Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:50])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][O:23][C:24]2[CH:29]=[C:28]([O:30]CC3C=CC=CC=3)[C:27]([C:38]3[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=3)=[CH:26][C:25]=2[CH2:45][CH3:46])[C:12]=1[CH2:47][CH2:48][CH3:49]>C(Cl)(Cl)Cl>[CH2:47]([C:12]1[C:13]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][O:23][C:24]2[CH:29]=[C:28]([OH:30])[C:27]([C:38]3[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=3)=[CH:26][C:25]=2[CH2:45][CH3:46])=[CH:14][CH:15]=[CH:16][C:11]=1[O:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[C:3]([OH:50])=[O:2])[CH2:48][CH3:49]
Reactant: CCCc1c(OCCCCCOc2cc(OCc3ccccc3)c(-c3ccc(F)cc3)cc2CC)cccc1Oc1ccccc1C(=O)OC
Solvent: ClC(Cl)Cl
Product: CCCc1c(OCCCCCOc2cc(O)c(-c3ccc(F)cc3)cc2CC)cccc1Oc1ccccc1C(=O)O

Procedure:
2-[2-Propyl-3-[5-[2-ethyl-4-(4-fluorophenyl)-5-(phenylmethoxy)phenoxy]pentoxy]phenoxy]benzoic acid methyl ester (3.60 g, 5.32 mmol) was submitted to de-benzylation and hydrolysis as described above for the preparation of Example 60. The product was isolated via vacuum filtration as a white crystalline solid: mp 65° C. (dec); NMR (CDCl3) 8.25 (dd, J=7.9, 1.7 Hz, 1H), 7.44 (m, 3H), 7.18 (m, 4H), 6.97 (s, 1H), 6.80 (d, J=8.2 Hz, 1H), 6.75 (d, J=8.5 Hz, 1H), 6.65 (d, J=8.1 Hz, 1H), 6.54 (s, 1H), 5.15 (bs, 1H, --OH), 4.10 (t, J=6.1 Hz, 2H), 4.05 (t, J=5.6 Hz, 2H), 2.61 (m, 4H), 1.93 (m, 4H), 1.75 (m, 2H), 1.54 (hextet, J=7.4 Hz, 2H), 1.18 (t, J=7.4 Hz, 3H), 0.89 (t, J=7.3 Hz, 3H); MS-FD m/e 572 (p); IR (CHCl3, cm-1) 3350 (b), 2965, 1739, 1605, 1496, 1455, 1238, 1108. Analysis for C35H37O6F: Calc: C, 73.41; H, 6.51; Found: C, 73.13; H, 6.59.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[O:18][C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:16][C:15](=[O:24])[CH:14]=2)=[CH:9][CH:8]=1.O>ClCCl>[OH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[O:18][C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:16][C:15](=[O:24])[CH:14]=2)=[CH:11][CH:12]=1
Reactant: CCOC(=O)c1cc(=O)cc(-c2ccc(OC)cc2)o1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1cc(=O)cc(-c2ccc(O)cc2)o1
Reaction time: 2 h

Procedure:
Boron tribromide (5.0 g) was added dropwise to a stirred solution of ethyl 6-(4-methoxyphenyl)-4-oxo-4H-pyran-2-carboxylate (5.48 g) in dichloromethane (40 ml) cooled to 0°-5° C. After 2 hours at below 5° C., water was cautiously added to the reaction mixture, with cooling, and the yellow solid which precipitated was filtered off. Recrystallisation from ethanol and then from ethyl acetate gave the title product as yellow crystals (mp 213°-215° C.).
Reaction SMILES: C1(C([NH:20][C:21]2([CH2:26][O:27][CH2:28][C:29]3[CH:34]=[CH:33][C:32]([C:35]4[O:36][C:37]5[CH:43]=[CH:42][CH:41]=[CH:40][C:38]=5[N:39]=4)=[CH:31][CH:30]=3)[CH2:25][CH2:24][CH2:23][CH2:22]2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[ClH:44]>C(O)C.C(Cl)Cl>[ClH:44].[NH2:20][C:21]1([CH2:26][O:27][CH2:28][C:29]2[CH:34]=[CH:33][C:32]([C:35]3[O:36][C:37]4[CH:43]=[CH:42][CH:41]=[CH:40][C:38]=4[N:39]=3)=[CH:31][CH:30]=2)[CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: c1ccc(C(NC2(COCc3ccc(-c4nc5ccccc5o4)cc3)CCCC2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: CCO
Solvent: ClCCl
Product: NC1(COCc2ccc(-c3nc4ccccc4o3)cc2)CCCC1
Reaction time: 72 h

Procedure:
To a solution of 1-triphenylmethylamino-(4-[benzoxazol-2-yl]benzyloxymethyl)cyclopentane (1.24 g; 2.20 mmol) of 1-triphenylmethylamino-(4-[benzoxazol -2-yl]benzyloxymethyl)cyclopentane in ethanol/CH2Cl2 is added ethanolic HCl until ph≅2. This is then stirred for 72 hrs., concentrated to about one-half the volume and the white precipitate which forms is filtered to obtain 1-amino-[4-(benzoxazol-2-yl)benzyloxymethyl]cyclopentane hydrochloride (m.p. >250° C.).
Reaction SMILES: [N:1]1([C:7](=[O:24])[CH2:8][C:9]2[CH:14]=[CH:13][C:12](B3OC(C)(C)C(C)(C)O3)=[CH:11][CH:10]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[C:26]1[CH:27]=[C:28]([C:33]2[N:34]=[N:35][N:36]([CH:38]([CH3:40])[CH3:39])[CH:37]=2)[C:29]([NH2:32])=[N:30][CH:31]=1.C([O-])([O-])=O.[Cs+].[Cs+].N#N>O1CCOCC1.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.O>[NH2:32][C:29]1[N:30]=[CH:31][C:26]([C:12]2[CH:11]=[CH:10][C:9]([CH2:8][C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)=[O:24])=[CH:14][CH:13]=2)=[CH:27][C:28]=1[C:33]1[N:34]=[N:35][N:36]([CH:38]([CH3:40])[CH3:39])[CH:37]=1
Reactant: CC(C)n1cc(-c2cc(Br)cnc2N)nn1
Reactant: CC1(C)OB(c2ccc(CC(=O)N3CCOCC3)cc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)n1cc(-c2cc(-c3ccc(CC(=O)N4CCOCC4)cc3)cnc2N)nn1
Temperature: 100 °C
Reaction time: 16 h
Yield: 28.1 %

Procedure:
To a solution of 1-Morpholin-4-yl-2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-ethanone (129 mg, 0.39 mmol) and 5-bromo-3-(1-isopropyl-1H-[1,2,3]triazol-4-yl)-pyridin-2-ylamine (100 mg, 0.35 mmol) in 1,4-dioxane (6.0 mL)/water (4.0 mL) was added Cs2CO3 (284 mg, 0.87 mmol) at room temperature. N2 was purged through the reaction mixture for 10 min. Pd(PPh3)4 (20 mg, 0.017 mmol) was added and through the reaction mixture N2 was purged for 10 min and stirred at 100° C. for 16 h. The reaction mixture was cooled to RT, diluted with EtOAc (50 mL) and washed with water (50 mL). The organic layer was washed with brine solution (50 mL), dried over anhydrous Na2SO4 and solvent was evaporated under reduced pressure. Crude compound was purified by column chromatography using 100-200 mesh silica gel and eluted with 2-3% MeOH in DCM to afford 40 mg (yield: 27.7%) of the title compound as brown semisolid. Product was converted to its HCl salt by using 2M HCl in ether to afford 42 mg of an off-white solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1([NH:6]C(=O)OC(C)(C)C)[CH2:5][CH2:4]1.[F:14][C:15]1[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[C:16]=1[CH2:17][O:18][C:19]1[N:24]2[N:25]=[C:26]([CH3:31])[C:27]([C:28](O)=[O:29])=[C:23]2[CH:22]=[C:21]([CH3:32])[CH:20]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C.ClCCl>[NH2:6][C:3]1([CH2:2][NH:1][C:28]([C:27]2[C:26]([CH3:31])=[N:25][N:24]3[C:19]([O:18][CH2:17][C:16]4[C:33]([F:37])=[CH:34][CH:35]=[CH:36][C:15]=4[F:14])=[CH:20][C:21]([CH3:32])=[CH:22][C:23]=23)=[O:29])[CH2:4][CH2:5]1
Reactant: CC(C)(C)OC(=O)NC1(CN)CC1
Reactant: Cc1cc(OCc2c(F)cccc2F)n2nc(C)c(C(=O)O)c2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1cc(OCc2c(F)cccc2F)n2nc(C)c(C(=O)NCC3(N)CC3)c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
20.5 mg (0.11 mmol) of tert-butyl [1-(aminomethyl)cyclopropyl]carbamate were initially charged in a 96-well deep well multititre plate. A solution of 33.2 mg (0.1 mmol) of 7-[(2,6-difluorobenzyl)oxy]-2,5-dimethylpyrazolo[1,5-a]pyridine-3-carboxylic acid from Example 4A in 0.4 ml of DMF/dichloromethane (1:1, v/v) and a solution of 49.4 mg (0.13 mol) of HATU in 0.4 ml of DMF/dichloromethane (1:1, v/v) were added successively. After adding 20.2 mg (0.20 mmol) of 4-methylmorpholine, the mixture was shaken at RT overnight. Subsequently, the mixture was heated to 60° C. and shaken at this temperature for 7 h. Then the solvent was evaporated off completely. The residue was admixed with 0.6 ml of TFA and shaken at room temperature overnight. Then the mixture was concentrated fully, the residue was dissolved in 0.8 ml of DMF and filtered, and the target compound was isolated from the filtrate by preparative LC-MS (Method 9). The product-containing fractions were concentrated under reduced pressure using a centrifugal dryer. The residue of each product fraction was dissolved in 0.6 ml of DMSO. These were combined and finally freed of the solvent in a centrifugal dryer. 0.5 mg (1.3% of theory) of the title compound were obtained.
Reaction SMILES: N[C@H](C(O)=O)C(C)(C)C.[BH4-].[Li+].[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]2[C:26](=[O:27])[C:25](=[O:28])[NH:24][C:23]3[CH:29]=[CH:30][CH:31]=[CH:32][C:22]=3[S:21]2)=[CH:16][CH:15]=1>O1CCCC1>[OH:27][C@H:26]1[C:25](=[O:28])[NH:24][C:23]2[CH:29]=[CH:30][CH:31]=[CH:32][C:22]=2[S:21][C@H:20]1[C:17]1[CH:18]=[CH:19][C:14]([O:13][CH3:12])=[CH:15][CH:16]=1
Reactant: COc1ccc(C2Sc3ccccc3NC(=O)C2=O)cc1
Agent: CC(C)(C)[C@H](N)C(=O)O
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc([C@@H]2Sc3ccccc3NC(=O)[C@@H]2O)cc1
Temperature: -10 °C
Reaction time: 15 h
Yield: 93.7 %

Procedure:
A mixture of L-tert-leucine (433 mg), lithium borohydride (65.4 mg) and tetrahydrofuran (28 ml) is refluxed under nitrogen atmosphere for one hour. The mixture is cooled to -10° C., and thereto is added 2-(4-methoxyphenyl)-1,5-benzothiazepine-3,4(2H,5H)-dione (299 mg), and the mixture is further stirred at -10° C. for 15 hours. The mixture is evaporated under reduced pressure to remove the solvent, and to the residue is added 1N hydrochloric acid (10 ml). The precipitated crystal is collected by filtration, washed with water, and dried to give (2S,3S)-3-hydroxy-2-(4-methoxyphenyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one (282 mg).
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]([O:12]CC)=[O:11])[N:5]=[CH:4][C:3]=1[NH:15][C@@H:16]1[CH2:21][C@@H:20]2[CH2:22][C@@H:18]([C:19]2([CH3:24])[CH3:23])[C@H:17]1[CH3:25].[OH-].[Na+].C(OCC)(=O)C>O1CCOCC1>[Br:1][C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]([OH:12])=[O:11])[N:5]=[CH:4][C:3]=1[NH:15][C@@H:16]1[CH2:21][C@@H:20]2[CH2:22][C@@H:18]([C:19]2([CH3:24])[CH3:23])[C@H:17]1[CH3:25]
Reactant: CCOC(=O)Cn1ncc(N[C@@H]2C[C@@H]3C[C@H]([C@H]2C)C3(C)C)c(Br)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: C[C@@H]1[C@H]2C[C@@H](C[C@H]1Nc1cnn(CC(=O)O)c(=O)c1Br)C2(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
Ethyl 2-{5-bromo-6-oxo-4-[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-1(6H)-yl}acetate (646 mg, 1.57 mmol) in 1,4-dioxane (6.5 mL) was mixed with 1 M aqueous sodium hydroxide (4.71 mL, 4.71 mmol) and stirred at room temperature for 1 hour. After completion of the reaction, ethyl acetate was added, and the organic layer was washed with 1 M hydrochloric acid and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated under reduced pressure to give the desired product (567 mg, 94% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[S:15][C:14]3=[N:16][C:17]([CH3:20])=[C:18](I)[N:13]3[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[N:21]1[CH:26]=[CH:25][CH:24]=[C:23](B(O)O)[CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.C(Cl)Cl.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[S:15][C:14]3=[N:16][C:17]([CH3:20])=[C:18]([C:23]4[CH:22]=[N:21][CH:26]=[CH:25][CH:24]=4)[N:13]3[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(-c2nn3c(I)c(C)nc3s2)cc1OC
Reactant: OB(O)c1cccnc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: ClCCl
Product: COc1ccc(-c2nn3c(-c4cccnc4)c(C)nc3s2)cc1OC
Yield: 89.7 %

Procedure:
A mixture of 2-(3,4-dimethoxy-phenyl)-5-iodo-6-methyl-imidazo[2,1-b][1,3,4]thiadiazole (0.070 g, 0.174 mmol), pyridine-3-boronic acid (0.026 g, 0.209 mmol), Pd(dppf)Cl2.DCM (0.014 g. 0.017 mmol) and potassium carbonate (0.5 mL, sat. aq) in DME (1.7 mL) was heated in the microwave oven at 150° C. for 2 h. Since the conversion was incomplete, another 1.2 eq of pyridine-3-boronic acid and 0.1 eq of Pd(dppf)Cl2.DCM were added, and the mixture was subjected to another 7 hours of microwave irradiation at 150° C. The reaction mixture was cooled, diluted with DCM, washed with water, dried (Na2SO4) and concentrated. A yellow solid (0.055 g) was obtained that was purified by silica gel chromatography (cyclohexane/0-60% EtOAc) to give the desired product (white solid, 0.042 g, 39%). HPLC-MS: (5-100% B in 8 min, 0.8 mL/min, 50° C.): tR=4.09 min, [M+H]+ m/z 353.1. 1H NMR (300 MHz, CDCl3) δ/ppm 9.00 (d, J=2.2, 1H), 8.53 (dd, J=4.8, 1.6, 1H), 8.00 (dd, J=8.0, 1.8, 1H), 7.48-7.29 (m, 3H), 6.88 (d, J=9.0, 1H), 3.90 (d, J=5.0, 7H), 2.50 (s, 3H).
Reaction SMILES: Br[C:2]1[C:3]([NH:9][C:10]([CH3:15])([CH3:14])[CH2:11][O:12][CH3:13])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[B]1OC2C(=CC=CC=2)O1.[CH2:25]([O:27][C:28]#[CH:29])[CH3:26]>>[Cl:8][C:5]1[N:4]=[C:3]([NH:9][C:10]([CH3:15])([CH3:14])[CH2:11][O:12][CH3:13])[C:2](/[CH:26]=[CH:25]/[O:27][CH2:28][CH3:29])=[CH:7][N:6]=1
Reactant: COCC(C)(C)Nc1nc(Cl)ncc1Br
Reactant: C#COCC
Agent: [B]1Oc2ccccc2O1
Product: CCO/C=C/c1cnc(Cl)nc1NC(C)(C)COC

Procedure:
The title compound was prepared according to the method described for Preparation 61 using (5-Bromo-2-chloro-pyrimidin-4-yl)-(2-methoxy-1,1-dimethyl-ethyl)-amine (Preparation 256), catechol borane and ethoxyacetylene (40% in hexane) to afford the title compound as light brown gum in 44% yield, 2.6 g.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)=[N:10][C:9]=2[C:20]([NH:22][C:23]2[S:24][CH:25]=[CH:26][N:27]=2)=[O:21])=[CH:4][CH:3]=1.[CH3:28][N:29]([CH3:33])[CH2:30][CH2:31]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:31][CH2:30][N:29]([CH3:33])[CH3:28])=[CH:15][CH:14]=3)=[N:10][C:9]=2[C:20]([NH:22][C:23]2[S:24][CH:25]=[CH:26][N:27]=2)=[O:21])=[CH:4][CH:3]=1
Reactant: CN(C)CCO
Reactant: O=C(Nc1nccs1)c1nc(-c2ccc(O)cc2)[nH]c1-c1ccc(Cl)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CN(C)CCOc1ccc(-c2nc(C(=O)Nc3nccs3)c(-c3ccc(Cl)cc3)[nH]2)cc1

Procedure:
5-(4-Chlorophenyl)-2-(4-hydroxyphenyl)-N-(2-thiazolyl)-imidazole-4-carboxamide, 2-dimethylaminoethanol, triphenylphosphine and diethyl azodicarboxylate are reacted and treated in the same manner as in Example 24 to give 5-(4-chlorophenyl)-2-(4-(2-dimethylamino-ethyloxy)phenyl)-N-(2-thiazolyl)imidazole-4-carboxamide.
Reaction SMILES: C1COCC1.Br[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1.Br[C:15]1[S:19][C:18]([C:20]2[N:24]3[N:25]=[C:26]([CH3:34])[CH:27]=[C:28]([CH:29]([CH2:32][CH3:33])[CH2:30][CH3:31])[C:23]3=[N:22][C:21]=2[CH3:35])=[C:17]([CH3:36])[CH:16]=1>CCOC(C)=O.[Zn].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:30]([CH:29]([C:28]1[C:23]2[N:24]([C:20]([C:18]3[S:19][C:15]([C:7]4[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=4)=[CH:16][C:17]=3[CH3:36])=[C:21]([CH3:35])[N:22]=2)[N:25]=[C:26]([CH3:34])[CH:27]=1)[CH2:32][CH3:33])[CH3:31]
Reactant: CCC(CC)c1cc(C)nn2c(-c3sc(Br)cc3C)c(C)nc12
Reactant: Fc1ccc(Br)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCC(CC)c1cc(C)nn2c(-c3sc(-c4ccc(F)cc4)cc3C)c(C)nc12
Yield: 24.7 %

Procedure:
A slurry of 0.05 g/mL of Reike® Zn in THF (0.26 g, 4.01 mmol) and 1-bromo-4-fluoro-benzene (0.29 mL, 2.68 mmol) is heated at a reflux overnight. The solution is filtered under nitrogen. 3-(5-bromo-3-methyl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.35 g, 0.89 mmol) and PdCl2(dppf) (0.033 g, 0.045 mmol) are added, and the solution is heated at a reflux overnight diluted with EtOAc (30 mL), washed with 10% citric acid (20 mL), water (20 mL), brine (20 mL), dried over MgSO4, filtered and concentrated. The residue is purified by ISCO column chromatography (10%-15% EtOAc/hexane gradient) furnish the title compound (0.091 g, 0.22 mmol, 25%). 1H NMR (CDCl3), δ 0.88 (t, J=7.5 Hz, 6H), 1.74-1.92 (m, 4H), 2.15 (s, 3H), 2.50 (s, 3H), 2.52 (s, 3H), 3.30-3.38 (m, 1H), 6.68 (s, 1H), 7.08 (d, J=8.8 Hz, 2H), 7.18 (s, 1H), 7.59 (dd, J=8.5, 5.3 Hz, 2H). LC/MS (m/z): calcd. for C24H26FN3S (M+H)+: 408.7; found: 408.3.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:9]=[C:8]([Cl:10])[N:7]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[N:6]=1)=[O:4].[OH-].[K+:20]>CCO.CCOCC>[K+:20].[Cl:10][C:8]1[N:7]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:17])([CH3:18])[CH3:16])[N:6]=[C:5]([C:3]([O-:4])=[O:2])[N:9]=1
Reactant: COC(=O)c1nc(Cl)n(COCC[Si](C)(C)C)n1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOCC
Product: C[Si](C)(C)CCOCn1nc(C(=O)[O-])nc1Cl
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 91 %

Procedure:
To a solution of 4-(4-{[5-chloro-1-(2-trimethylsilanyl-ethoxymethyl)-1H-[1,2,4]triazole-3-carboxylic acid methyl ester (as prepared in the previous step, 227 mg, 0.780 mmol) in EtOH (2 mL), 2 N KOH (0.4 mL, 0.8 mmol) was added. The resulting solution was stirred at RT for 20 min and concentrated in vacuo. The residue obtained was suspended in ether (10 mL) and sonicated for 5 min. The ether was then removed and the resulting residue was dried in vacuo for 4 h to obtain 4-(4-{[5-chloro-1-(2-trimethylsilanyl-ethoxymethyl)-1H-[1,2,4]triazole-3-carboxylic acid potassium salt (223 mg, 91%) which was directly used in the next step without any further purification.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2([CH2:18][N:19]([CH3:21])[CH3:20])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:8][CH:7]=1.[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:20][N:19]([CH3:21])[CH2:18][C:12]1([C:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][CH2:2][N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[CH:7][CH:8]=2)[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: CN(C)CC1(c2ccc(OCCCCl)cc2)CCOCC1
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN(C)CC1(c2ccc(OCCCN3CCOCC3)cc2)CCOCC1
Yield: 52.6 %

Procedure:
A mixture of 1-{4-[4-(3-chloropropoxy)phenyl]tetrahydro-2H-pyran-4-yl}-N,N-dimethylmethanamine (100 mg, 0.32 mmol), morpholine (100 mg, 1.1 mmol) and potassium carbonate (100 mg, 0.72 mmol) was heated at reflux in acetonitrile (5 ml) for 8 hours. Further morpholine (100 mg, 1.1 mmol) and potassium carbonate (100 mg, 0.72 mmol) were added and the reaction mixture heated at reflux for 6 hours. The reaction mixture was concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with dichloromethane:methanol:ammonia (90:10:1 by volume) to provide the title compound (61 mg, 52%). 1H NMR (400 MHz, CD3OD) δ 0.81-0.87 (m, 2H), 1.04-2.01 (m, 8H), 2.13-2.18 (m, 2H), 2.48-2.50 (m, 6H), 2.56 (t, 2H), 3.50 (t, 2H), 3.68-3.77 (m, 6H), 4.03 (t, 2H), 6.90 (d, 2H), 7.27 (d, 2H). HRMS ESI+ m/z 363.2635 [MH]+.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][N:23]([C:26]4[CH2:27][CH2:28][C:29]5[N:30]([C:32]([C:35]([F:38])([F:37])[F:36])=[N:33][N:34]=5)[N:31]=4)[CH2:22][CH2:21]3)=[CH:16][CH:15]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[C:39](O)(=O)[CH2:40][CH2:41]CC>>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]([N:20]3[CH2:25][CH2:24][N:23]([C:26]4[CH2:27][CH2:28][C:29]5[N:30]([C:32]([C:35]([F:37])([F:36])[F:38])=[N:33][N:34]=5)[N:31]=4)[CH2:22][CH2:21]3)=[CH:18][CH:19]=2)[CH2:6][CH2:5]1)(=[O:3])[CH2:2][CH2:39][CH2:40][CH3:41]
Reactant: CC(=O)N1CCN(CCCOc2ccc(N3CCN(C4=Nn5c(nnc5C(F)(F)F)CC4)CC3)cc2)CC1
Reactant: CCCCC(=O)O
Product: CCCCC(=O)N1CCN(CCCOc2ccc(N3CCN(C4=Nn5c(nnc5C(F)(F)F)CC4)CC3)cc2)CC1
Yield: 70 %

Procedure:
Obtained in 70% yield by an analogous method to Example 4.1, starting from 6-{4-[4-(3-piperazin-1-ylpropoxy)phenyl]piperazin-1-yl}-3-(trifluoromethyl)-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazine (obtained as described in Example 29, preparation of starting materials) and pentanoic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:16]2[O:15][CH:14]([CH2:17]OS(C3C=CC(C)=CC=3)(=O)=O)[CH2:13][C:12]=2[CH:11]=[C:10]([O:29][CH3:30])[CH:9]=1.[CH3:31][NH2:32]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:16]2[O:15][CH:14]([CH2:17][NH:32][CH3:31])[CH2:13][C:12]=2[CH:11]=[C:10]([O:29][CH3:30])[CH:9]=1
Reactant: CN
Reactant: COc1cc2c(c(-c3ccccc3Cl)c1)OC(COS(=O)(=O)c1ccc(C)cc1)C2
Product: CNCC1Cc2cc(OC)cc(-c3ccccc3Cl)c2O1

Procedure:
The title compound was prepared (0.040 g, 52%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-{[7-(2-chlorophenyl)-5-methoxy-2,3-dihydro-1-benzofuran-2-yl]methyl}4-methylbenzenesulfonate (0.102 g, 0.23 mmol) and methylamine (0.071 g, 2.3 mmol). mp 185-186° C.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:6]([CH3:12])=[CH:7][CH:8]=[CH:9][C:10]=1[CH3:11])(=[O:3])[CH3:2].C(O)(=O)C.S(=O)(=O)(O)O.[N+:22]([O-])([OH:24])=[O:23]>>[C:1]([NH:4][C:5]1[C:10]([CH3:11])=[CH:9][CH:8]=[C:7]([N+:22]([O-:24])=[O:23])[C:6]=1[CH3:12])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1c(C)cccc1C
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CC(=O)Nc1c(C)ccc([N+](=O)[O-])c1C
Yield: 94.7 %

Procedure:
To a mixture of 30.1 g of N-acetyl-2,6-xylidine (0.18 mole) and 40 ml of acetic acid (0.70 mole) was added gradually 80 ml of concentrated sulfuric acid (0.50 mole) with stirring under ice-cooling. Then, to the mixture was added slowly 10 ml of fuming nitric acid (0.24 mole) in a manner such that the temperature of the reaction mixture did not exceed 10° C. The reaction mixture was returned to room temperature and, after stirring for 2 hours, poured onto ice. The resulting crystalline precipitate was collected by filtration and recrystallized from ethanol to give 35.5 g (92%) of the title compound (m.p. 171°-173° C.; pale yellow needles).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]([CH3:67])[C@H:9]([C:13]([NH:15][C@H:16]([C:20]([N:22]([C@@H:24]([C@@H:63]([CH3:66])[CH2:64][CH3:65])[C@H:25]([O:61][CH3:62])[CH2:26][C:27]([N:29]1[CH2:33][CH2:32][CH2:31][C@H:30]1[C@H:34]([O:59][CH3:60])[C@@H:35]([CH3:58])[C:36]([NH:38][C@@H:39]([CH2:48][C:49]1[C:57]2[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=2)[NH:51][CH:50]=1)[C:40]([N:42]1[CH2:47][CH2:46][CH2:45][CH2:44][O:43]1)=[O:41])=[O:37])=[O:28])[CH3:23])=[O:21])[CH:17]([CH3:19])[CH3:18])=[O:14])[CH:10]([CH3:12])[CH3:11].[S:68]([CH2:82][CH2:83][C:84](ON1C(=O)CCC1=O)=[O:85])[S:69][CH2:70][CH2:71][C:72]([O:74][N:75]1[C:79](=[O:80])[CH2:78][CH2:77][C:76]1=[O:81])=[O:73].C(N(CC)C(C)C)(C)C>CN(C=O)C>[O:80]=[C:79]1[CH2:78][CH2:77][C:76](=[O:81])[N:75]1[O:74][C:72](=[O:73])[CH2:71][CH2:70][S:69][S:68][CH2:82][CH2:83][C:84]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]([CH3:67])[C@H:9]([C:13]([NH:15][C@H:16]([C:20]([N:22]([C@@H:24]([C@@H:63]([CH3:66])[CH2:64][CH3:65])[C@H:25]([O:61][CH3:62])[CH2:26][C:27]([N:29]1[CH2:33][CH2:32][CH2:31][C@H:30]1[C@H:34]([O:59][CH3:60])[C@@H:35]([CH3:58])[C:36]([NH:38][C@@H:39]([CH2:48][C:49]1[C:57]2[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=2)[NH:51][CH:50]=1)[C:40]([N:42]1[CH2:47][CH2:46][CH2:45][CH2:44][O:43]1)=[O:41])=[O:37])=[O:28])[CH3:23])=[O:21])[CH:17]([CH3:18])[CH3:19])=[O:14])[CH:10]([CH3:12])[CH3:11])=[O:85]
Reactant: O=C(CCSSCCC(=O)ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N1CCCCO1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCCCCN)C(C)C
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N1CCCCO1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCCCCNC(=O)CCSSCCC(=O)ON1C(=O)CCC1=O)C(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
8 mg (10 μmol) of Intermediate 101 were dissolved in 2 ml of DMF and admixed with 8.6 mg (20 μmol) of 1,1′-{disulphanediylbis[(1-oxopropane-3,1-diyl)oxy]}dipyrrolidine-2,5-dione and 3.7 μl of N,N-diisopropylethylamine. The reaction mixture was stirred at RT for 2 h and then the solvent was evaporated off under reduced pressure and the residue was purified by preparative HPLC. 7.2 mg (68% of theory) of the title compound were obtained.