([N+](=O)[O-])cc3N21
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CO
Product: C[C@@H]1C(=O)NN=C2COc3ccc(N)cc3N21
Temperature: 50 °C
Reaction time: 16 h
Yield: 112.6 %

Procedure:
To a solution of (R)-4-methyl-6-nitro-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (50 g, 191 mmol) and ammonium chloride (102 g, 1907 mmol) in MeOH (700 mL) and THF (700 mL) was added zinc powder (125 g, 1907 mmol) in portions. After addition, the reaction mixture was stirred at 50° C. for 16 h. The reaction mixture was cooled to ambient temperature and filtered. The filter cake was washed with hot MeOH (3×1 L) and the combined organic phase was concentrated in vacuo. The residue was washed with THF (3×500 mL) and the combined organic phase was concentrated to give the crude (R)-6-amino-4-methyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (50 g, 215 mmol, containing residual NH4Cl), which was used in the next step without further purification. 1H NMR (CDCl3, 400 MHz): δ 6.68 (d, J=8.4 Hz, 1H), 6.43 (d, J=2.4 Hz, 1H), 6.16 (dd, J=2.4, 8.4 Hz, 1H), 4.83 (br. s., 1H), 4.56-4.52 (m, 1H), 4.47-4.39 (m, 2H), 1.31 (d, J=6.5 Hz, 3H). LCMS (Table 1, Method 3) Rt=0.803 min; MS m/z: 233 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][S:12][C:11](=[CH:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N:22]3[CH2:27][CH2:26][N:25](C)[CH2:24][CH2:23]3)[C:10]2=[O:29])[CH:5]=[CH:6][C:7]=1[Cl:8]>ClCCCl>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][S:12][C:11](=[CH:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[C:10]2=[O:29])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CN1CCN(c2ccccc2C=C2SCCN(c3ccc(Cl)c(Cl)c3)C2=O)CC1
Solvent: ClCCCl
Product: O=C1C(=Cc2ccccc2N2CCNCC2)SCCN1c1ccc(Cl)c(Cl)c1

Procedure:
Under a nitrogen atmosphere, a mixture of 4-(3,4-dichlorophenyl)-2-[2-(4-methylpiperazin-1-yl)-benzylidene]-thiomorpholin-3-one (338 mg, 0.756 mmol) in 9 mL of anhydrous 1,2-dichloroethane was treated with α-chloroethyl chlorofonnate (98 μL 0.907 mmol) and refluxed overnight. The solvent was then removed in vacuo and 10 mL of methanol was added and refluxed for 30 minutes. Following removal of the solvent, the residue was extracted into methylene chloride and washed with saturated aqueous sodium carbonate (Na2CO3) and saturated brine, dried with magnesium sulfate and concentrated to a foam. Flash chromatography using triethyl amine/methanol/ethyl acetate (1:2:97) gave the purified free base of the title compound.