Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[N:4]([CH2:13][C:14]([O:16][C:17](C)(C)[CH3:18])=[O:15])[C:3]1=[O:21].C1(C)C=CC(S(O)(=O)=O)=CC=1.O.C(O)C>C1(C)C=CC=CC=1>[NH2:1][C@H:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[N:4]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:3]1=[O:21]
Reactant: CC(C)(C)OC(=O)CN1C(=O)[C@@H](N)CCc2ccccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: CCOC(=O)CN1C(=O)[C@@H](N)CCc2ccccc21
Yield: 79.7 %

Procedure:
5.0 g of tert-butyl (3S)-3-amino-2,3,4,5-tetrahydro-2-oxo-1H-benzazepine-1-acetate (preparation see Example 3E)) and 3.75 g of p-toluenesulfonic acid were boiled in a water separator for 2.5 hours in 80 ml of toluene. A total of 200 ml of ethanol was then added in portions, and the resulting reaction mixture was refluxed for 3.5 hours. The mixture was then concentrated in vacuo, and the residue was taken up with dichloromethane. The mixture was shaken with ice-cold sodium carbonate solution, and the organic phase was washed with water until neutral. The organic phase was dried over sodium sulfate, evaporated in vacuo and the residue which remained was dried. 3.6 g of ethyl (3S)-3-amino-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepine-1-acetate were obtained, m.p.=106.5°-108° C.; IR: 3350, 3300, 2930, 1735, 1660 cm-1 (film); [α]D20 =-288.4° (c=0.5 in methanol).
Reaction SMILES: [NH2:1][C:2](=[N:36][C:37](=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C@H:10]([C:23]2[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[C:25]([O:31][CH2:32][CH2:33][OH:34])[C:24]=2[F:35])[C:11]2[NH:15][C:14](=[O:16])[N:13]([C:17]3[N:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:12]=2)=[CH:5][CH:4]=1.CC(N(C)C)=O.[CH:51]1([O:57][C:58](=[O:64])[O:59][CH:60](Cl)[CH2:61][CH3:62])[CH2:56][CH2:55][CH2:54][CH2:53][CH2:52]1.C(=O)([O-])O.[K+]>O.C(OCC)(=O)C>[CH:51]1([O:57][C:58](=[O:64])[O:59][CH:60]([O:16][C:14]2[N:13]([C:17]3[N:18]=[CH:19][CH:20]=[CH:21][N:22]=3)[N:12]=[C:11]([C@H:10]([NH:9][C:6]3[CH:7]=[CH:8][C:3]([C:2]([NH2:1])=[N:36][C:37](=[O:44])[C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=4)=[CH:4][CH:5]=3)[C:23]3[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[C:25]([O:31][CH2:32][CH2:33][OH:34])[C:24]=3[F:35])[N:15]=2)[CH2:61][CH3:62])[CH2:56][CH2:55][CH2:54][CH2:53][CH2:52]1
Reactant: COc1cc(OCCO)c(F)c([C@@H](Nc2ccc(C(N)=NC(=O)c3ccccc3)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)c1
Reactant: CCC(Cl)OC(=O)OC1CCCCC1
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CCC(OC(=O)OC1CCCCC1)Oc1nc([C@H](Nc2ccc(C(N)=NC(=O)c3ccccc3)cc2)c2cc(OC)cc(OCCO)c2F)nn1-c1ncccn1
Temperature: 55 °C
Reaction time: 36 h

Procedure:
To a mixture of N-[1-amino-1-(4-{[(R)-[2-fluoro-3-(2-hydroxyethoxy)-5-methoxyphenyl]-(5-oxo-1-pyrimidin-2-yl-4,5-dihydro-1H-[1,2,4]triazol-3-yl)methyl]amino}phenyl)methylidene]benzamide (Example 12b, 200 mg) and DMA (2 mL), carbonic acid 1-chloropropyl ester cyclohexyl ester [CAS No. 108098-53-9] (300 mg) and potassium hydrogen carbonate (100 mg) were added, and the resulting mixture was stirred at 55° C. for 36 hours. The resulting mixture was poured into ethyl acetate and water. After shaking the mixture, the organic layer was collected, sequentially washed twice with water and with saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The resulting mixture was filtered, and the filtrate obtained was concentrated under reduced pressure. The residue obtained was crudely purified by NAM silica gel column chromatography (mixed solvent of methanol-ethyl acetate) to obtain a crudely purified product (120 mg).
Reaction SMILES: [CH3:1][CH:2]1[CH2:9][CH:8]2[CH:4]([CH2:5][N:6](C(OCC)=O)[CH2:7]2)[NH:3]1>Cl>[CH3:1][CH:2]1[CH2:9][CH:8]2[CH:4]([CH2:5][NH:6][CH2:7]2)[NH:3]1
Reactant: CCOC(=O)N1CC2CC(C)NC2C1
Agent: Cl
Product: CC1CC2CNCC2N1

Procedure:
17 g (85.7 mmol) of ethyl 3-methyl-2,7-diazabicyclo[3.3.0]octane-7-carboxylate are heated under reflux overnight with 100 ml of concentrated hydrochloric acid. The mixture is concentrated, the residue is taken up in 50 ml of water, rendered alkaline with potassium carbonate and extracted ten times using 50 ml of chloroform each time. The extracts are dried over potassium carbonate and concentrated, and the residue is distilled.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[S:21]1[CH:25]=[C:24]([C:26]2[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=2)[CH:29]=O)[N:23]=[CH:22]1>>[CH3:18][O:17][C:16]1[CH:15]=[CH:14][CH:13]=[C:12]([O:19][CH3:20])[C:11]=1[CH:2]1[N:1]([CH2:29][C:28]2[CH:31]=[CH:32][CH:33]=[C:26]([C:24]3[N:23]=[CH:22][S:21][CH:25]=3)[CH:27]=2)[C:5](=[O:7])[CH:4]([CH3:10])[CH2:3]1
Reactant: CCOC(=O)C(C)CC(N)c1c(OC)cccc1OC
Reactant: O=Cc1cccc(-c2cscn2)c1
Product: COc1cccc(OC)c1C1CC(C)C(=O)N1Cc1cccc(-c2cscn2)c1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2,6-dimethoxyphenyl)-2-methylbutanoate with 3-(thiazol-4-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.83 min.; [M+H]+: 409.03 g/mol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:13][C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21]4[C:30]5[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=5)[C:24]([C:31]5[CH:36]=[CH:35][C:34]([C:37]#[C:38][Si](CC)(CC)CC)=[CH:33][CH:32]=5)=[N:23][N:22]=4)=[CH:16][CH:15]=3)=[CH:8][CH:9]=[N:10]2)=[N:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+]>CO>[C:37]([C:34]1[CH:35]=[CH:36][C:31]([C:24]2[C:25]3[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:21]([NH:20][C:17]3[CH:16]=[CH:15][C:14]([O:13][C:7]4[C:6]5[C:11](=[CH:12][C:3]([O:2][CH3:1])=[CH:4][N:5]=5)[N:10]=[CH:9][CH:8]=4)=[CH:19][CH:18]=3)=[N:22][N:23]=2)=[CH:32][CH:33]=1)#[CH:38]
Reactant: CC[Si](C#Cc1ccc(-c2nnc(Nc3ccc(Oc4ccnc5cc(OC)cnc45)cc3)c3ccccc23)cc1)(CC)CC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1ccc(-c2nnc(Nc3ccc(Oc4ccnc5cc(OC)cnc45)cc3)c3ccccc23)cc1
Temperature: 20 °C
Reaction time: 24 h

Procedure:
In a nitrogen purged sealed tube was dissolved N-(4-(7-methoxy-1,5-naphthyridin-4-yloxy)phenyl)-4-(4-(2-(triethylsilyl)ethynyl)phenyl)phthalazin-1-amine (0.100 g, 0.164 mmol) in MeOH (2.00 mL). Potassium carbonate (0.068 g, 0.492 mmol) was added and the reaction was stirred at 20° C. for 24 h and then concentrated. The crude was extracted into DCM, washed 1× with water, 1× with brine, dried over Na2SO4, filtered through fritted funnel, concentrated. The resulting crude material was purified by silica gel chromatography eluting with 0-100% CH2Cl2:MeOH(90:10)/CH2Cl2. The product fractions were concentrated to afford 4-(4-ethynylphenyl)-N-(4-(7-methoxy-1,5-naphthyridin-4-yloxy)phenyl)phthalazin-1-amine as light yellow solid. MS [M+H]=496; Calc'd 495.5 for C31H21N5O2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([C:32]#[N:33])([CH3:31])[CH3:30])=[CH:25][C:24]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:4][CH:3]=1.[N:37]1([CH2:43][C:44]([NH2:46])=[O:45])[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20]([N:40]3[CH2:41][CH2:42][N:37]([CH2:43][C:44]([NH2:46])=[O:45])[CH2:38][CH2:39]3)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([C:32]#[N:33])([CH3:31])[CH3:30])=[CH:25][C:24]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCOc1cc(C(C)(C)C#N)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: NC(=O)CN1CCNCC1
Product: CCOc1cc(C(C)(C)C#N)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(N)=O)CC1

Procedure:
2-(4-{(4S,5R)-4,5-Bis-(4-chloro-phenyl)-2-[4-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-dihydro-imidazole-1-carbonyl}-piperazin-1-yl)-acetamide was prepared from (4S,5R)-4,5-bis-(4-chloro-phenyl)-2-[4-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-dihydro-imidazole-1-carbonyl chloride (example 12j) and 2-piperazin-1-yl-acetamide (Matrix) in an analogous manner as described in example 25. LR-MS: 647.3 [(M+H)+]
Reaction SMILES: [CH3:1][C@@:2]12[C@H:12]3[C:13]([CH2:15][C@:16]4([CH3:22])[C:20](=[O:21])[CH2:19][CH2:18][C@H:17]4[C@@H:11]3[CH2:10][CH2:9][C:8]1=[CH:7][C:5](=[O:6])[CH2:4][CH2:3]2)=[O:14].C(N(CC)CC)C.FC(F)(F)S(O[Si:36]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37])(=O)=O>ClCCl>[O:6]([C:5]1[CH2:4][CH2:3][C@@:2]2([CH3:1])[C:8](=[CH:9][CH2:10][C@@H:11]3[C@@H:12]2[C:13](=[O:14])[CH2:15][C@@:16]2([CH3:22])[C@H:17]3[CH2:18][CH2:19][C:20]2=[O:21])[CH:7]=1)[Si:36]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2C(=O)C[C@]2(C)C(=O)CC[C@@H]12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC1=CC2=CC[C@@H]3[C@H](C(=O)C[C@]4(C)C(=O)CC[C@@H]34)[C@@]2(C)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of adrenosterone (6.0 g, 20 mmol) in dry dichloromethane (120 ml) was added triethylamine (8.4 ml, 60 mmol) followed by tert-butyldimethylsilyl trifluoromethanesulfonate (5.0 ml, 22 mmol) and the mixture stirred at room temperature for 3 h. The dichloromethane was evaporated and the residue redissolved in diethyl ether (100 ml), then allowed to stand for 30 min, after which time an oil separated. The ether phase was decanted off the oil and the solvent evaporated to give the title compound which was used directly in step (b). IR νmax 1705, 1747 cm-1 ; 1H-NMR(CDCl3) inter alia δ0.12 (6H,s,Me2Si), 0.85 (3H,s,18-CH3), 0.92 (9H,s,tBuSi) 1.17(3H,s,19-CH3), 4.73 (1H,dm, J 6.9 Hz, 6-H), 5.36 (1H,m,4-H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[C:27](Cl)([Cl:29])=[O:28]>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([O:17][C:27]([Cl:29])=[O:28])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)Cl
Reactant: O=C(OCc1ccccc1)N1CCC(O)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: O=C(Cl)OC1CCN(C(=O)OCc2ccccc2)CC1

Procedure:
1-Benzyloxycarbonyl-4-hydroxypiperidine (15 g., 0.0638 mole) and N,N-diisopropylethylamine (12.3 ml., 9.13 g., 0.0707 mole) were dissolved in toluene (150 ml.), and the solution was added over 30 min. to a solution. of phosgene (12.63 g., 0.128 mole) in toluene (150 ml.). The reaction mixture was protected from. atmospheric moisture (drying tube), stirred magnetically, and kept at ambient temperature in a water bath during the addition. When the addition was complete the mixture was filtered and the solid residue washed with toluene (ca. 50 ml.). The solvent in the combined filtrate and washings was evaporated in vacuo (1 mm. pressure, solid CO2 cold finger condenser) to give 1-benzyloxycarbonyl-4-chlorocarbonyloxypiperidine, I.R. λ max 1775cm.-1 and 1700 cm.-1.
Reaction SMILES: [CH2:1]([O:8][C:9]([CH:11]([N:15]1[CH:21]2[CH:17]([N:18]=[C:19]([CH2:22][O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[S:20]2)[C:16]1=[O:30])[N:12]=[N+:13]=[N-:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[B-](F)(F)F.[Ag+:36].[O:37]1CCCC1>O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Ag:36].[N:12]([CH:11]([N:15]1[CH:21]([SH:20])[CH:17]([NH:18][C:19](=[O:37])[CH2:22][O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:16]1=[O:30])[C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10])=[N+:13]=[N-:14]
Reactant: C1CCOC1
Reactant: [N-]=[N+]=NC(C(=O)OCc1ccccc1)N1C(=O)C2N=C(COc3ccccc3)SC21
Reactant: [Ag+]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: F[B-](F)(F)F
Solvent: O
Product: [Ag]
Product: [N-]=[N+]=NC(C(=O)OCc1ccccc1)N1C(=O)C(NC(=O)COc2ccccc2)C1S

Procedure:
To a cooled solution of 7-(1-benzyloxycarbonyl-1-azidomethyl)-3-phenoxymethyl-6-oxo-2-thia-4,7-diazabicyclo[3,2,0]hept-3-ene (3.0 g.) in tetrahydrofuran (48 ml.) was added silver tetrafluoroborate (2.05 g.), followed by a solution of p-toluenesulfonic acid (145.8 mg.) in water (8.1 ml.). After the resultant mixture was stirred at 0° C. for 9 hours, it was concentrated to a volume of 10 ml. To the concentrate was added a mixture of methanol (5 ml.) and water (10 ml.) and precipitates were triturated, filtered and washed with water (three times), a mixture of methanol (5 ml.) and water (10 ml.) (several times), methanol, diethyl ether and hexane, successively to give silver salt at the mercapto group of benzyl 2-azido-2-(3-phenoxyacetamido-4-mercapto-2-oxo-1-azetidinyl)acetate (3.75 g.).
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([CH2:11][N:12]([CH:21]=[O:22])[O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:23][C:24]1[NH:25][C:26]([NH:33][CH2:34][C:35]([CH3:43])([N:37]2[CH2:42][CH2:41][O:40][CH2:39][CH2:38]2)[CH3:36])=[C:27]([F:32])[C:28](=[N:30][NH2:31])[N:29]=1.CN1CCOCC1.C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[Cl:23][C:24]1[N:29]=[C:28]([NH:30][NH:31][C:8](=[O:10])[C@H:7]([CH2:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[CH2:11][N:12]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:21]=[O:22])[C:27]([F:32])=[C:26]([NH:33][CH2:34][C:35]([CH3:43])([N:37]2[CH2:42][CH2:41][O:40][CH2:39][CH2:38]2)[CH3:36])[N:25]=1
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)O)OCc1ccccc1
Reactant: CC(C)(CNc1[nH]c(Cl)nc(=NN)c1F)N1CCOCC1
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: ClCCCl
Product: CC(C)(CNc1nc(Cl)nc(NNC(=O)[C@H](CC2CCCC2)CN(C=O)OCc2ccccc2)c1F)N1CCOCC1
Reaction time: 8 h
Yield: 35.7 %

Procedure:
(2R)-3-Cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoic acid (0.238 g, 0.78 mmol), 2-chloro-5-fluoro-6-{[2-methyl-2-(4-morpholinyl)propyl]amino}-4(1H)-pyrimidinone hydrazone (0.249 g), NMM (0.26 mL, 2.35 mmol), HOAt (0.106 g, 0.78 mmol), EDC (0.150 g, 0.78 mmol) and DMF (4 mL) were combined, and the solution was stirred overnight. Purification by RP-HPLC provided [(2R)-3-[2-(2-chloro-5-fluoro-6-{[2-methyl-2-(4-morpholinyl)propyl]amino}-4-pyrimidinyl)hydrazino]-2-(cyclopentylmethyl)-3-oxopropyl][(phenylmethyl)oxy]formamide as a brown oil (0.169 g). LCMS: (M+H)+=606.3.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][C:12]4[O:20][CH2:19][O:18][C:13]=4[CH:14]=3)[C:9]2=[O:21])[CH2:2]1.[CH3:22][C:23]1[CH:24]=[C:25]([CH:31]=[CH:32][CH:33]=1)[O:26][CH2:27][CH2:28][CH2:29][Cl:30]>>[ClH:30].[CH3:22][C:23]1[CH:24]=[C:25]([CH:31]=[CH:32][CH:33]=1)[O:26][CH2:27][CH2:28][CH2:29][N:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][C:12]4[O:20][CH2:19][O:18][C:13]=4[CH:14]=3)[C:9]2=[O:21])[CH2:2]1
Reactant: O=C1c2cc3c(cc2CCN1CC1CCCNC1)OCO3
Reactant: Cc1cccc(OCCCCl)c1
Product: Cc1cccc(OCCCN2CCCC(CN3CCc4cc5c(cc4C3=O)OCO5)C2)c1
Product: Cl

Procedure:
Prepared from 2-[(piperidin-3-yl)-methyl]-6,7-methylenedioxy-1-oxo-1,2,3,4-tetrahydro-isoquinoline and 3-(3-methyl-phenoxy)-1- chloro-propane analogously to Example 1.
Reaction SMILES: [C:1]1([CH:7]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH:18][C:19]3[CH:20]=[CH:21][C:22]4[N:23]([CH:25]=[C:26]([C:28]([CH3:35])([CH3:34])[C:29]([O:31]CC)=[O:30])[N:27]=4)[N:24]=3)[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].Cl.C(OCC)(=[O:47])C>O>[OH2:8].[OH2:47].[C:36]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[O:8][CH:9]2[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH2:17][NH:18][C:19]3[CH:20]=[CH:21][C:22]4[N:23]([CH:25]=[C:26]([C:28]([CH3:35])([CH3:34])[C:29]([OH:31])=[O:30])[N:27]=4)[N:24]=3)[CH2:13][CH2:14]2)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CCOC(C)=O
Reactant: CCOC(=O)C(C)(C)c1cn2nc(NCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)ccc2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)(C(=O)O)c1cn2nc(NCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)ccc2n1
Temperature: 60 °C
Reaction time: 1 h
Yield: 80.1 %

Procedure:
In 24 L of dimethyl sulfoxide were suspended 14.5 kg (44.68 mol) of 4-(diphenylmethoxy)-1-piperidinepropaneamine, 8.0 kg (29.88 mol) of ethyl 2-(6-chloroimidazo[1,2-b]pyridazin-2-yl)-2-methylpropionate, 6.3 kg (59.43 mol) of sodium carbonate and 300 g (2.92 mol) of sodium bromide, which were then heated to 145±5° C. under a nitrogen atmosphere and stirred for 7 hours. After cooling to room temperature, 80 L of ethyl acetate and 80 L of water were added, followed by separation into two layers. The organic layer was washed with 40 L of water twice and concentrated under reduced pressure. To the residue was added 60 L of ethanol and concentrated until the total volume became 40 L under reduced pressure to yield a solution of crude ethyl 2-[6-[3-[4-(diphenylmethoxy)piperidino]propylamino]imidazo[1,2-b]pyridazin-2-yl]-2-methylpropionate in ethanol. To the ethanol solution was added 2.4 kg of sodium hydroxide dissolved in 8 L of water. The reaction mixture was heated to 60±5° C. and stirred for 1 hour. The reaction mixture was cooled to 30±5° C. and adjusted to pH 10 or lower by the addition of 13 L of 3N hydrochloric acid, followed by the addition of 56 L of ethyl acetate. The mixture was adjusted to pH 6-7 by the addition of 13 L of 3N hydrochloric acid and 6 L of water was added thereto. The crystals formed were collected by filtration, washed with 40 L of a mixed solvent of water:ethanol:ethyl acetate (1:1:1), and dried to yield 13.5 kg of the title compound. HPLC purity area percentage 98.0%, Yield 80.1%.
Reaction SMILES: C(N(CC)CC)C.CC1C=CC(S([Cl:18])(=O)=O)=CC=1.[CH3:19][O:20][C:21]([C:23]1[O:24][C:25]([CH3:30])=[C:26]([CH2:28]O)[CH:27]=1)=[O:22]>ClCCl>[CH3:19][O:20][C:21]([C:23]1[O:24][C:25]([CH3:30])=[C:26]([CH2:28][Cl:18])[CH:27]=1)=[O:22]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)c1cc(CO)c(C)o1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(CCl)c(C)o1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 33.8 %

Procedure:
Triethylamine (196 μl, 1.41 mmoles), followed by 4-methyl-benzenesulphonyl chloride (247 mg, 1.293 mmoles) were added to a stirred solution of 4-hydroxymethyl-5-methyl-furan-2-carboxylic acid methyl ester (16) (200 mg, 1.176 mmoles) in dry dichloromethane at 0° C. under an argon atmosphere. The reaction mixture was stirred at 0° C. for 15 minutes, then allowed to warm to room temperature and was stirred for a further 4 hours. The mixture was washed with saturated aqueous sodium bicarbonate (50 ml) and brine (50 ml), and dried (MgSO4). After removal of the solvent, the residue was purified by flash chromatography, using petrol/diethyl ether 19:1 v/v as eluent, to afford compound 159 (75 mg) as a white solid. LC/MS System D; Rt=6.34 mins, m/z (ES+)=189 (M+H for C8H9ClO3).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([NH:16][C:17]([NH2:19])=[S:18])=[N:11][CH:12]=[C:13]([Br:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Br[CH2:28][C:29]([CH:31]1[CH2:36][CH2:35][N:34](C(OC(C)(C)C)=O)[CH2:33][CH2:32]1)=O.[ClH:44]>>[ClH:44].[ClH:44].[CH2:1]([O:8][C:9]1[C:10]([NH:16][C:17]2[S:18][CH:28]=[C:29]([CH:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)[N:19]=2)=[N:11][CH:12]=[C:13]([Br:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=S)Nc1ncc(Br)cc1OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)CBr)CC1
Agent: Cl
Solvent: CCN(CC)CC
Product: Brc1cnc(Nc2nc(C3CCNCC3)cs2)c(OCc2ccccc2)c1
Yield: 51.4 %

Procedure:
1-(3-(Benzyloxy)-5-bromopyridin-2-yl)thiourea (200 mg, 0.59 mmol), triethylamine (0.144 ml, 1.03 mmol) and tert-butyl 4-(2-bromoacetyl)piperidine-1-carboxylate (253 mg, 0.82 mmol) were reacted according to the procedure in Example 1, Step D to afford the title compound (157.6 mg, 51.4% yield) as a white solid after HCl salt formation. 1H NMR (DMSO-d6) δ 10.30 (bs, 1H), 8.83 (bs, 1H), 8.60 (bs, 1H), 7.99 (dd, 1H), 7.67 (d, 1H), 7.59 (m, 2H), 7.45-7.33 (m, 3H), 6.75 (s, 1H), 5.30 (s, 2H), 3.32 (d, 2H), 3.05-2.85 (m, 3H), 2.11 (d, 2H), 1.79 (m, 2H). Mass spectrum (apci) m/z=445.2 (M+H-2HCl).
Reaction SMILES: [Na+].[C:2]1(=[O:17])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](S([O-])(=O)=O)=[CH:4][C:3]1=[O:16].O.[CH2:19]([N:21]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:22][CH2:23][OH:24])[CH3:20]>CO>[CH2:19]([N:21]([CH2:22][CH2:23][OH:24])[C:25]1[CH:26]=[CH:27][C:28]([C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:2](=[O:17])[C:3](=[O:16])[CH:4]=2)=[CH:29][CH:30]=1)[CH3:20]
Reactant: CCN(CCO)c1ccccc1
Reactant: O=C1C=C(S(=O)(=O)[O-])c2ccccc2C1=O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCN(CCO)c1ccc(C2=CC(=O)C(=O)c3ccccc32)cc1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
A suspension of 1,2-napthoquinone-4-sulfonic acid sodium salt (10.5 g, 40.35 mmol) in a 9:1 mixture of water:MeOH (250 ml) was treated in one portion with 2-(ethyl(phenyl)amino)ethanol (6.67 g, 40.35 mmol) and stirred at 50° C. for 18 hrs. The mixture was then cooled, the MeOH removed in vacuo and the resulting suspension filtered. The precipitate was then washed with water and oven dried at 50° C. to give the product, 4-(4-(ethyl(2-hydroxyethyl)amino)phenyl)naphthalene-1,2-dione, as a dark purple solid (6.8 g, 54%). Analysis of the product by 1H NMR gave a spectrum consistent with the structure.
Reaction SMILES: [NH2:1][C:2]1[CH:32]=[C:5]2[N:6]=[C:7]([CH3:31])[C:8]([C@H:22]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[C:23]([OH:25])=[O:24])=[C:9]([C:10]3[C:11]([CH3:21])=[C:12]4[C:17](=[C:18]([F:20])[CH:19]=3)[O:16][CH2:15][CH2:14][CH2:13]4)[N:4]2[N:3]=1.[N:33]([C:36]1[CH:41]=[CH:40][C:39]([CH3:42])=[CH:38][CH:37]=1)=[C:34]=[O:35].CCN(C(C)C)C(C)C>C1COCC1>[C:27]([O:26][C@@H:22]([C:8]1[C:7]([CH3:31])=[N:6][C:5]2[N:4]([N:3]=[C:2]([NH:1][C:34]([NH:33][C:36]3[CH:41]=[CH:40][C:39]([CH3:42])=[CH:38][CH:37]=3)=[O:35])[CH:32]=2)[C:9]=1[C:10]1[C:11]([CH3:21])=[C:12]2[C:17](=[C:18]([F:20])[CH:19]=1)[O:16][CH2:15][CH2:14][CH2:13]2)[C:23]([OH:25])=[O:24])([CH3:28])([CH3:29])[CH3:30]
Reactant: Cc1nc2cc(N)nn2c(-c2cc(F)c3c(c2C)CCCO3)c1[C@H](OC(C)(C)C)C(=O)O
Reactant: Cc1ccc(N=C=O)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)Nc2cc3nc(C)c([C@H](OC(C)(C)C)C(=O)O)c(-c4cc(F)c5c(c4C)CCCO5)n3n2)cc1

Procedure:
A mixture of Example 1 (22 mg, 0.050 mmol), 1-isocyanato-4-methylbenzene (7.28 mg, 0.055 mmol), Hunig's base (0.026 mL, 0.149 mmol) in THF (2 mL) was stirred at rt for 16 h. It was then concentrated and purified by prep HPLC (TFA/MeOH). The fractions were combined and adjusted pH=6 using 1N NaOH. The residue was adjusted pH=3-4 by adding 1-2 drops of 1N HCl. It was then extracted with EtOAc, dried, filtered and concentrated to obtained Example (18 mg, 60%) as light yellow solid. LCMS (M+H)=576.31.