Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C(N)=C2C(N=CN2)=NC=1.[NH:11]1[C:20](=[O:21])[C:19]2NC=N[C:15]=2N=C1N.[NH2:22][C@H:23]([C:31]([OH:33])=[O:32])CCCNC(=N)N.N[C@H](C(O)=O)C>>[NH2:22][C@H:23]([C:31]([OH:33])=[O:32])[CH2:15][CH2:19][C:20](=[O:21])[NH2:11]
Reactant: Nc1nc2nc[nH]c2c(=O)[nH]1
Reactant: N=C(N)NCCC[C@H](N)C(=O)O
Agent: C[C@H](N)C(=O)O
Agent: Nc1ncnc2nc[nH]c12
Product: NC(=O)CC[C@H](N)C(=O)O
Reaction time: 12 h

Procedure:
Site-specific mutagenesis was carried out according to standard techniques described by Kunkel (Kunkel T A. Rapid and efficient site-specific mutagenesis without phenotypic selection; Proc Natl Acad Sci USA 1985, 82: 488-492) by inserting an adenine in place of guanine in position 34099 (the mutagenesis was also repeated by inserting an adenine in place of guanine in position 34099, and a guanine in place of adenine in position 34100). Sequencing of the cDNA was carried out for assurance that the mutation was correct and that any new mutations had not been introduced. Expression of the recombinant FIX was obtained using “human embryonic kidney cell line 293” and the methods already reported in the literature (Chang J L, Jin J P, Lollar P, et al. Changing residue 338 in human factor IX from arginine to alanine causes an increase in catalytic activity. J. Biol. Chem. 1998; 273:12089-12094). The recombinant FIX was isolated from the supernatant (culture medium) by means of an immunoaffinity column, as aforedescribed. Briefly, the supernatant of the cell culture was collected every 24 hours for 10 days and conserved at −20° C. For the purification the supernatant was thawed out and benzamidine and EDTA were added to a final concentration of 5 milliMoles and 4 milliMoles respectively. After filtration through a Millipore filter, the supernatant was incubated with fast-flow Sepharose Q resin for 12 hours at 4° C. The resin was then re-equilibrated in Tris, NaCl and benzamidine buffer and loaded onto the column. Elution was undertaken with a 0-60 nM calcium gradient. The eluate was then dialyzed in a Tris-NaCl buffer. The preparation was then applied to the immunoaffinity column following the method described in example 2 (in the “in vitro” expression of the recombinant protein). Starting from the culture medium, the procedure was the same as for the plasma, except for the precipitation procedure using BaCl. The culture medium was centrifuged at 4000 g for 20 minutes then subjected to dialysis in Tris-NaCl and loaded onto the immunoaffinity column at a rate of 0.5 ml/min. The remaining steps were the same as those taken for the plasma.
Reaction SMILES: FC1C=CC([NH:8][C:9]2[C:14]([C:15]([F:18])([F:17])[F:16])=[CH:13][N:12]=[C:11]([NH:19][C:20]3[CH:34]=[CH:33][C:23]([CH2:24][P:25](=[O:32])([O:29][CH2:30][CH3:31])[O:26][CH2:27][CH3:28])=[CH:22][C:21]=3[O:35][CH3:36])[N:10]=2)=C(C(=O)NC)C=1.ClC1C(C(F)(F)F)=CN=C(NC2C=CC(CP(=O)(OCC)OCC)=CC=2OC)N=1.N[C:71]1[C:80]([F:81])=[CH:79][CH:78]=[CH:77][C:72]=1[C:73]([NH:75][CH3:76])=[O:74]>>[F:81][C:80]1[CH:79]=[CH:78][CH:77]=[C:72]([C:73](=[O:74])[NH:75][CH3:76])[C:71]=1[NH:8][C:9]1[C:14]([C:15]([F:18])([F:17])[F:16])=[CH:13][N:12]=[C:11]([NH:19][C:20]2[CH:34]=[CH:33][C:23]([CH2:24][P:25](=[O:32])([O:29][CH2:30][CH3:31])[O:26][CH2:27][CH3:28])=[CH:22][C:21]=2[O:35][CH3:36])[N:10]=1
Reactant: CNC(=O)c1cccc(F)c1N
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(F)cc3C(=O)NC)n2)c(OC)c1)OCC
Agent: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)c1)OCC
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3c(F)cccc3C(=O)NC)n2)c(OC)c1)OCC

Procedure:
The title compound was prepared according to the procedure from Example 102 (Diethyl (4-{[4-{[4-fluoro-2-(methylcarbamoyl)-phenyl]amino}-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate) using diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate and the commercially available 2-amino-3-fluoro-N-methylbenzamide. 1H NMR (CDCl3, 400 MHz): δ=1.26 (t, J=7.07 Hz, 6H), 2.92 (d, J=4.80 Hz, 3H), 3.03-3.12 (m, 2H), 3.86 (s, 3H), 3.95-4.07 (m, 4H), 6.21 (q, J=4.97 Hz, 1H), 6.57 (d, J=9.09 Hz, 1H), 6.81 (t, J=1.89 Hz, 1H), 7.28-7.36 (m, 3H), 7.73 (br. s., 1H), 7.85 (br. s., 1H), 8.34 (s, 1H), 8.89 (br. s., 1H). MS (ES+): m/z 586.14 [MH+] (TOF, polar).
Reaction SMILES: C1(C)C=CC=CC=1.[F:8][C:9]1[C:10]([N:26]2[C:35]3[C:30](=[C:31](F)[C:32]([F:38])=[C:33]([F:37])[C:34]=3[F:36])[C:29](=[O:40])[C:28]([C:41]([O:43][CH2:44][CH3:45])=[O:42])=[CH:27]2)=[N:11][C:12]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[C:13]([F:15])[CH:14]=1.[CH2:46]([NH2:53])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>CCCCCC>[CH2:46]([NH:53][C:31]1[C:32]([F:38])=[C:33]([F:37])[C:34]([F:36])=[C:35]2[C:30]=1[C:29](=[O:40])[C:28]([C:41]([O:43][CH2:44][CH3:45])=[O:42])=[CH:27][N:26]2[C:10]1[C:9]([F:8])=[CH:14][C:13]([F:15])=[C:12]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[N:11]=1)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1
Reactant: NCc1ccccc1
Reactant: CCOC(=O)c1cn(-c2nc(NCc3ccc(OC)cc3)c(F)cc2F)c2c(F)c(F)c(F)c(F)c2c1=O
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cn(-c2nc(NCc3ccc(OC)cc3)c(F)cc2F)c2c(F)c(F)c(F)c(NCc3ccccc3)c2c1=O
Temperature: 110 °C
Reaction time: 0.33 h
Yield: 65.4 %

Procedure:
To 8 ml of toluene were added 1.58 g of ethyl 1-[3,5-difluoro-6-(p-methoxybenzylamino)pyridine-2-yl]-5,6,7,8-tetrafluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate together with 0.68 g of benzylamine, and the mixture was stirred at 110° C. for 20 minutes and allowed to cool. After adding 15 ml of toluene and 15 ml of n-hexane, the mixture was washed twice with 300 ml of distilled water. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. To the residue was added 4 ml of ethanol, and the solution was allowed to stand, and the precipitate was collected by filtration and washed with ethanol to obtain 1.20 g of the title compound as a yellow powder.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C:12]([OH:14])=[O:13].CCN(C(C)C)C(C)C.Br[CH2:25][CH:26]1[CH2:28][CH2:27]1>CN1CCCC1=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:25][CH:26]1[CH2:28][CH2:27]1)[CH:6]=[C:5]2[CH2:11][C:12]([OH:14])=[O:13]
Reactant: O=C(O)Cc1c[nH]c2ccc(Br)cc12
Reactant: BrCC1CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: O=C(O)Cc1cn(CC2CC2)c2ccc(Br)cc12
Temperature: 50 °C
Yield: 85.9 %

Procedure:
To 5-bromoindole-3-acetic acid (890 mg, 3.5 mmol) in 1-methyl-2-pyrrolidinone (12 mL) at 0° C. were added iPr2NEt (21 mmol) and bromomethylcyclopropane (10.5 mmol). The reaction mixture was heated at 50° C. for 19 h before partitioning between diethyl ether and ice water. After adjusting the pH to 3, the aqueous layer was extracted with diethyl ether. The organic layers were combined, washed with NaH2PO4, dried over MgSO4 and evaporated to dryness. Purification on silica gel column (30% EtOAc in hexane) yielded 927 mg (86% yield) of the product.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)[CH2:10][CH:9]1[C:21]([OH:23])=[O:22])=O)(C)(C)C.CCOCC>Cl.O1CCOCC1>[Cl:20][C:16]1[CH:15]=[C:14]([NH:13][C@@H:11]2[CH2:12][NH:8][C@H:9]([C:21]([OH:23])=[O:22])[CH2:10]2)[CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CC(Nc2cccc(Cl)c2)CC1C(=O)O
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: O=C(O)[C@@H]1C[C@H](Nc2cccc(Cl)c2)CN1
Yield: 82 %

Procedure:
4-(3-Chloro-phenylamino)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (Preparation 41, 155 mg, 0.456 mmol) was stirred in 4 M HCl in dioxan (4 ml) at 0° C. for 2 hours. Ether (4 ml) was added and the resultant white hygroscopic solid filtered off and dried in vacuo at 40° C. to give the title compound (90 mg, 60.3%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][OH:4].Cl[C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].C(N(CC)CC)C>ClCCl>[OH:4][CH2:3][CH2:2][NH:1][C:6](=[O:7])[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCCO)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.1 %

Procedure:
944 mg(15.46 mmol) of 2-aminoethanol was dissolved in 50 ml of dichloromethane, and then 1.8 ml(12.88 mmol) of benzyl chloroformate and 2.7 ml(19.32 mmol) of triethylamine were added thereto. The mixture was stirred at room temperature for one hour. After the reaction was completed, the mixture was concentrated and 50 ml of water was added thereto to obtain a white solid. The obtained white solid was filtered and dried to give 1.94 g(9.93 mmol) of the title compound in a yield of 77%.
Reaction SMILES: CS[C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1.[NH2:20][CH:21]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:22][CH2:23][OH:24].CCN(C(C)C)C(C)C>>[OH:24][CH2:23][CH2:22][CH:21]([NH:20][C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CSC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1
Reactant: NC(CCO)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1N=C(NC(CCO)c2ccccc2)S/C1=C\c1ccc2ncccc2c1

Procedure:
Similar procedure as described in example 1b was used, starting from 2-methylsulfanyl-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one, 3-amino-3-phenyl-propan-1-ol and DIEA to give 2-(3-hydroxy-1-phenyl-propylamino)-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one. LC-MS m/e 390 (MH+).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([CH2:13][O:12][C:11]3[CH:14]=[C:15]4[C:19](=[CH:20][C:10]2=3)[CH2:18][CH2:17][O:16]4)[C:2]1=[O:21].CC1C2C=C3C4(C5C(=CC=CC=5)NC4=O)COC3=CC=2ON=1.Cl[CH2:45][CH:46]1[O:50][C:49](=[O:51])[NH:48][CH2:47]1.BrCC1OC(C(F)(F)F)=CC=1>>[O:51]=[C:49]1[NH:48][CH2:47][CH:46]([CH2:45][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]3([CH2:13][O:12][C:11]4[CH:14]=[C:15]5[C:19](=[CH:20][C:10]3=4)[CH2:18][CH2:17][O:16]5)[C:2]2=[O:21])[O:50]1
Reactant: O=C1NCC(CCl)O1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCO3
Agent: Cc1noc2cc3c(cc12)C1(CO3)C(=O)Nc2ccccc21
Agent: FC(F)(F)c1ccc(CBr)o1
Product: O=C1NCC(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)O1

Procedure:
Following the procedure as described in EXAMPLE 9 and making non-critical variations using 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one to replace 3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1H)-one, and 5-chloromethyl-2-oxazolidinone to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, 1′-[(2-oxo-1,3-oxazolidin-5-yl)methyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1H)-one was obtained (32%) as a colorless solid: mp 197-198° C.; 1H NMR (300 MHz, DMSO-d6) δ7.58 (s, 1H), 7.37-7.29 (m, 1H), 7.26-7.20 (m, 1H), 7.19-7.13 (m, 1H), 7.09-7.01 (m, 1H), 6.49-6.39 (m, 2H), 4.98-4.75 (m, 2H), 4.74-4.66 (m, 1H), 4.54-4.45 (m, 2H), 4.15-3.84 (m, 2H), 3.67-3.56 (m, 1H), 3.31-3.23 (m, 1H), 3.02-2.90 (m, 2H); 13C NMR (75 MHz, DMSO-d6) δ177.9, 177.6, 161.2, 160.6, 160.5, 158.3, 142.6 (2C), 132.2, 132.0, 128.7, 128.6, 123.5, 123.4, 123.0, 120.6, 120.5, 119.9, 119.0, 118.9, 109.7, 109.6, 92.5, 92.4, 79.8, 73.3, 73.2, 72.1, 56.8, 43.1, 42.7, 42.6, 28.4; MS (ES+) m/z 379.3 (M+1).
Reaction SMILES: [CH3:1][S:2][C:3]1[S:4][C:5]2[CH:11]=[C:10]([NH2:12])[CH:9]=[CH:8][C:6]=2[N:7]=1.O1CCOCC1.C1C=C[NH+]=CC=1.[Br:25][Br-]Br>CCOC(C)=O>[Br:25][C:11]1[C:5]2[S:4][C:3]([S:2][CH3:1])=[N:7][C:6]=2[CH:8]=[CH:9][C:10]=1[NH2:12]
Reactant: CSc1nc2ccc(N)cc2s1
Agent: c1cc[nH+]cc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CSc1nc2ccc(N)c(Br)c2s1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a round bottom flask was added 2-(methylthio)-1,3-benzothiazol-6-amine (0.301 g, 1.533 mmol), Dioxane (10 mL), and pyridinium bromide perbromide (0.589 g, 1.840 mmol). The reaction mixture was then stirred at room temperature for ˜5 minutes, then suspended in EtOAc, washed with sat'd Na2S2O3, then with sat'd NaHCO3, then water, then brine. Organics were then dried over Na2SO4 filtered & concentrated. The resulting residue was purified using silica gel chromatography (0-45% ethyl acetate/hexanes) to give 7-bromo-2-(methylthio)-1,3-benzothiazol-6-amine (13-1) as a tan solid. HRMS (M+H)+: observed=274.9307, calculated=274.9307.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:38])=[C:4]([CH:35]=[CH:36][CH:37]=1)[C:5]([N:7]1[CH2:12][CH2:11][CH:10]([CH2:13][C:14]2[N:19]=[C:18]([NH:20][C:21]3[CH:25]=[CH:24][N:23](COCC[Si](C)(C)C)[N:22]=3)[CH:17]=[C:16]([CH3:34])[N:15]=2)[CH2:9][CH2:8]1)=[O:6].O.[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43]>>[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43].[Cl:1][C:2]1[C:3]([F:38])=[C:4]([CH:35]=[CH:36][CH:37]=1)[C:5]([N:7]1[CH2:12][CH2:11][CH:10]([CH2:13][C:14]2[N:19]=[C:18]([NH:20][C:21]3[CH:25]=[CH:24][NH:23][N:22]=3)[CH:17]=[C:16]([CH3:34])[N:15]=2)[CH2:9][CH2:8]1)=[O:6]
Reactant: Cc1cc(Nc2ccn(COCC[Si](C)(C)C)n2)nc(CC2CCN(C(=O)c3cccc(Cl)c3F)CC2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Cc1cc(Nc2cc[nH]n2)nc(CC2CCN(C(=O)c3cccc(Cl)c3F)CC2)n1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
24.9 mg of 2-((1-(3-chloro-2-fluorobenzoyl)piperidin-4-yl)methyl)-6-methyl-N-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)pyrimidin-4-amine was dissolved in 0.9 ml of trifluoroacetic acid and 0.1 ml of water at room temperature, followed by stirring the reaction mixture at 60° C. for 30 minutes. The reaction mixture was cooled to room temperature, and concentrated in vacuo. The reaction mixture was purified by a reversed phase preparative liquid chromatography, followed by concentrating the obtained fraction in vacuo to give the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[C:15]3[O:16][CH2:17][CH:18]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[N:13]4[C:14]=3[C:10]([CH:11]=[N:12]4)=[CH:9][CH:8]=2)=[C:5]([CH3:25])[O:4][N:3]=1.[Br:26]N1C(=O)CCC1=O>C(#N)C.CCOC(C)=O>[Br:26][C:9]1[CH:8]=[C:7]([C:6]2[C:2]([CH3:1])=[N:3][O:4][C:5]=2[CH3:25])[C:15]2[O:16][CH2:17][CH:18]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:13]3[C:14]=2[C:10]=1[CH:11]=[N:12]3
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1noc(C)c1-c1ccc2cnn3c2c1OCC3c1ccccc1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Cc1noc(C)c1-c1cc(Br)c2cnn3c2c1OCC3c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 66.5 %

Procedure:
A solution of 9-(3,5-dimethylisoxazol-4-yl)-3-phenyl-2,3-dihydro[1,4]oxazino[2,3,4-hi]indazole (0.011 g, 0.033 mmol) in acetonitrile (0.4 mL) at 0° C. was treated with N-bromosuccinimide (8.3 mg, 0.047 mmol) and stirred at 0° C. for 30 min. The reaction mixture was diluted with EtOAc (20 mL) and washed with saturated sodium bicarbonate solution (20 mL), dried over sodium sulfate, filtered, and concentrated to a colorless residue. Purification via preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% trifluoroacetic acid, at flow rate of 30 mL/min) gave desired product (9 mg, 70%). 1H NMR (300 MHz, DMSO-d6) δ 8.11 (s, 1H), 7.40-7.32 (m, 3H), 7.28 (s, 1H), 7.16-7.05 (m, 2H), 5.99-5.89 (m, 1H), 4.81 (dd, J=11.7, 3.4 Hz, 1H), 4.71 (dd, J=11.6, 4.8 Hz, 1H), 2.32 (s, 3H), 2.16 (s, 3H); LCMS calculated for C20H17BrN3O2 (M+H)+: m/z=410.0, 412.0. found: 410.0, 412.0.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH2:11]O)[CH:8]=[CH:9][CH:10]=1)[CH:2]=[CH2:3].C(Br)(Br)(Br)[Br:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH2:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][Br:14])[CH:6]=1)[CH:2]=[CH2:3]
Reactant: BrC(Br)(Br)Br
Reactant: C=CCOc1cccc(CO)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=CCOc1cccc(CBr)c1
Temperature: 5 °C
Reaction time: 1 h
Yield: 24 %

Procedure:
To a solution of (3-allyloxy-phenyl)-methanol (Tetrahedron, 2000, 56(13), 1873-1882) (1.07 g, 6.49 mmol) in THF (7 mls) at 3° C. was added carbon tetrabromide (2.69 g, 8.11 mmol) then triphenylphosphine (2.13 g, 8.11 mmol) in THF (2 mls). The reaction mixture was stirred at 5° C. for 1 hour. The reaction mixture was filtered and concentrated in vacuo. The residue was washed with pentane to give a yellow solid which was purified by column chromatography on silica gel, eluting with pentane:ethyl acetate, 100:0, to 95:5 to afford the title compound as a pale yellow oil in 24% yield, 350 mg.
Reaction SMILES: [O:1]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:13][C:14]([CH3:20])([CH2:18][CH3:19])[C:15](Cl)=[O:16]>>[CH3:13][C:14]([CH3:20])([CH2:18][CH3:19])[C:15]([N:4]1[CH2:5][CH2:6][O:7][CH2:8][CH2:9][N:10]([C:15](=[O:16])[C:14]([CH3:20])([CH3:13])[CH2:18][CH3:19])[CH2:11][CH2:12][O:1][CH2:2][CH2:3]1)=[O:16]
Reactant: CCC(C)(C)C(=O)Cl
Reactant: C1COCCNCCOCCN1
Product: CCC(C)(C)C(=O)N1CCOCCN(C(=O)C(C)(C)CC)CCOCC1

Procedure:
Analogously to Example 2 from 1,7-dioxa-4,10-diazacyclododecane and 2,2-dimethylbutyryl chloride.
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][O:4][CH:3]=1.C([Li])CCC.COCN[C:16](=[O:27])[CH2:17][CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23].[Cl-].[NH4+]>O1CCCC1>[CH3:25][C:22]([O:21][C:20](=[O:26])[NH:19][CH2:18][CH2:17][C:16]([C:2]1[CH:6]=[CH:5][O:4][CH:3]=1)=[O:27])([CH3:23])[CH3:24]
Reactant: COCNC(=O)CCNC(=O)OC(C)(C)C
Reactant: Brc1ccoc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCC(=O)c1ccoc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
3-Bromofuran (5.88 g, 40 mmol) was dissolved in anhydrous tetrahydrofuran (60 ml) and the solution cooled to −78° C. n-Butyllithium (2.29M, 17.5 ml, 40 mmol) was added dropwise and the solution stirred for 1 h at −78° C. [3-(Methoxymethylamino)-3-oxopropyl]carbamic acid, 1,1-dimethylethyl ester as a solution in tetrahydrofuran (40 ml) was added dropwise over 1 h. The solution was stirred overnight whilst allowing to warm to room temperature. Aqueous saturated ammonium chloride solution (30 ml) was added and the mixture extracted with ethyl acetate (3×70 ml). The combined organic extracts were washed with water (3×30 ml), dried (sodium sulphate) and evaporated in vacuo. The residue was chromatographed on flash silica, eluting with hexane:ethyl acetate (7:3), to afford the title compound as a pale yellow solid (3.03 g, 63%).
Reaction SMILES: [K].S1N=C(C(O)=[O:8])C(C(O)=O)=N1.[C:13]([C:15]1[C:19]([C:20]#[N:21])=[N:18][S:17][N:16]=1)#[N:14].[OH-].[K+]>>[C:13]([C:15]1[C:19]([C:20](=[O:8])[NH2:21])=[N:18][S:17][N:16]=1)#[N:14]
Reactant: N#Cc1nsnc1C#N
Reactant: O=C(O)c1nsnc1C(=O)O
Agent: [K+]
Agent: [K]
Agent: [OH-]
Product: N#Cc1nsnc1C(N)=O

Procedure:
A method for preparing the monopotassium salt of 1,2,5-thiadiazol-3,4-dicarboxylic acid by double stage saponification of 3,4-dicyano-1,2,5-thiadiazole, this method comprising adding aqueous KOH to an aqueous suspension of 3,4-dicyano-1,2,5-thiadiazole in such amount that the molar ratio of 3,4-dicyano-1,2,5-thiadiazole to KOH is from about 1:1.01 to 1:0.8, and maintaining the temperature at from about 20° to 50° C. to thereby catalytically hydrogenate and form 3-cyano-4-carbamoyl-1,2,5-thiadiazole, effecting further hydrolysis by adding additional aqueous KOH in such amount as to result in an overall molar ratio of 3,4-dicyano-1,2,5-thiadiazole to KOH of from about 1:2.0 to 1:2.35 and an overall molar ratio of 3,4-dicyano-1,2,5-thiadiazole to H2O of from about 1:20 to 1:23, at a temperature of from about 85° to 100° C., to thereby form a solution of the dipotassium salt of 1,2,5-thiadaizole-3,4-dicarboxylic acid, and separating the monopotassium salt by acidifying, to a pH of from about 2 to 3, said solution of dipotassium salt of 1,2,5-thiadiazole-3,4-dicarboxylic acid.
Reaction SMILES: C[O:2][C:3]1[C:12]2[O:11][CH2:10][CH2:9][CH2:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.Br.C1(O)C=CC=CC=1>C(O)(=O)C>[OH:2][C:3]1[C:12]2[O:11][CH2:10][CH2:9][CH2:8][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2c1OCCC2
Agent: Br
Solvent: CC(=O)O
Solvent: Oc1ccccc1
Product: Oc1cccc2c1OCCC2

Procedure:
The compound obtained in Step C (1 g; 6.09 mmol) is dissolved in glacial acetic acid (10.2 ml) and then hydrobromic acid (48% solution in water) (3.7 eq.; 47 mmol; 2.54 ml) is added dropwise. The phenol is fully deprotected after 5 hours' reflux. After removal of the solvent under reduced pressure, the dry residue is taken up in aqueous medium and then neutralised with a saturated sodium hydrogen carbonate solution to a pH of 8. Extraction with ethyl acetate yields an orange oil after drying and concentration. After purification of the latter over a silica column. AcOEt/PE (3:7), the oil is yellow in colour.
Reaction SMILES: [OH:1][CH:2]=[C:3]([C:8]1[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=1/[CH:16]=[CH:17]/[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:4]([O:6][CH3:7])=[O:5].CI.[C:26](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH:13]([C:11]1[S:12][C:8](/[C:3](=[CH:2]\[O:1][CH3:26])/[C:4]([O:6][CH3:7])=[O:5])=[C:9]([CH:16]=[CH:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:10]=1)([CH3:15])[CH3:14]
Reactant: COC(=O)C(=CO)c1sc(C(C)C)nc1/C=C/c1ccccc1
Reactant: O=C([O-])[O-]
Agent: CO/C=C(/C(=O)OC)c1sc(C(C)C)nc1/C=C/c1ccccc1
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CO/C=C(/C(=O)OC)c1sc(C(C)C)nc1C=Cc1ccccc1
Temperature: 20 °C
Reaction time: 16 h

Procedure:
The product of Step G was dissolved in 20 ml of acetone and then 3 ml of methyl iodide and 4 g of potassium carbonate were added. The mixture was stirred for 16 hours at 20° C. After bringing the mixture to dryness, the residue was chromatographed on silica, eluting with a hexane-ethyl acetate mixture (8-2) to obtain 1.3 g of the desired product. Thin layer chromatography; Rf=0.20 [eluant: hexane-ethyl acetate (8-2)].
Reaction SMILES: [NH:1]([C:5]1[C:14]([NH:15][C:16]([CH3:18])=[O:17])=[CH:13][C:8]2[O:9][CH2:10][CH2:11][O:12][C:7]=2[C:6]=1[C:19]([OH:21])=O)[C:2]([CH3:4])=[O:3].NC1C(N)=CC2OCCOC=2C=1C(O)=O.[N:37]1([CH:43]([NH2:46])[CH2:44][CH3:45])[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1>>[N:37]1([CH:43]([NH:46][C:19]([C:6]2[C:7]3[O:12][CH2:11][CH2:10][O:9][C:8]=3[CH:13]=[C:14]([NH:15][C:16]([CH3:18])=[O:17])[C:5]=2[NH:1][C:2]([CH3:4])=[O:3])=[O:21])[CH2:44][CH3:45])[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1
Reactant: CC(=O)Nc1cc2c(c(C(=O)O)c1NC(C)=O)OCCO2
Reactant: CCC(N)N1CCCCC1
Agent: Nc1cc2c(c(C(=O)O)c1N)OCCO2
Product: CCC(NC(=O)c1c(NC(C)=O)c(NC(C)=O)cc2c1OCCO2)N1CCCCC1

Procedure:
In the same manner as described in Example 53, the 6,7-diacetamino-1,4-benzodioxane-5-carboxylic acid (prepared by acetylation of the 6,7-diamino-1,4-benzodioxane-5-carboxylic acid) was condensed with the 1-piperidinopropylamine in the presence of the isobutyl chloroformiate. The N-(1-piperidinopropyl)-6,7-diacetamino-1,4-benzodioxane-5-carboxamide was obtained (M.P.: above 260° C. with decomposition). The structure was confirmed by nuclear magnetic resonance analysis.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([OH:15])[CH2:4][N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1.[C:16](O)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.O>[CH2:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:13][CH2:14][N:5]1[CH2:4][C@@H:3]([OH:15])[CH2:2][NH:1][C:16](=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NC[C@H](O)CN1CCc2ccccc2C1
Reactant: O=C(O)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: ClCCl
Product: O=C(NC[C@H](O)CN1CCc2ccccc2C1)c1ccccc1
Yield: 18.3 %

Procedure:
A solution of (S)-1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (200 mg, 0.97 mmol), benzoic acid (122.5 mg, 1.07 mmol), HATU (387.6 mg, 1.02 mmol) and TEA (196.1 mg, 1.94 mmol) in DCM (20 mL) was stirred at room temperature for 2 h until completion of the reaction. The reaction mixture was then diluted with water and extracted with DCM (20 ml×2). The combined organic layers were dried and concentrated with the residue purified by pre-HPLC and SFC separation to give the desired compound (55 mg, Yield 18%). 1H NMR (400 MHz, MeOD): 7.66 (d, J=8.0 Hz, 2H), 7.36-7.34 (m, 1H), 7.26 (d, J=7.6 Hz, 2H), 6.99-6.89 (m, 4H), 4.01-3.96 (m, 1H), 3.61 (s, 2H), 3.43-3.37 (m, 2H), 2.77-2.72 (m, 4H), 2.56-2.53 (m, 2H). LCMS (m/z): 311.1 (M+1).