Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([C:17]4[N:22]=[CH:21][N:20]=[C:19]([NH:23][CH2:24][C@@H:25]([C:37]([O:39]C(C)(C)C)=[O:38])[NH:26][C:27]([O:29][CH2:30][C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)=[O:28])[C:18]=4[CH3:44])[CH2:13][CH2:12]3)[N:9]=2)[CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O.C1(C)C=CC=CC=1>ClCCl>[NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:11]3[CH2:12][CH2:13][N:14]([C:17]4[N:22]=[CH:21][N:20]=[C:19]([NH:23][CH2:24][C@@H:25]([C:37]([OH:39])=[O:38])[NH:26][C:27]([O:29][CH2:30][C:31]5[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=5)=[O:28])[C:18]=4[CH3:44])[CH2:15][CH2:16]3)[N:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: Cc1c(NC[C@H](NC(=O)OCc2ccccc2)C(=O)OC(C)(C)C)ncnc1N1CCC(c2ccc3c(n2)NCCC3)CC1
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(NC[C@H](NC(=O)OCc2ccccc2)C(=O)O)ncnc1N1CCC(c2ccc3c(n2)NCCC3)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.4 %

Procedure:
A mixture of 38 mg (0.06 mmoles) of (1,1-dimethylethyl) 3-[[6-[4-(1,2,3,4-tetrahydro-1,8-naphthyridin-7-yl)-1-piperidinyl]-5-methyl-4-pyrimidinyl]amino]-N-[(phenyl methoxy)carbonyl]alaninate and 2 ml of trifluoroacetic acid in 10 ml of dichloromethane is stirred at ambient temperature for 3 hours. Then 5 ml of toluene is added followed by evaporating the mixture to dryness. 26 mg (Yield=76%) of expected product is obtained in the form of an amorphous solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13]CC)=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[N:26]=3)=[CH:19][CH:18]=2)[N:5]=1)[CH3:2].[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[N:26]=3)=[CH:19][CH:18]=2)[N:5]=1)[CH3:2]
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCc3cccc(-c4ccccc4)n3)cc2)nc1OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOc1nn(Cc2ccc(OCc3cccc(-c4ccccc4)n3)cc2)cc1CCC(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.7 %

Procedure:
After a mixture of ethyl 3-[3-ethoxy-1-[4-(6-phenyl-2-pyridylmethoxy)benzyl]-1H-pyrazol-4-yl]propionate (685 mg), 1N aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (6 ml) and ethanol (6 ml) was stirred at room temperature for 3 hours, 1 N hydrochloric acid (3 ml) was added to the mixture, and then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated. The resulting colorless crystals were collected by filtration to obtain 3-[3-ethoxy-1-[4-(6-phenyl-2-pyridylmethoxy)benzyl]-1H-pyrazol-4-yl]propionic acid (482 mg, yield: 75%). This was recrystallized from ethanol-hexane. Melting point: 95–96° C.
Reaction SMILES: O1CCCCC1[C:7]1([S:37][C@H:36]([CH2:38][O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C@@H:27]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C@H:18]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@H:9]1[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[OH:8].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(O)C>[CH2:11]([O:10][C@@H:9]1[C@@H:18]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@H:27]([O:28][CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C@@H:36]([CH2:38][O:39][CH2:40][C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[S:37][CH:7]1[OH:8])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: OC1(C2CCCCO2)S[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCO
Product: OC1S[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 100.8 %

Procedure:
A mixture of tetrahydro-2H-pyran-2-yl 2,3,4,6-tetra-O-benzyl-5-thio-D-glucopyranose (3.30 g, 5.15 mmol), pyridinium p-toluenesulfonate (518 mg, 2.06 mmol) and ethanol (58 mL) was stirred at 80° C. for two hours. The reaction mixture was cooled to room temperature and the solvent was concentrated. The obtained residue was dissolved in ethyl acetate. After this solution was washed with a saturated sodium bicarbonate aqueous solution and brine, it was dried with anhydrous magnesium sulfate. After the desiccant was filtered off, the residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to obtain 2,3,4,6-tetra-O-benzyl-5-thio-D-glucopyranose (2.89 g, quant) as a colorless crystal.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([N:16]3[C:20]4[CH:21]=[C:22]([OH:25])[CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[S:11][C:12]=2[C:13]([NH2:15])=[O:14])[CH:5]=[CH:6][CH:7]=1.[N:26]1([CH2:32][CH2:33][CH2:34]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([N:16]3[C:20]4[CH:21]=[C:22]([O:25][CH2:34][CH2:33][CH2:32][N:26]5[CH2:31][CH2:30][O:29][CH2:28][CH2:27]5)[CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[S:11][C:12]=2[C:13]([NH2:15])=[O:14])[CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)c1sc(-n2cnc3ccc(O)cc32)nc1-c1cccc(Cl)c1
Reactant: Cc1ccc(S(=O)(=O)OCCCN2CCOCC2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: NC(=O)c1sc(-n2cnc3ccc(OCCCN4CCOCC4)cc32)nc1-c1cccc(Cl)c1
Yield: 56.2 %

Procedure:
A mixture of 0.037 g (0.1 mmole) of 4-(3-chloro-phenyl)-2-(6-hydroxy-benzoimidazol-1-yl)-thiazole-5-carboxylic acid amide (I.25d), 0.060 g (0.2 mmole) of toluene-4-sulfonic acid 3-morpholin-4-yl-propyl ester, 1 mL of dimethylformamide and 0.160 g (0.5 mmole) of cesium carbonate was heated at 100 degrees for 30 minutes. The mixture was cooled, the solid was removed by filtration and the filtrate purified by reverse phase silica gel chromatography, eluting with acetonitrile-water (gradient 20:80-100:0) to give 0.028 g of 4-(3-chloro-phenyl)-2-[6-(3-morpholin-4-yl-propoxy)-benzoimidazol-1-yl]-thiazole-5-carboxylic acid amide (I.30) as a white powder. MH+/Z=498
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[N:4][CH:3]=1.[Br:12]N1C(=O)CCC1=O.N>S(=O)(=O)(O)O>[Br:12][C:10]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:11]=1[C:2]([CH3:1])=[CH:3][N:4]=[CH:5]2
Reactant: Cc1cncc2ccccc12
Reactant: O=C1CCC(=O)N1Br
Agent: N
Agent: O=S(=O)(O)O
Product: Cc1cncc2cccc(Br)c12
Reaction time: 2 h

Procedure:
4-Methylisoquinoline (0.1 ml, synthesized according to the method described in Tetrahedron. Lett. 34, 45, 7239 (1993)) was dissolved in concentrated sulfuric acid (1 ml), then added with N-bromosuccinimide (125 mg) with ice cooling and stirred for 2 hours. The reaction mixture was added with 28% aqueous ammonia (5 ml) and extracted twice with dichloromethane (10 ml for each time). The organic layer was dried over anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=50:1) to obtain the title compound (108 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15]([N:17]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[CH2:21][N:20]3[C:28]([C:31](O)=[O:32])=[CH:29][CH:30]=[C:19]3[CH2:18]2)=[O:16])=[CH:11][C:10]=1[CH3:34].[CH3:35][NH:36][CH2:37][CH:38](O)[CH2:39][OH:40].[OH2:42].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C>CN(C)C=O.C(OCC)(=O)C>[OH:42][CH:38]([CH2:39][OH:40])[CH2:37][N:36]([CH3:35])[C:31]([C:28]1[N:20]2[C:19]([CH2:18][N:17]([C:15]([C:12]3[CH:13]=[CH:14][C:9]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[O:2][CH3:1])=[C:10]([CH3:34])[CH:11]=3)=[O:16])[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[CH2:21]2)=[CH:30][CH:29]=1)=[O:32]
Reactant: CNCC(O)CO
Reactant: O
Reactant: COc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)O)n3Cc3ccccc32)cc1C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)N(C)CC(O)CO)n3Cc3ccccc32)cc1C
Reaction time: 8 h
Yield: 18.5 %

Procedure:
To a solution of 10-[(2′-methoxy-2-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H— pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic acid of Step E (0.50 g, 1.10 mmol) and 3-methylamino-1,2-propanediol (0.14 mL, 1.33 mmol) in N,N-dimethylformamide (4 mL) was added 1-hydroxybenzotriazole monohydrate (0.16 g, 1.18 mmol) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.23 g, 1.20 mmol) followed by N,N-diisopropylethyl amine (0.29 mL, 1.66 mmol). The reaction mixture was stirred overnight, diluted with ethyl acetate and washed with water and saturated aqueous sodium bicarbonate. The organic phase was then dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a yellow oil. Purification by flash chromatography using a solvent system of 3% methanol in chloroform gave a white foam which was crystallized by trituration with diethyl ether-hexane to provide 0.11 g of title product as a white amorphous solid.
Reaction SMILES: C([O:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]2[O:17][CH2:16][C:15]3[N:18]=[CH:19][CH:20]=[CH:21][C:14]=3[C:13](=[CH:22][CH2:23][CH2:24][N:25]3[CH2:30][CH2:29][C:28]([C:32]4[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=4)([OH:31])[CH2:27][CH2:26]3)[C:12]=2[CH:39]=1)(=O)C.[OH-].O.C(OCC)(=O)C>C(O)C>[Cl:38][C:35]1[CH:36]=[CH:37][C:32]([C:28]2([OH:31])[CH2:27][CH2:26][N:25]([CH2:24][CH2:23][CH:22]=[C:13]3[C:12]4[CH:39]=[C:8]([O:7][CH2:6][CH2:5][OH:4])[CH:9]=[CH:10][C:11]=4[O:17][CH2:16][C:15]4[N:18]=[CH:19][CH:20]=[CH:21][C:14]3=4)[CH2:30][CH2:29]2)=[CH:33][CH:34]=1
Reactant: CC(=O)OCCOc1ccc2c(c1)C(=CCCN1CCC(O)(c3ccc(Cl)cc3)CC1)c1cccnc1CO2
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: OCCOc1ccc2c(c1)C(=CCCN1CCC(O)(c3ccc(Cl)cc3)CC1)c1cccnc1CO2
Yield: 92.8 %

Procedure:
To a solution of 1-[3-(7-(2-acetoxyethyl)oxy-5,11-pyrido[2,3-c][1]benzoxepin-5-ylidene)propyl]-4-(4-chlorophenyl)piperidin-4-ol (Example 50) (140 mg) in ethanol (5 ml) were added 15% sodiun hydroxide aqueous solution (2 ml) and the mixture was heated to reflux for 1 hour. Water and ethyl acetate were added to the reaction mixture, the organic layer was separated and washed with saturated aqueous sodium chloride, and dried with magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography eluting with methylene chloride-methanol (10:1) to give the titled compound (120 mg).
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[C:6]([NH2:9])[N:5]=[C:4]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[CH:16][CH:17]=3)[N:12]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[F:26])[N:11]=2)[N:3]=1.C(N(CC)C(C)C)(C)C.[C:36](N1C=CN=C1)(N1C=CN=C1)=[O:37]>CN(C)C=O>[NH2:9][C:6]1[C:7]2[O:8][C:36](=[O:37])[NH:1][C:2]=2[N:3]=[C:4]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[CH:16][CH:17]=3)[N:12]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[F:26])[N:11]=2)[N:5]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc(N)c1O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Nc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc2[nH]c(=O)oc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.7 %

Procedure:
159 mg (0.453 mmol) of the compound prepared in example 58A in dimethylformamide (10 ml) were admixed with 94 μl (0.543 mmol) of N,N-diisopropylethylamine and 88 mg (0.543 mmol) of carbonyldiimidazole, and the mixture was stirred at RT overnight. The mixture was filtered, the filtrate was concentrated and the residue was purified by means of preparative HPLC (acetonitrile:water (+0.05% formic acid) gradient). 90 mg of the title compound were obtained (52% of theory).
Reaction SMILES: [C:1]([C:3]1[CH:29]=[CH:28][CH:27]=[CH:26][C:4]=1[O:5][C:6]1[CH:7]=[C:8]([NH2:25])[C:9]([NH2:24])=[CH:10][C:11]=1[O:12][C:13]1[CH:14]=[N:15][C:16]([S:19]([CH2:22][CH3:23])(=[O:21])=[O:20])=[CH:17][CH:18]=1)#[N:2].CO[C:32]([C:34]1[CH:39]=[N:38][CH:37]=[CH:36][N:35]=1)=N>>[C:1]([C:3]1[CH:29]=[CH:28][CH:27]=[CH:26][C:4]=1[O:5][C:6]1[C:11]([O:12][C:13]2[CH:14]=[N:15][C:16]([S:19]([CH2:22][CH3:23])(=[O:20])=[O:21])=[CH:17][CH:18]=2)=[CH:10][C:9]2[NH:24][C:32]([C:34]3[CH:39]=[N:38][CH:37]=[CH:36][N:35]=3)=[N:25][C:8]=2[CH:7]=1)#[N:2]
Reactant: COC(=N)c1cnccn1
Reactant: CCS(=O)(=O)c1ccc(Oc2cc(N)c(N)cc2Oc2ccccc2C#N)cn1
Product: CCS(=O)(=O)c1ccc(Oc2cc3[nH]c(-c4cnccn4)nc3cc2Oc2ccccc2C#N)cn1

Procedure:
The entitled compound was obtained as a brown solid in the same method as in Example 205 or in accordance with the method or by combining it with an ordinary method but using 4-(2-cyano-phenoxy)-5-(6-ethanesulfonyl-pyridin-3-yloxy)-benzene-1,2-diamine obtained in Example 221 (step 3) and methylpyrazin-2-imidate.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[N:9]=[C:8]([NH2:10])[C:7]([O:11][C:12]2[CH:17]=[C:16](I)[C:15]([O:19][CH3:20])=[CH:14][C:13]=2[CH:21]([CH3:23])[CH3:22])=[CH:6][N:5]=1)[CH3:2].[C:24]([Cu])#[N:25].O>CN(C=O)C>[NH2:10][C:8]1[C:7]([O:11][C:12]2[C:13]([CH:21]([CH3:23])[CH3:22])=[CH:14][C:15]([O:19][CH3:20])=[C:16]([CH:17]=2)[C:24]#[N:25])=[CH:6][N:5]=[C:4]([NH:3][CH2:1][CH3:2])[N:9]=1
Reactant: N#C[Cu]
Reactant: CCNc1ncc(Oc2cc(I)c(OC)cc2C(C)C)c(N)n1
Solvent: CN(C)C=O
Solvent: O
Product: CCNc1ncc(Oc2cc(C#N)c(OC)cc2C(C)C)c(N)n1
Temperature: 120 °C
Yield: 71 %

Procedure:
To a solution of N*2*-Ethyl-5-(5-iodo-2-isopropyl-4-methoxy-phenoxy)-pyrimidine-2,4-diamine (1.65 g, 4.12 mmol) in anhydrous DMF (10 ml) was added CuCN, and the reaction mixture was heated to 120° C. for 3 hrs. The reaction mixture was poured into water (200 ml) and the insoluble portion was collected by filtration. The solid was triturated with 10% MeOH/methylene chloride/0.1% NH4OH solution (100 ml) and filtered again. The filtrate was concentrated and flash chromatographed on silica (3% MeOH in methylene chloride with 0.1% NH4OH) to give 5-(4-Amino-2-ethylamino-pyrimidin-5-yloxy)-4-isopropyl-2-methoxy-benzonitrile (0.87 g, 71%) as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:16])[CH2:10][NH:11][CH2:12][CH2:13][CH2:14][OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]([O:28][C@H:29]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[CH2:30][C:31]([OH:33])=O)(=[O:27])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].C(Cl)CCl.CI>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:16])[CH2:10][N:11]([CH2:12][CH2:13][CH2:14][OH:15])[C:31](=[O:33])[CH2:30][C@H:29]([O:28][C:17](=[O:27])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CNCCCO)OCc1ccccc1
Reactant: CCCCCCCCCCC[C@H](CC(=O)O)OC(=O)CCCCCCCCC
Solvent: CI
Solvent: ClCCCl
Solvent: ClCCl
Product: CCCCCCCCCCC[C@H](CC(=O)N(CCCO)CC(=O)OCc1ccccc1)OC(=O)CCCCCCCCC
Yield: 62.9 %

Procedure:
In the same manner as described in Example 2-(5), N-(3-hydroxypropyl)glycine benzyl ester (450 mg, 2.0 mmol) was acylated with (R)-3-decanoyloxytetradecanoic acid (1.0 g, 2.5 mmol) in the presence of EDC·MeI (900 mg, 3.0 mmol) in CH2Cl2 to afford 0.76 g (63%) of N-(3-hydroxypropyl)-N-[(R)-3-decanoyloxytetradecanoyl]glycine benzyl ester as a colorless oil: 1H NMR (CDCl3) (1:1 mixture of rotomers) δ 0.88 (t, 6H, J=6.6 Hz), 1.1-1.7 (m, 35H), 1.78 (m, 1H), 2.26 (q, 2H, J=7.6 Hz), 2.37 and 2.54 (2 dd, 1H, J=14.9, 6.9 Hz), 2.60 and 2.89 (2 dd, 1H, J=14.8, 6.0 Hz), 3.51 (m, 4H), 3.70 (m, 1H), 3.95-4.25 (m, 2H), 5.1-5.25 (m, 3H),7.35(m, 5H).
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([CH:12]([O:14][C:15]2[CH:36]=[CH:35][C:18]3[C:19]4[N:23]([CH2:24][CH2:25][O:26][C:17]=3[CH:16]=2)[CH:22]=[C:21]([C:27]2[N:28]([CH:32]([CH3:34])[CH3:33])[N:29]=[CH:30][N:31]=2)[N:20]=4)[CH3:13])[CH2:9]1)=O)(C)(C)C.[CH3:37]O.O1[CH2:44][CH2:43]OCC1>Cl>[CH:32]([N:28]1[C:27]([C:21]2[N:20]=[C:19]3[C:18]4[CH:35]=[CH:36][C:15]([O:14][CH:12]([CH:10]5[CH2:9][N:8]([CH:43]([CH3:44])[CH3:37])[CH2:11]5)[CH3:13])=[CH:16][C:17]=4[O:26][CH2:25][CH2:24][N:23]3[CH:22]=2)=[N:31][CH:30]=[N:29]1)([CH3:33])[CH3:34]
Reactant: CC(Oc1ccc2c(c1)OCCn1cc(-c3ncnn3C(C)C)nc1-2)C1CN(C(=O)OC(C)(C)C)C1
Reactant: CO
Reactant: C1COCCO1
Agent: Cl
Product: CC(Oc1ccc2c(c1)OCCn1cc(-c3ncnn3C(C)C)nc1-2)C1CN(C(C)C)C1
Reaction time: 18 h
Yield: 23 %

Procedure:
A solution of 3-{1-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-8-yloxy]ethyl}azetidine-1-carboxylic acid tert-butyl ester (312 mg, 0.63 mmol) in 4M HCl in dioxane (2 mL) and MeOH (5 mL) was stirred at RT for 1 h then concentrated in vacuo. The resulting residue was combined with Pd/C (150 mg) and NEt3 (0.5 mL) in MeOH (3 mL) and acetone (5 mL) and stirred under an atmosphere of H2 for 18 h. The reaction mixture was filtered and the filtrate partitioned between H2O and EtOAc. The combined organic phases were dried (MgSO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient 0-10% MeOH in EtOAc) then reverse phase HPLC (Phenomenex Gemini 5 μm C18, on a gradient 10-90%, 0.1% HCO2H in acetonitrile/water) to afford 166 (63 mg, 23%). LCMS: RT 2.92 min [M+H]+ 437.3. 1H NMR (CDCl3, 400 MHz): δ 8.63 (1H, s), 8.45 (1H, d, J=8.95 Hz), 7.87 (1H, s), 7.60 (1H, s), 6.74 (1H, dd, J=8.97, 2.56 Hz), 6.57 (1H, d, J=2.52 Hz), 6.00-5.93 (1H, m), 4.52-4.47 (3H, m), 4.44-4.42 (2H, m), 3.95-3.92 (2H, m), 3.61 (1H, t, J=8.14 Hz), 3.44 (1H, t, J=8.17 Hz), 2.89-2.87 (1H, m), 1.59 (6H, d, J=6.64 Hz), 1.24 (3H, d, J=6.14 Hz), 1.17 (3H, d, J=6.36 Hz), 1.14 (3H, d, J=6.41 Hz)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([C:17]#[C:18][CH2:19]CO)=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:22][CH2:23][N:24]([CH:28](C)C)[CH:25](C)C.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[CH3:46][O:47]CCNC>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([C:17]#[C:18][CH2:19][CH2:25][N:24]([CH2:23][CH2:22][O:47][CH3:46])[CH3:28])=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: CNCCOC
Reactant: OCCC#Cc1ccc2c(-c3ccc(Br)cc3)nsc2c1
Reactant: CCN(C(C)C)C(C)C
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: COCCN(C)CCC#Cc1ccc2c(-c3ccc(Br)cc3)nsc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56 %

Procedure:
100 mg (0.28 mmol)) 4-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yl]-but-3-yn-1-ol in 2 ml CH2Cl2 were treated with 53 μl (0.31 mmol) Huenig's base at 51 μl (0.31 mmol) trifluoromethane sulfonic acid anhydride at −15° C. The solution was stirred at that temperature for 1 h, additional 10 μL trifluoromethane sulfonic acid anhydride were added and stirring continued for 1 h. 48 μl (0.28 mmol) Huenig's base and 75 μl (0.84 mmol) N-(2-Methoxyethyl)methylamine were added at −15° C. The solution was warmed to RT and stirred for 1.5 h. The solution was diluted with CH2Cl2 and washed with Na2CO3 solution, brine and dried with Na2SO4. Column chromatography gave 66.1 mg (56%) {4-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yl]-but-3-ynyl}-(2-methoxy-ethyl)-methyl-amine as brown oil, MS: 429 (MH+, 1Br).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].Br[C:27]1[CH:28]=[CH:29][C:30]([CH3:40])=[C:31]([S:33]([NH:36][CH2:37][CH2:38][OH:39])(=[O:35])=[O:34])[CH:32]=1>>[OH:39][CH2:38][CH2:37][NH:36][S:33]([C:31]1[CH:32]=[C:27]([C:2]#[C:1][C:3]2[CH:4]=[N:5][N:6]3[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=4)=[N:8][C:7]=23)[CH:28]=[CH:29][C:30]=1[CH3:40])(=[O:35])=[O:34]
Reactant: Cc1ccc(Br)cc1S(=O)(=O)NCCO
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: Cc1ccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)cc1S(=O)(=O)NCCO

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (150 mg, 0.9 mmol) and 5-Bromo-N-(2-hydroxy-ethyl)-2-methyl-benzenesulfonamide (example B.17) (129 mg, 1.0 mmol) according to general procedure II. Obtained as an orange solid (59 mg, 25%). MS (ISP) 569.2 [(M+H)+]; mp 174–175° C.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])(=O)C.[CH2:18]([O:24][C:25]1[CH:26]=[C:27]([C:38]2[CH:43]=[CH:42][C:41]([O:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])=[C:40]([O:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH3:57])[CH:39]=2)[CH:28]=[CH:29][C:30]=1[O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>ClCCl.[Fe](Cl)Cl>[OH:4][C:5]1[C:6]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:7][C:8]2[C:43]3[C:38](=[CH:39][C:40]([O:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH3:57])=[C:41]([O:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])[CH:42]=3)[C:27]3[C:28](=[CH:29][C:30]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[C:25]([O:24][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:26]=3)[C:9]=2[CH:10]=1
Reactant: CCCCCCOc1ccc(-c2ccc(OCCCCCC)c(OCCCCCC)c2)cc1OCCCCCC
Reactant: CCCCCCOc1ccccc1OC(C)=O
Agent: Cl[Fe]Cl
Solvent: ClCCl
Product: CCCCCCOc1cc2c(cc1O)c1cc(OCCCCCC)c(OCCCCCC)cc1c1cc(OCCCCCC)c(OCCCCCC)cc21
Reaction time: 5 h
Yield: 66.9 %

Procedure:
Anhydrous iron chloride (4.7 g, 28.9 mmol) was added to a stirred mixture of 2-acetoxy-1-hexyloxybenzene (3.4 g, 14.4 mmol) and 3,3′,4,4′-tetrahexyloxybiphenyl (4.0 g, 7.2 mmol) in dichloromethane. The mixture was stirred for 5 h and poured onto methanol (300 ml). The resultant precipitate was filtered off and saponified with potassium carbonate in ethanol (5% water) under reflux for over night. After cooling, water (50 ml) was added and the product was extracted with dichloromethane, dried (MgSO4), concentrated and purified by column chromatography on silica gel using dichloromethane and petroleum spirit (1:1) as eluent and then recrystallised from ethanol to yield a white solid (3.59 g, 67%). Found: C, 77.30; H, 9.85. C48H72O6 requires C, 77.38; H, 9.74. δH (CHCl3) 7.96 (s, 1H, ArH), 7.83-7.82 (m, 4H, ArH), 7.77 (s, 1H, ArH), 5.92 (1H, s, OH), 4.31-4.18 (m, 10H, OCH2), 1.99-1.92 (m, 10H, CH2), 1.58-1.55 (m, 10H, CH2), 1.46-1.38 (m, 20H, CH2), 0.97-0.83 (15H, m, CH3).
Reaction SMILES: [H-].[Na+].[CH3:3][CH2:4][O:5][C:6]([CH:8](P(OCC)(OCC)=O)[CH3:9])=[O:7].[CH:18]([C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=1)([CH3:20])[CH3:19].O>CN(C)C=O>[CH:18]([C:21]1[CH:28]=[CH:27][C:24]([CH:25]=[C:8]([CH3:9])[C:6]([O:5][CH2:4][CH3:3])=[O:7])=[CH:23][CH:22]=1)([CH3:20])[CH3:19]
Reactant: CCOC(=O)C(C)P(=O)(OCC)OCC
Reactant: CC(C)c1ccc(C=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(C)=Cc1ccc(C(C)C)cc1
Reaction time: 0.17 h
Yield: 96 %

Procedure:
To a suspension of sodium hydride (a 60% dispersion in liquid paraffin, 5.92 g, 148 mmol) in N,N-dimethylformamide (150 ml) was added at 0° C. triethyl 2-phosphonopropionate (35.0 g, 148 mmol) and the resulting mixture was stirred at the same temperature for 10 minutes. To the reaction solution was added 4-isopropylbenzaldehyde (20.0 g, 135 mmol) and the resulting mixture was stirred at room temperature for 30 minutes. Water was added into the reaction solution and the product was extracted twice with ethyl acetate. The combined extracts were washed with water, dried on magnesium sulfate, and then concentrated under reduced pressure to obtain 30.1 g (96% yield) of the oily title compound.