Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]2[N:16]=[C:15]([NH2:17])[C:14]3[C:9](=[CH:10][C:11]([O:20][CH3:21])=[C:12]([O:18][CH3:19])[CH:13]=3)[N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:23]1[S:24][C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[N:27]=1.C(N(CC)CC)C>C(O)CCC>[S:24]1[C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[N:27]=[C:23]1[N:4]1[CH2:5][CH2:6][N:1]([C:7]2[N:16]=[C:15]([NH2:17])[C:14]3[C:9](=[CH:10][C:11]([O:20][CH3:21])=[C:12]([O:18][CH3:19])[CH:13]=3)[N:8]=2)[CH2:2][CH2:3]1
Reactant: Clc1nc2ccccc2s1
Reactant: COc1cc2nc(N3CCNCC3)nc(N)c2cc1OC
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: COc1cc2nc(N3CCN(c4nc5ccccc5s4)CC3)nc(N)c2cc1OC

Procedure:
A suspension of 2-(1-piperazinyl)-4-amino-6,7-dimethoxyquinazoline (1.96 g), 2-chlorobenzthiazole (1.02 g), triethylamine (1.82 g) in butanol (100 ml) was refluxed for 72 hr and filtered. The precipitate was taken up in a solution of methanol and dimethyl sulfoxide, and 1 N sodium hydroxide was added until the mixture was alkaline. The precipitate was collected, washed with water, dried (1.3 g) and crystallized from methanol to give the title compound: mp 242°-245° C.; ir (nujol) 3460 and 3370 cm-1 : uv max (MeOH) 227 (ε=4130), 250 (ε=5280), 276 (ε=3649) and 340 nm (ε=690); nmr (DMSO-d6) δ 3.65 (m, 4H), 3.9 (m, 4H), 3.85 (s, 3H), 3.93 (s, 3H), 5.2 (s, 2H) and 7.2 (m, 6H); and Anal. Calcd for C21H22N6O2S.CH3OH: C, 58.14% H, 5.72% N, 18.50% and Found: C, 57.88% H, 5.90% N, 18.47%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[CH3:9][N:10]([CH3:22])[C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[C:13]([N+:19]([O-:21])=[O:20])[CH:12]=1>>[S:8]1[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=[C:15]1[C:14]1[CH:17]=[CH:18][C:11]([N:10]([CH3:9])[CH3:22])=[CH:12][C:13]=1[N+:19]([O-:21])=[O:20]
Reactant: Nc1ccccc1S
Reactant: CN(C)c1ccc(C=O)c([N+](=O)[O-])c1
Product: CN(C)c1ccc(-c2nc3ccccc3s2)c([N+](=O)[O-])c1

Procedure:
The amine may be obtained, for example in analogy to methods described in DE-A-2333378. For example, the educts 2-aminothiophenol and 4-dimethylamino-2-nitrobenzaldehyde may be reacted to obtain (4-benzothiazol-2-yl-3-nitrophenyl)-dimethylamine, whose nitro group may be reduced to the amine in a conventional manner (e.g. using SnCl2/HCl), and the product is reacted with methane sulfochloride.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)(=[O:22])=[O:21])[CH:15]=2)[N:8]=1)=O.[Cl:30][C:31]1[CH:32]=[C:33]2[C:38](=[CH:39][CH:40]=1)[N:37]=[CH:36][CH:35]=[C:34]2[NH:41][NH2:42]>>[Cl:30][C:31]1[CH:32]=[C:33]2[C:38](=[CH:39][CH:40]=1)[N:37]=[CH:36][CH:35]=[C:34]2[N:41]1[C:5]([C:7]2[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([N:23]4[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]4)(=[O:21])=[O:22])[CH:15]=3)[N:8]=2)=[CH:4][CH:3]=[N:42]1
Reactant: NNc1ccnc2ccc(Cl)cc12
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(S(=O)(=O)N3CCCCC3)c2)ccc1=O
Product: O=c1ccn(-c2cccc(S(=O)(=O)N3CCCCC3)c2)nc1-c1ccnn1-c1ccnc2ccc(Cl)cc12

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-[3-(piperidine-1-sulfonyl)-phenyl]-1H-pyridazin-4-one (A-26) and (6-chloro-quinolin-4-yl)-hydrazine according to the method described for example 91. MS: M=547.2 (M+H)+
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH:8]([CH2:24][CH3:25])[CH2:9][N:10]([N:19]1[CH:23]=[N:22][N:21]=[CH:20]1)[C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=1.[OH:26][C:27]1[CH:32]=[CH:31][C:30]([SH:33])=[CH:29][CH:28]=1>CN(C=O)C.C(OCC)(=O)C>[OH:26][C:27]1[CH:32]=[CH:31][C:30]([S:33][CH2:25][CH2:24][CH2:8][CH2:9][N:10]([N:19]2[CH:23]=[N:22][N:21]=[CH:20]2)[C:11]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=2)=[CH:29][CH:28]=1
Reactant: CCC(Br)CN(c1ccc(C#N)cc1)n1cnnc1
Reactant: Oc1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(N(CCCCSc2ccc(O)cc2)n2cnnc2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Potassium carbonate (500 mg) was added to a solution of 4-[(2-bromo-butyl)-[1,2,4]triazol-4-yl-amino]-benzonitrile (CAB03001, 384 mg, 1.2 mmol) and 4-hydroxy-thiophenol (227 mg, 1.8 mmol) in DMF (20 mL). The mixture was stirred for 18 hours at r.t., diluted with ethyl acetate (100 mL) and extracted with water (two times 30 mL) and brine (30 mL). The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: ethyl acetate, Rf: 0.30). The resulting oil was dissolved in a small amount of ethyl acetate and the product was precipitated by addition of hexane. Yield: 289 mg (66%). 1H-NMR (400 MHz, d6-DMSO) δ=1.48-1.64 (m, 4H) 2.81 (t, J=6.6 Hz, 2H), 3.81 (t, J=6.8 Hz, 2H), 6.62 (d, J=9.0 Hz, 2H), 6.72 (d, J=8.6 Hz, 2H), 7.19 (d, J=9.0 Hz, 2H), 7.72 (d, J=9.0, 2H), 8.94 (s, 2H), 9.56 (s, 1H, —OH). LRMS (FAB+): 366.1 (100, [M+H]+).
Reaction SMILES: [ClH:1].[CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH2:12][CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.[OH:19][C:20]1[CH:29]=[CH:28][C:23]([O:24][CH2:25][CH2:26]Br)=[CH:22][CH:21]=1.C([O-])(O)=O.[Na+]>>[ClH:1].[OH:19][C:20]1[CH:29]=[CH:28][C:23]([O:24][CH2:25][CH2:26][N:16]2[CH2:17][CH2:18][CH:13]([CH2:12][C:3]3[CH:4]=[CH:5][C:6]4[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=4)[CH:2]=3)[CH2:14][CH2:15]2)=[CH:22][CH:21]=1
Reactant: Oc1ccc(OCCBr)cc1
Reactant: c1ccc2cc(CC3CCNCC3)ccc2c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Oc1ccc(OCCN2CCC(Cc3ccc4ccccc4c3)CC2)cc1

Procedure:
The title compound was prepared from 4-((2-naphthyl)methyl)piperidine hydrochloride (150 mg, 573 μmol), 2-(4-hydroxyphenoxy)ethyl bromide (130 mg, 602 μmol) and NaHCO3 (97 mg, 1.17 mmol) as a pale yellow solid (182 mg): mp 221-222° C.; 1H NMR (CD3OD) 1.53-1.72 (m, 2H), 1.87-2.12 (m, 3H), 2.81 (d, J=6.9 Hz, 2H), 2.92-3.18 (m, 2H), 3.43-3.70 (m, 4H), 4.25 (t, J=4.8 Hz, 2H), 6.73 (d, J=9.3 Hz, 2H), 6.85 (d, J=9.3 Hz, 2H), 7.32-7.49 (m, 3H), 7.66 (s, 1H), 7.76-7.85 (m, 3H); Anal. Calcd for C24H28ClNO2 ·0.4H2O: C, 71.15; H, 7.16; N, 3.46. Found: C, 71.17; H. 6.80; N, 3.11.
Reaction SMILES: C([Li])CCC.[O:6]1[CH:10]=[CH:9][CH:8]=[CH:7]1.[CH:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[N:13][N:12]=1>O1CCCC1>[O:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[CH:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:11]=[N:12][NH:13]1
Reactant: c1ccc2cnncc2c1
Reactant: c1ccoc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C1=NNC(c2ccco2)c2ccccc21
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
22.5 ml of an about 1.6M solution of butyllithium are slowly added dropwise at -78° C. to a solution of 2.46 g of furan in 30 ml of tetrahydrofuran. The mixture is stirred at -78° C. for 20 min., then at -20° C. for 2 hrs. The solution is again cooled to -78° C. and treated slowly with a solution of 4.68 g of phthalazine in 36 ml of tetrahydrofuran. The mixture is stirred at -78° C. for 2 hrs., then poured on to about 500 ml of ice-water and extracted 4 times with 150 ml of ethyl acetate each time. The organic phases are dried, concentrated and the residue is chromatographed immediately on 120 g of silica gel; eluent: hexane/ethyl acetate 3:7. 4.08 g of dark, impure 1-furan-2-yl-1,2-dihydrophthalazine are isolated.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:8])[CH:5]=[CH:6][CH:7]=1.[CH3:9][C:10]1([CH3:17])[CH2:14][C:13](=O)[O:12][C:11]1=[O:16].C(N1C=CN=C1)(N1C=CN=C1)=O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13](=[O:12])[CH2:14][C:10]([CH3:17])([CH3:9])[C:11]2=[O:16])[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(Br)c1
Reactant: CC1(C)CC(=O)OC1=O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CC1(C)CC(=O)N(c2cccc(Br)c2)C1=O
Temperature: 50 °C
Reaction time: 3 h
Yield: 56.7 %

Procedure:
3-Bromophenylamine (10.0 g, 58.1 mmol) and 3,3-dimethyl-dihydro-furan-2,5-dione (8.2 g, 63.9 mmol) were suspended in 300 ml DCM. The reaction was stirred at 50° C. for 3 h. The reaction was cooled to room temperature and 1,1′-carbonyldiimidazole (11.3 g, 69.7 mmol) was added in portions. The reaction was heated again to 50° C. and stirred overnight. The solvent was evaporated and the product was crystallized from isopropyl alcohol to give 9.3 g of 1-(3-bromophenyl)-3,3-dimethyl-pyrrolidine-2,5-dione. The mother liquor was concentrated and chromatographed using a gradient of 0% to 20% ethyl acetate in hexanes to give another 1.3 g of product for a combined yield of 10.6 g (65%).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH:8]([CH3:14])[C:9]([O:11]CC)=[O:10])=[CH:6][CH:5]=[C:4]([N:15]2[CH:19]=[N:18][N:17]=[N:16]2)[N:3]=1.O[Li].O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO.C1COCC1.O>[CH3:1][C:2]1[C:7]([CH:8]([CH3:14])[C:9]([OH:11])=[O:10])=[CH:6][CH:5]=[C:4]([N:15]2[CH:19]=[N:18][N:17]=[N:16]2)[N:3]=1
Reactant: CCOC(=O)C(C)c1ccc(-n2cnnn2)nc1C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1nc(-n2cnnn2)ccc1C(C)C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of ethyl 2-[2-methyl-6-(1H-tetrazol-1-yl)pyridin-3-yl]propanoate (300 mg, 1.1 mmol) in 8 mL of MeOH/THF/H2O (2:2:1) was added LiOH.H2O (75 mg, 1.8 mmol) and stirred for 30 min at room temperature. The reaction was acidified with citric acid until pH about 3-4. Extracted with EtOAc, the combined organic layer was washed with brine, dried over anhydrous Na2SO4, concentrated to give title compound. 1H-NMR (400 MHz, CDCl3) δ ppm 9.51 (s, 1H), 7.86-7.91 (m, 2H), 4.00-4.05 (m, 1H), 2.64 (s, 3H), 1.57 (d, J=7.8 Hz, 3H).
Reaction SMILES: [OH-].[Na+].[CH2:3]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:33]=[CH:32][C:21]3[N:22]=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=4)[S:24][C:20]=3[CH:19]=2)=[CH:14][CH:13]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].Br[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][OH:41].[I-].[K+].Cl>O.CO>[CH2:3]([C:12]1[CH:13]=[CH:14][C:15]([C:18]2[CH:33]=[CH:32][C:21]3[N:22]=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([O:31][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][OH:41])=[CH:27][CH:26]=4)[S:24][C:20]=3[CH:19]=2)=[CH:16][CH:17]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: OCCCCCCBr
Reactant: CCCCCCCCCc1ccc(-c2ccc3nc(-c4ccc(O)cc4)sc3c2)cc1
Agent: Cl
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CCCCCCCCCc1ccc(-c2ccc3nc(-c4ccc(OCCCCCCO)cc4)sc3c2)cc1
Yield: 58.5 %

Procedure:
A solution of sodium hydroxide (0.08 g, 0.0020 mol) in water (20 cm3) was added dropwise to a solution of 4-[6-(4-nonylphenyl)benzothiazol-2yl]phenol (0.42 g, 0.0010 mol) in methanol (50 cm3). The 6-bromohexanol (0.18 g, 0.001 mol) was then added dropwise, followed by the potassium iodide (0.02 g, 0.00125 mol) in one portion. The reaction mixture was heated under reflux overnight and the poured onto a mixture of water (100 cm3) and 10% hydrochloric acid (20 cm3). The resultant precipitate was filtered off and recrystallised from ethanol to yield 0.31 g (62%) of the pure compound.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[N:20]([CH3:21])[C:19]4[CH:22]=[CH:23][CH:24]=[CH:25][C:18]=4[N:17]=3)=[CH:11][CH:10]=2)[C:3]=1[N+:26]([O-])=O>[Pd].CO.C1COCC1>[CH3:21][N:20]1[C:19]2[CH:22]=[CH:23][CH:24]=[CH:25][C:18]=2[N:17]=[C:16]1[O:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:4]2[C:3]([NH2:26])=[CH:2][N:7]=[CH:6][N:5]=2)=[CH:10][CH:11]=1
Reactant: Cn1c(Oc2ccc(Nc3ncnc(Cl)c3[N+](=O)[O-])cc2)nc2ccccc21
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Cn1c(Oc2ccc(Nc3ncncc3N)cc2)nc2ccccc21
Reaction time: 8 h
Yield: 39.8 %

Procedure:
A mixture of 6-chloro-N-{4-[(1-methyl-1H-benzimidazol-2-yl)oxy]phenyl}-5-nitropyrimidin-4-amine (240 mg) and 10% palladium on carbon (160 mg) in MeOH (10 mL) and THF (10 mL) was hydrogenated under balloon pressure at room temperature overnight. To the mixture was added TEA (0.50 mL). The catalyst was removed by filtration and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 0%-5% MeOH in AcOEt) to give N4-{4-[(1-methyl-1H-benzimidazol-2-yl)oxy]phenyl}pyrimidine-4,5-diamine (80 mg) as a colorless solid.
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1[CH:10]=O.[C:16]([O:25]CC)(=[O:24])[CH2:17][CH2:18][C:19]([O:21]CC)=[O:20]>C(O)(C)(C)C>[CH3:7][C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1/[CH:10]=[C:18](\[CH2:17][C:16]([OH:25])=[O:24])/[C:19]([OH:21])=[O:20]
Reactant: CCOC(=O)CCC(=O)OCC
Reactant: Cc1ccccc1C=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: Cc1ccccc1/C=C(\CC(=O)O)C(=O)O
Yield: 32.7 %

Procedure:
To a solution of potassium t-butoxide (8.5 g) in t-butanol (100 ml) was added a mixture of 2-methylbenzaldehyde (6.0 g) and diethyl succinate (12.0 g) and the mixture was refluxed for 3 hours. After the solvent was evaporated under reduced pressure, 10% sodium hydroxide solution (100 ml) was added to the resulting residue and the mixture was refluxed for 5 hours. The reaction mixture was acidified with hydrochloric acid under ice-cooling and the precipitated crystals were collected by filtration to give 3.6 g of (E)-2-methylbenzylidenesuccinic acid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]([C:11]2[N:19]3[C:14]([CH:15]=[C:16]([CH:20]([CH3:22])[CH3:21])[CH:17]=[CH:18]3)=[C:13]([C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[C:12]=2[CH2:29][C:30]([CH3:36])([CH3:35])[C:31]([O:33][CH3:34])=[O:32])=[O:10])[CH:6]=[CH:7][CH:8]=1)#[N:2].C(N)(=[O:39])C>C1COCC1.O.[Pd](Cl)Cl>[C:1]([C:3]1[CH:4]=[C:5]([C:9]([C:11]2[N:19]3[C:14]([CH:15]=[C:16]([CH:20]([CH3:22])[CH3:21])[CH:17]=[CH:18]3)=[C:13]([C:23](=[O:28])[C:24]([CH3:25])([CH3:26])[CH3:27])[C:12]=2[CH2:29][C:30]([CH3:36])([CH3:35])[C:31]([O:33][CH3:34])=[O:32])=[O:10])[CH:6]=[CH:7][CH:8]=1)(=[O:39])[NH2:2]
Reactant: CC(N)=O
Reactant: COC(=O)C(C)(C)Cc1c(C(=O)C(C)(C)C)c2cc(C(C)C)ccn2c1C(=O)c1cccc(C#N)c1
Agent: Cl[Pd]Cl
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)Cc1c(C(=O)C(C)(C)C)c2cc(C(C)C)ccn2c1C(=O)c1cccc(C(N)=O)c1
Temperature: 23 °C
Yield: 87.9 %

Procedure:
A solution of methyl 3-{3-[(3-cyanophenyl)carbonyl]-1-(2,2-dimethylpropanoyl)-7-(propan-2-yl)indolizin-2-yl}-2,2-dimethylpropanoate (125 mg, 0.257 mmol), palladium(II) chloride (9.1 mg, 0.051 mmol), and acetamide (152 mg, 2.57 mmol) in THF (1.5 mL) and water (0.5 mL) is heated at 50° C. for 3 h then cooled to 23° C. and partitioned between water and Et2O. The organics are washed with water, dried with MgSO4, filtered, and concentrated in vacuo. Purification of the crude by flash chromatography (SiO2, hexanes to 75% EtOAc in hexanes) gives methyl 3-{3-[(3-carbamoylphenyl)carbonyl]-1-(2,2-dimethylpropanoyl)-7-(propan-2-yl)indolizin-2-yl}-2,2-dimethylpropanoate (114 mg, 88%).
Reaction SMILES: [CH2:1]([NH:5][C:6]([NH2:8])=[S:7])[CH2:2][CH2:3][CH3:4].[C:9](Cl)(=[O:13])[C:10](Cl)=[O:11]>>[CH2:1]([N:5]1[C:10](=[O:11])[C:9](=[O:13])[NH:8][C:6]1=[S:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNC(N)=S
Reactant: O=C(Cl)C(=O)Cl
Product: CCCCN1C(=O)C(=O)NC1=S

Procedure:
N-Butylthiourea is treated with oxalyl chloride to give 1-butyl-2-thioxo-4,5-imidazolidinedione which when substituted for 1-methyl-2-thioxo-4,5-imidazolidinedione in the procedure of Example 1 gives S-[5-(N'-butylthioureido)pentyl]isothiourea.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].C([O:10][C@H:11]([C:40]([CH3:43])([CH3:42])[CH3:41])[C:12]([N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][C@H:15]1[C:20](=[O:39])[NH:21][CH2:22][C:23]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:24]=1[CH2:30][NH:31]C(OC(C)(C)C)=O)=[O:13])(=O)C.NO.[F:46][C:47]([F:52])([F:51])[C:48]([OH:50])=[O:49]>CO.CCOC(C)=O.C(Cl)Cl>[F:46][C:47]([F:52])([F:51])[C:48]([OH:50])=[O:49].[NH2:31][CH2:30][C:24]1[CH:25]=[CH:26][C:27]([Cl:29])=[CH:28][C:23]=1[CH2:22][NH:21][C:20]([C@@H:15]1[CH2:16][CH2:17][CH2:18][CH2:19][N:14]1[C:12](=[O:13])[C@H:11]([OH:10])[C:40]([CH3:43])([CH3:42])[CH3:41])=[O:39]
Reactant: CC(=O)O[C@@H](C(=O)N1CCCC[C@H]1C(=O)NCc1cc(Cl)ccc1CNC(=O)OC(C)(C)C)C(C)(C)C
Agent: NO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)[C@@H](O)C(=O)N1CCCC[C@H]1C(=O)NCc1cc(Cl)ccc1CN
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Solid K2CO3 (7.5 mg, 0.052 mmol) was added to a solution of (R)-1-{(S)-2-[2-{(tert-butoxycarbonylamino)methyl}-5-chlorobenzylcarbamoyl]-piperidin-1-yl}-3,3-dimethyl-1-oxobutan-2-yl acetate (0.14 g, 0.26 mmol) in MeOH (5 mL) and the resulting mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with EtOAc (50 mL) and washed sequentially with 0.1 N aqueous HCl (20 mL), water (2×20 mL), and brine solution (20 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by reverse phase combiflash column chromatography (C18; eluent: 10-100% acetonitrile/water) to provide the intermediate BOC protected amino alcohol (0.12 g, crude) as an off-white solid. The crude intermediate was dissolved in CH2Cl2 (2 mL) then trifluoroacetic acid (0.5 mL, 27.20 mmol) was added. The reaction mixture was stirred at room temperature for 2 h then volatile byproducts were removed under reduced pressure residue. The residue was purified by reverse phase combiflash column chromatography (C18; eluent: 10-100% acetonitrile:water) to afford the title compound as a white solid. 1H NMR (MeOD, 400 MHz) (δ) ppm: 7.36-7.46 (m, 3H), 4.99-5.08 (m, 1H), 4.01-4.51 (m, 6H), 3.36-3.37 (m, 1H), 2.15-2.21 (m, 1H), 1.64-1.68 (m, 3H), 1.39-1.54 (m, 2H), 0.98 (s, 9H).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:34]([CH3:35])=[CH:33][C:15]2[N:16]=[C:17]([N:19]3[CH2:24][CH2:23][O:22][C:21]([C:26]4[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=4)([CH3:25])[CH2:20]3)[S:18][C:14]=2[C:13]=1[C:36]1[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO.C1COCC1>[C:1]([O:5][C@@H:6]([C:12]1[C:34]([CH3:35])=[CH:33][C:15]2[N:16]=[C:17]([N:19]3[CH2:24][CH2:23][O:22][C:21]([C:26]4[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=4)([CH3:25])[CH2:20]3)[S:18][C:14]=2[C:13]=1[C:36]1[CH:37]=[CH:38][C:39]([Cl:42])=[CH:40][CH:41]=1)[C:7]([OH:9])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(N3CCOC(C)(c4ccc(Cl)cc4)C3)sc2c1-c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc2nc(N3CCOC(C)(c4ccc(Cl)cc4)C3)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Temperature: 50 °C

Procedure:
To a solution of (2S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(2-(4-chlorophenyl)-2-methylmorpholino)-5-methylbenzo[d]thiazol-6-yl)acetate (63.7 mg, 0.101 mmol) in CH3OH/THF (1:1, 4 mL) was added NaOH (2N, 1 mL, 2 mmol), the resulting mixture was heated at 50° C. for 14 hr. The mixture was evaporated to a small volume, acidified to pH 3 and taken into partitioned between CH2Cl2 and brine. The organic layer was separated, dried (Na2SO4), filtered and evaporated to dryness. The residue was purified on CombiFlash (50% EtOAc/Hex) to give (2S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(2-(4-chlorophenyl)-2-methylmorpholino)-5-methylbenzo[d]thiazol-6-yl)acetic acid. LCMS-ESI+: calc'd for C31H32Cl2N2O4S: 599.2, 601.2 (M+H+); found: 599.2, 601.2 (M+H+). 1H-NMR: 400 MHz, (CD3OD) δ: 7.62 (m, 1H), 7.44-7.53 (m, 5H), 7.32 (m, 3H), 5.13 (s, 1H), 4.31 (t, J=14.4 Hz, 1H), 3.81 (m, 1H), 3.62 (m, 1H), 3.44-3.53 (m, 3H), 2.50 (s, 3H), 1.46 (s, 3H), 0.95 (s, 9H).
Reaction SMILES: [CH3:1][N:2]([CH3:30])[CH2:3][CH2:4][CH2:5][N:6]([C:25]([NH:27][CH2:28][CH3:29])=[O:26])[C:7]([C@@H:9]1[CH2:23][C@H:22]2[C@@H:12]([CH2:13][C:14]3[C:24]4[C:17](=[CH:18][CH:19]=[CH:20][C:21]2=4)[NH:16][CH:15]=3)[NH:11][CH2:10]1)=[O:8].C(O[CH2:35][CH:36]=[CH2:37])(=O)C>C1(C)C=CC=CC=1.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>[CH2:37]([N:11]1[C@H:12]2[C@@H:22]([C:21]3[CH:20]=[CH:19][CH:18]=[C:17]4[C:24]=3[C:14]([CH2:13]2)=[CH:15][NH:16]4)[CH2:23][C@@H:9]([C:7]([N:6]([CH2:5][CH2:4][CH2:3][N:2]([CH3:1])[CH3:30])[C:25]([NH:27][CH2:28][CH3:29])=[O:26])=[O:8])[CH2:10]1)[CH:36]=[CH2:35]
Reactant: C=CCOC(C)=O
Reactant: CCNC(=O)N(CCCN(C)C)C(=O)[C@H]1CN[C@@H]2Cc3c[nH]c4cccc(c34)[C@H]2C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=CCN1C[C@H](C(=O)N(CCCN(C)C)C(=O)NCC)C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]21
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.3 %

Procedure:
To a suspension of 9.0 g (21.87 mmol) N-[3-(dimethylamino)propyl]-N-[(ethylamino)carbonyl)-ergoline-8β-carboxamide (XIX) in 250 ml of toluene 0.5 g of tetrakis(triphenylphosphine)palladium(0) and 5 ml of allyl acetate was added, and the reaction mixture was stirred at ambient temperature for 2 hours. The resulting mixture was washed with 100 ml of water. The organic layer was dried over anhydrous sodium sulphate. The dried solution was concentrated in vacuum and the product was purified on a silica plug to give 9.1 g (92.3%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:13])[C:5]([CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])=[N:6][CH:7]=1.Cl.Cl[C:16]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][C:19]([CH2:25][C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)=[CH:18][N:17]=1>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH3:13])[C:5]([CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:16]2[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][C:19]([CH2:25][C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)=[CH:18][N:17]=2)=[N:6][CH:7]=1
Reactant: O=[N+]([O-])c1cc(Cc2cccnc2)cnc1Cl
Reactant: Cc1cc(Br)cnc1CCCCN
Agent: Cl
Solvent: CCO
Product: Cc1cc(Br)cnc1CCCCNc1ncc(Cc2cccnc2)cc1[N+](=O)[O-]

Procedure:
A mixture of 4-(5-bromo-3-methylpyrid-2-yl)butylamine (11.79 g) and 2-chloro-3-nitro-5-(pyrid-3-ylmethyl)pyridine hydrochloride (4.57 g) was refluxed in ethanol (100 ml) for 8 hours. The solvent was removed in vacuo, the residue was dissolved in water (100 ml) and then extracted with chloroform (100 ml). The chloroform extract was chromatographed on silica eluted with 5% v/v methanol in chloroform followed by recrystallisation from chloroform/hexane to give the title compound as a yellow solid, m.p. 82°-84° C.
Reaction SMILES: [P:1]([O:21]C)([O:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([O:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:2].C[Si](Br)(C)C.[OH-].[Na+:29]>C(#N)C.CO>[P:1]([O-:21])([O:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([O:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:2].[Na+:29]
Reactant: COP(=O)(OCCc1ccccc1)OCCc1ccccc1
Agent: C[Si](C)(C)Br
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC#N
Product: O=P([O-])(OCCc1ccccc1)OCCc1ccccc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
A solution of 0.26 g (0.8 mmol) of bis(phenethyl) methyl phosphate in 3.2 mL of dry acetonitrile was stirred at 0° C. under N2 while 0.23 mL (2.18 eq.) of TMSBr was added dropwise. The solution was stirred at 0° C. for 1.5 hours. The solvent was removed and the residue was dissolved in NaOH (1.0 eq.) in MeOH solution. After 30 minutes at room temperature, the solution was concentrated, and the white solid was taken up in ether (6.0 mL) and filtered to give sodium bis(phenethyl) phosphate.