Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[C:8]2[CH:9]=[CH:10][C:11]([N+:13]([O-])=O)=[CH:12][C:7]=2[NH:6][C:5](=[O:16])[CH:4]([NH:17][C:18](=[O:20])[CH3:19])[CH2:3]1.Cl[C:23]1[N:28]=[C:27]([NH:29][C:30]2[C:39]([F:40])=[CH:38][CH:37]=[CH:36][C:31]=2[C:32]([NH:34][CH3:35])=[O:33])[C:26]([Cl:41])=[CH:25][N:24]=1>>[C:18]([NH:17][CH:4]1[CH2:3][C:2]([CH3:21])([CH3:1])[C:8]2[CH:9]=[CH:10][C:11]([NH:13][C:23]3[N:28]=[C:27]([NH:29][C:30]4[C:39]([F:40])=[CH:38][CH:37]=[CH:36][C:31]=4[C:32]([NH:34][CH3:35])=[O:33])[C:26]([Cl:41])=[CH:25][N:24]=3)=[CH:12][C:7]=2[NH:6][C:5]1=[O:16])(=[O:20])[CH3:19]
Reactant: CC(=O)NC1CC(C)(C)c2ccc([N+](=O)[O-])cc2NC1=O
Reactant: CNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Product: CNC(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)NC(=O)C(NC(C)=O)CC3(C)C)ncc1Cl

Procedure:
2-[2-(3-Acetylamino-5,5-dimethyl-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-8-ylamino)-5-chloro-pyrimidin-4-ylamino]-3-fluoro-N-methyl-benzamide was prepared from N-(5,5-Dimethyl-8-nitro-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl)-acetamide and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-3-fluoro-N-methyl-benzamide in an analogous manner to Example 1221d. (62 mg, 43%). HPLC purity=99%, LCMS 524 (M+H), 1H-NMR (DMSO-d6, 400 MHz) δ 9.53 (s, 1H), 9.39 (s, 1H), 9.35 (s, 1H), 8.51 (d, J=4.6 Hz, 1H), 8.19 (s, 1H), 8.04 (d, J=8.0 Hz, 1H), 7.49-7.45 (m, 2H), 7.33-7.26 (m, 2H), 7.15 (s, 1H), 7.08 (d, J=9.0 Hz, 1H), 4.22-4.17 (m, 1H), 2.73 (d, J=4.4 Hz, 3H), 2.08-2.06 (m, 1H), 1.87-1.84 (m, 1H), 1.84 (s, 3H), 1.32 (s, 3H), 1.23 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]2[CH:12]=[C:13]([C:15]([O:17]CC)=[O:16])[N:14]=[C:4]2[CH:3]=1.[OH-].[Na+].Cl.C>O.C(O)C.C(Cl)(Cl)Cl.CO>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]2[CH:12]=[C:13]([C:15]([OH:17])=[O:16])[N:14]=[C:4]2[CH:3]=1
Reactant: CCOC(=O)c1cn2c(cc(Br)c3ccccc32)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CCO
Solvent: CO
Product: O=C(O)c1cn2c(cc(Br)c3ccccc32)n1
Temperature: 25 °C

Procedure:
1.28 g of ethyl 5-bromoimidazo-[1,2-a]-quinoline-2-carboxylate were heated on a steam bath with 5 ml of 1 N sodium hydroxide solution in 20 ml of water and 50 ml of ethanol until a clear solution was obtained (approx. 15 mins). 5 ml of 1 N hydrochloric acid were then added thereto and the solution was allowed to cool slowly to room temperature. The pale green crystals thus formed were filtered off and were washed with methanol. The mother liquors were reduced in volume and cooled to give a second crop. The two crops were combined in 50 ml of chloroform and 50 methanol and the solution obtained was decolorized with charcoal. The solution was reduced in volume under vacuum and the residue was cooled in ice to give colorless plates of 5-bromoimidazo-[1,2-a]-quinoline-2-carboxylic acid melting at 288°-90° C. (decomp).
Reaction SMILES: [CH2:1]([N:4]([C@@H:17]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:18]([N:20]1[CH2:24][CH2:23][C@H:22]([OH:25])[CH2:21]1)=[O:19])[S:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N+:14]([O-:16])=[O:15])(=[O:7])=[O:6])[CH:2]=[CH2:3].N1C=CN=C1.[Si:37](Cl)([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38].O>CN(C)C=O>[CH2:1]([N:4]([C@@H:17]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:18]([N:20]1[CH2:24][CH2:23][C@H:22]([O:25][Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38])[CH2:21]1)=[O:19])[S:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N+:14]([O-:16])=[O:15])(=[O:6])=[O:7])[CH:2]=[CH2:3]
Reactant: C=CCN([C@H](C(=O)N1CC[C@H](O)C1)c1ccccc1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: C=CCN([C@H](C(=O)N1CC[C@H](O[Si](C)(C)C(C)(C)C)C1)c1ccccc1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution N-allyl-N-[2-(3-(S)-hydroxy-pyrrolidin-1-yl)-2-oxo-1-(S)-phenyl-ethyl]-2-nitro-benzenesulfonamide (7.13 g, 16.0 mmol) in anhydrous dimethylformamide (16 cm3) was added imidazole (2.18 g, 32.0 mmol). When the imidazole dissolved tert-butyldimethylsilyl chloride was added and stirred at ambient temperature for 3 hours. The solution was poured into water (200 cm3), extracted with ethyl ether (3×50 cm3), washed with water (2×40 cm3), brine (40 cm3), dried over sodium sulfate, vacuum filtered and the volatile fractions removed in vacuo to a yellow glass (8.73 g, 97.4%) with a positive ion ESI (M+H)+560.3
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([OH:23])[CH:10]([NH2:22])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[CH:5][CH:4]=1.[C:24](=[O:27])([O-])O.[Na+]>C(OCC)(=O)C.O>[F:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([OH:23])[CH:10]([NH:22][C:24](=[O:27])[C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[CH:7][CH:8]=1
Reactant: O=C([O-])O
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62 %

Procedure:
To a solution of (1RS,2RS)-1-(4-fluorophenyl)-1-hydroxy-3-(4-(trifluoromethyl)phenyl)-2-propylamine hydrochloride (150 mg, 0.43 mmol) in ethyl acetate (5 ml) were added 4-trifluorobenzoyl chloride (96 mg, 0.64 mmol) and saturated aqueous sodium hydrogen carbonate (5 ml) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (50 ml) and extracted with ethyl acetate (50 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) and recrystallized from ethyl acetate-hexane to give the title compound (129 mg, 62%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH2:10])[CH3:9])=[CH:4][CH:3]=1.Cl[CH2:12][CH2:13][N:14]([CH2:25][CH2:26]Cl)[S:15]([C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1)(=[O:17])=[O:16].CCN(C(C)C)C(C)C>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:26][CH2:25][N:14]([S:15]([C:18]3[CH:19]=[CH:20][C:21]([CH3:24])=[CH:22][CH:23]=3)(=[O:17])=[O:16])[CH2:13][CH2:12]2)[CH3:9])=[CH:4][CH:3]=1
Reactant: C[C@H](N)c1ccc(Br)cc1
Reactant: Cc1ccc(S(=O)(=O)N(CCCl)CCCl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)N2CCN([C@@H](C)c3ccc(Br)cc3)CC2)cc1
Temperature: 125 °C
Reaction time: 20 h
Yield: 76.4 %

Procedure:
A mixture of (S)-1-(4-bromophenyl)ethanamine (0.36 ml, 2.50 mmol) and N,N-bis(2-chloroethyl)-4-methylbenzenesulfonamide (864 mg, 2.62 mmol) in DIPEA (0.873 ml, 5.0 mmol) was heated at 125° C. and stirred for 20 h. The reaction mixture was cooled to RT then diluted into DCM (30 ml) and washed with Na2CO3 2M in water (40 ml). The aqueous phase was further extracted with DCM (3×20 ml) and the combined organic fractions were dried over Na2SO4, filtered and evaporated to dryness. AcOEt was added in small portions into a hot mixture of the crude in heptane until complete dissolution. The mixture was allowed to cooled to RT during which time precipitation occurred. The mixture was cooled to 0° C. (ice bath) for 30 min then filtered. The solid was washed with heptane, dried under air and finally under high vacuum to yield the title compound (810 mg, 1.91 mmol, 77% yield) as a brownish solid. HPLC: AtRet=1.66 min; LC-MS: m/z 425.4 [M+H]+; 1H NMR (400 MHz, CDCl3): 1.29 (d, J=6.8, 3H), 2.41-2.50 (m, 5H), 2.52-2.61 (m, 2H), 2.93-3.05 (m, 4H), 3.34 (q, J=6.7, 1H), 7.09-7.16 (m, 2H), 7.31-7.37 (m, 2H), 7.39-7.44 (m, 2H), 7.61-7.66 (m, 2H).
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[N:10]=[CH:9][N:8]([CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([OH:19])[CH2:17][OH:18])[C:7]=2[C:6](=[O:20])[N:5]([CH2:21][C:22](=[O:24])[CH3:23])[C:4]1=[O:25])[CH3:2].ClCC(O)C>>[CH2:1]([N:3]1[C:11]2[N:10]=[CH:9][N:8]([CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([OH:19])[CH2:17][OH:18])[C:7]=2[C:6](=[O:20])[N:5]([CH2:21][CH:22]([OH:24])[CH3:23])[C:4]1=[O:25])[CH3:2]
Reactant: CCn1c(=O)n(CC(C)=O)c(=O)c2c1ncn2CCCCC(O)CO
Agent: CC(O)CCl
Product: CCn1c(=O)n(CC(C)O)c(=O)c2c1ncn2CCCCC(O)CO

Procedure:
This compound was prepared starting from Compound 7 by reduction of the oxopropyl group according to the method described in Example 2, or by alkylation of 3-ethyl-7-(5,6-isopropylidenedioxyhexyl)-xanthine with 1-chloro-propan-2-ol according to the procedure as described in Example 1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:22]2[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][C:9]1[C:10](=[O:21])[NH:11][C:12]2[N:13]([N:18]=[CH:19][N:20]=2)[C:14]=1[CH2:15][CH2:16][CH3:17].Cl[CH2:31][O:32][CH3:33].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C>[CH3:31][O:32][CH2:33][N:11]1[C:10](=[O:21])[C:9]([CH2:8][C:7]2[CH:6]=[CH:5][C:4]([C:22]3[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=3)=[CH:3][C:2]=2[F:1])=[C:14]([CH2:15][CH2:16][CH3:17])[N:13]2[N:18]=[CH:19][N:20]=[C:12]12
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)[nH]c2ncnn12
Reactant: COCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n(COC)c2ncnn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 69 %

Procedure:
A mixture of 3′-fluoro-4′-[(5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (0.5 g), chloro(methoxy)methane (0.12 mL), potassium carbonate (0.36 g) and N,N-dimethylformamide (10 mL) was stirred at room temperature for 1 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.38 g, 69%).
Reaction SMILES: C(OC([N:8]1[CH2:15][CH2:14][CH:13]2[CH:10]([N:11]([C:16]([C:18]3[S:22][C:21]([CH3:23])=[N:20][C:19]=3[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[F:30])=[O:17])[CH2:12]2)[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>O1CCOCC1>[CH:10]12[N:11]([C:16]([C:18]3[S:22][C:21]([CH3:23])=[N:20][C:19]=3[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[F:30])=[O:17])[CH2:12][CH:13]1[CH2:14][CH2:15][NH:8][CH2:9]2
Reactant: Cc1nc(-c2ccccc2F)c(C(=O)N2CC3CCN(C(=O)OC(C)(C)C)CC32)s1
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(-c2ccccc2F)c(C(=O)N2CC3CCNCC32)s1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 8-[4-(2-fluoro-phenyl)-2-methyl-thiazole-5-carbonyl]-3,8-diaza-bicyclo[4.2.0]octane-3-carboxylic acid tert-butyl ester in dioxane (8 mL) was added trifluoro acetic acid (3 mL), the reaction mixture was stirred for 16 h at room temperature. The solvent and the excess of trifluoro acetic acid were removed under reduced pressure. The resulting trifluoro acetic acid salt of the title compound was used crude without further purification (54.0 mg, 56%). MS (ESI) mass calcd. for C17H18FN3OS, 331.41; m/z found, 332.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:11][O:10][CH2:9][CH:8]([C:12]3[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=3)[C:6]=2[N:7]=1.[CH2:21]([NH2:23])[CH3:22]>>[Cl:1][C:2]1[N:3]=[C:4]([NH:23][CH2:21][CH3:22])[C:5]2[CH2:11][O:10][CH2:9][CH:8]([C:12]3[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=3)[C:6]=2[N:7]=1
Reactant: CCN
Reactant: N#Cc1ccc(C2COCc3c(Cl)nc(Cl)nc32)cc1
Product: CCNc1nc(Cl)nc2c1COCC2c1ccc(C#N)cc1

Procedure:
4-(2,4-dichloro-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-8-yl)benzonitrile (Preparation AA) was reacted as described in Preparation Xa with ethanamine to give 4-(2-chloro-4-(ethylamino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-8-yl)benzonitrile (Preparation AAa). LC-MS (M+H)+=315.1.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]([F:16])([F:15])[F:14])=[CH:8][C:7]=1[C:17]1[NH:18][N:19]=[CH:20][N:21]=1)=[O:4].[OH-].[Na+].[Cl-].[NH4+]>O1CCOCC1>[F:14][C:13]([F:16])([F:15])[O:12][C:9]1[CH:10]=[CH:11][C:6]2[NH:5][C:3](=[O:4])[CH2:2][N:18]3[C:17](=[N:21][CH:20]=[N:19]3)[C:7]=2[CH:8]=1
Reactant: O=C(CCl)Nc1ccc(OC(F)(F)F)cc1-c1ncn[nH]1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C1Cn2ncnc2-c2cc(OC(F)(F)F)ccc2N1
Temperature: 25 °C
Reaction time: 19 h
Yield: 24.4 %

Procedure:
To a solution of 2-chloro-N-[2-(2H-[1,2,4]triazol-3-yl)-4-trifluoromethoxy-phenyl]-acetamide (3.15 g, 9.82 mmol) in dioxane (100 mL) was added aqueous sodium hydroxide (32%, 2.18 mL, 23.6 mmol) and the reaction mixture was stirred for 19 h at ambient temperature. It was poured onto aqueous ammonium chloride (1M, 50 mL) and the organic solvent was removed by destillation. The resulting suspension was filtered and the solid was washed with ice-cold water (50 mL). Drying in vacuo afforded the title compound (682 mg, 24%) as a light yellow solid. MS: m/e=285.0 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[CH3:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH2:25])=[CH:22][CH:21]=1>N1C=CC=CC=1>[CH3:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH:25][C:2]2[N:3]=[C:4]([N:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)[C:5]3[S:10][CH:9]=[CH:8][C:6]=3[N:7]=2)=[CH:22][CH:21]=1
Reactant: CN1CCN(c2nc(Cl)nc3ccsc23)CC1
Reactant: COc1ccc(CN)cc1
Solvent: c1ccncc1
Product: COc1ccc(CNc2nc(N3CCN(C)CC3)c3sccc3n2)cc1
Temperature: 200 °C

Procedure:
To a solution of 2-chloro-4-(4-methyl-piperazin-1-yl)-thieno[3,2-d]pyrimidine (0.11 g, 0.4 mmol) in pyridine (0.34 mL) in a microwave vial was added 4-methoxybenzylamine (0.55 mL, 4.2 mmol). The reaction mixture was heated to 200° C. in the microwave for 1 h, after which pyridine was removed under reduced pressure. The resultant residue was purified by FCC (2 M NH3 in MeOH/CH2Cl2) to yield (4-methoxy-benzyl)-[4-(4-methyl-piperazin-1-yl)-thieno[3,2-d]pyrimidin-2-yl]-amine. The intermediate was then dissolved in trifluroacetic acid (2.5 mL) and heated at 60° C. for 1.5 h. After concentrating, the residue was purified by reverse-phase chromatography (acidic conditions) to afford the desired product as a TFA salt (30 mg). MS: 250.1. 1H NMR (400 MHz, CD3OD) δ ppm 8.26 (d, J=5.6 Hz, 1H), 7.30 (d, J=5.6 Hz, 1H), 4.65-4.12 (m, 4H), 3.60-3.41 (m, 4H), 2.98 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([OH:14])[C:3]=1[CH2:15][C:16]1([CH3:21])OCCO1.[ClH:22]>>[ClH:22].[CH3:21][C:16]1[NH:1][C:2]2[N:7]=[C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[N:5]=[C:4]([OH:14])[C:3]=2[CH:15]=1
Reactant: CC1(Cc2c(N)nc(-c3ccccc3)nc2O)OCCO1
Agent: Cl
Product: Cc1cc2c(O)nc(-c3ccccc3)nc2[nH]1
Yield: 78 %

Procedure:
A solution of acetal 3 (700 mg, 2.44 mmol) in 1 N HCl (40 mL) was stirred for 2 h at RT. The resulting slurry was filtered yielding the HCl salt 4 as a tan solid (498 mg, 78.0%):
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Cl)=[CH:4][CH:3]=1.[Mg].[CH3:11][C:12]([CH3:14])=[O:13].Cl>CCOCC>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][C:12]([CH3:14])([OH:13])[CH3:11])=[CH:4][CH:3]=1
Reactant: CC(C)=O
Reactant: ClCc1ccc(Cl)cc1
Agent: Cl
Agent: [Mg]
Solvent: CCOCC
Product: CC(C)(O)Cc1ccc(Cl)cc1
Yield: 70 %

Procedure:
A solution of 4-chlorobenzyl chloride (165 g; 1.02 mole) in ether (500 ml) was added dropwise during one hour to magnesium (24.3 g; 1.00 mole) in a three-necked flask equipped with stirrer and reflux condenser. The spontaneous reflux was allowed to continue for another hour and the solution was cooled. Acetone (60.0 g. 1.30 mole) was added dropwise and the solution heated to reflux for three hours. After cooling, the reaction mixture was poured out on ice (500 ml) and concentrated hydrochloric acid (92 ml). The phases were separated. The organic phase was washed with water, dried (Na2SO4) and evaporated in vacuum. The residual oil was fractionated affording 1-(4-chlorophenyl)-2-methyl-2-propanol (b.p. 123°-124° C./12 mm Hg; nD25 =1.5300; 128.5 g, 70% yield).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.C(=O)=O.CC(C)=O.[F:20][CH:21]([P:23](=[O:30])([O:27][CH2:28][CH3:29])[O:24][CH2:25][CH3:26])[F:22].[Br:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36]Br>C1COCC1.CN(P(N(C)C)(N(C)C)=O)C>[Br:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][C:21]([P:23](=[O:30])([O:24][CH2:25][CH3:26])[O:27][CH2:28][CH3:29])([F:22])[F:20]
Reactant: CCOP(=O)(OCC)C(F)F
Reactant: BrCCOCCBr
Agent: O=C=O
Agent: [Li]CCCC
Solvent: CC(C)=O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)C(F)(F)CCOCCBr
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of diisopropylamine (2 eq) in dry THF (1 M) was cooled in an acetone-dry ice bath. To the solution was added n-butyllithium (1.5 M in cyclohexane, 1.6 eq) in dropwised fashion via syringe. The reaction mixture was warmed up in an ice-water bath upon completion of the addition, and stirred for 30 minutes. The reaction mixture was then cooled back down to −78° C. in the dry ice-acetone bath, and was treated with a solution of diethyl difluoromethylphosphonate (1 eq) in HMPA (1:1 v/v) via syringe. The reaction turned dark brown from pale yellow instantly. The stirring was allowed to proceed for an hour. To the above reaction mixture, a cooled solution of 1-bromo-2-(2-bromoethoxy)ethane (3 eq) in THF (0.6 M) was added quickly through a syringe, and the reaction was allowed to stir for another 3 hours before quenching with 1 N HCl. The reaction mixture was warmed to room temperature, and pH was adjusted to <4 with 1 N HCl, and was extracted with ethyl acetate three times. The combined organic phases were washed with brine, dried over anhydrous Na2SO4, and concentrated en vaccuo. The mixture was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-70% EtOAc/Hex followed by reverse phase high performance liquid chromatography (HPLC) with C18 column eluting with a gradient of 20-50% MeCN (0.035% TFA) in H2O (0.05% TFA) to afford the product as a pale yellow oil.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].C1(C)C=CC=CC=1.[CH3:18][N:19]1[C:23]([CH2:24][OH:25])=[N:22][CH:21]=[N:20]1.[Br:26][C:27]1[C:32](Cl)=[N:31][N:30]2[C:34]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[F:43])=[N:35][N:36]=[C:29]2[CH:28]=1>C1COCC1.[Cl-].[NH4+]>[Br:26][C:27]1[C:32]([O:25][CH2:24][C:23]2[N:19]([CH3:18])[N:20]=[CH:21][N:22]=2)=[N:31][N:30]2[C:34]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[F:43])=[N:35][N:36]=[C:29]2[CH:28]=1
Reactant: Cn1ncnc1CO
Reactant: Fc1ccccc1-c1nnc2cc(Br)c(Cl)nn12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cn1ncnc1COc1nn2c(-c3ccccc3F)nnc2cc1Br
Temperature: 0 °C
Reaction time: 3 h
Yield: 51.5 %

Procedure:
A solution of potassium bis(trimethylsilyl)amide in toluene (16.8 ml, 0.5M, 8.4 mmol) was added to a stirred solution of (2-methyl-2H-1,2,4-triazol-3-yl)methanol (0.95 g, 8.4 mmol) in anhydrous THF (30 ml) at room temperature under nitrogen. After 20 min the suspension was cooled to 0° C. and a suspension of 7-bromo-6-chloro-3-(2-fluorophenyl)-1,2,4-triazolo[4,3-b]pyridazine (2.28 g, 6.96 mmol) in anhydrous THF (100 ml) was added dropwise. The mixture was stirred for 3 h at 0° C. then poured into ice-water (400 ml), diluted with saturated aqueous ammonium chloride (100 ml) and extracted with dichloromethane-methanol (9:1, 3×100 ml). The extracts were dried (Na2SO4), filtered and concentrated. Flash column chromatography on silica gel, eluting with 3% methanol-dichloromethane, gave 7-bromo-3-(2-fluorophenyl)-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-1,2,4-triazolo[4,3-b]pyridazine (1.45 g, 52%) as a yellow solid; 1H NMR (360 MHz, CDCl3) δ 3.95 (3H, s), 5.54 (2H, s), 7.28 (1H, dd, J=10 and 10 Hz), 7.37 (1H, ddd, J=8, 8 and 1 Hz), 7.57-7.63 (1H, m), 7.86 (1H, ddd, J=8, 8 and 2 Hz), 7.90 (1H, s), 8.41 (1H, s); MS (ES+) m/e 404/406 [MH]+.
Reaction SMILES: C(C1[N:13]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23]([NH:25][S:26]([C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=3)(=[O:28])=[O:27])=[O:24])=[CH:16][CH:15]=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)C.[C:36]([CH2:40][C:41](Cl)=O)([CH3:39])([CH3:38])[CH3:37]>>[CH3:12][C:8]1[N:7]=[C:6]2[N:13]([C:14]3[CH:15]=[CH:16][C:17]([CH2:20][CH2:21][NH:22][C:23]([NH:25][S:26]([C:29]4[CH:30]=[CH:31][C:32]([CH3:35])=[CH:33][CH:34]=4)(=[O:27])=[O:28])=[O:24])=[CH:18][CH:19]=3)[C:41]([CH2:40][C:36]([CH3:37])([CH3:38])[CH3:39])=[N:4][C:5]2=[C:10]([CH3:11])[CH:9]=1
Reactant: CC(C)(C)CC(=O)Cl
Reactant: CCc1nc2c(C)cc(C)nc2n1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(C)cc2)cc1
Product: Cc1ccc(S(=O)(=O)NC(=O)NCCc2ccc(-n3c(CC(C)(C)C)nc4c(C)cc(C)nc43)cc2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 5 of Example 1 from 2-{4-[(3-amino-4,6-dimethyl-2-pyridinyl)amino]phenyl]ethanol (step 4 of Example 1) and tert-butylacetyl chloride.
Reaction SMILES: CC(=NO)C(C)=NO.[BH4-].[Na+].[CH2:11]([O:18][C:19]1[CH:32]=[CH:31][C:22]([CH:23]=[C:24]2[S:28][C:27](=[O:29])[NH:26][C:25]2=[O:30])=[CH:21][CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(O)(=O)C>O.[OH-].[Na+].C1COCC1.CN(C=O)C>[CH2:11]([O:18][C:19]1[CH:32]=[CH:31][C:22]([CH2:23][CH:24]2[S:28][C:27](=[O:29])[NH:26][C:25]2=[O:30])=[CH:21][CH:20]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C1NC(=O)C(=Cc2ccc(OCc3ccccc3)cc2)S1
Agent: CC(=NO)C(C)=NO
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: O=C1NC(=O)C(Cc2ccc(OCc3ccccc3)cc2)S1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To the suspension containing CoCl2.6H2O (4.49 mg, 0.016 mmol) and dimethylglyoxime (74.54 mg, 0.64 mmol) in 10 ml of water, 4 drops of 1.0N NaOH and NaBH4 (417.1 mg, 10.85 mmol) were subsequently added. The mixture was cooled to 0° C., and 5-(4-(benzyloxy)benzylidene)thiazolidine-2,4-dione (1 g, 3.27 mmol) in 15 ml of THF-DMF (2:1) was added thereto over 20 minutes. The mixture was stirred at room temperature for 18 hours, to which acetic acid was then added until the pH thereof reached about 6. The mixture was diluted with water and extracted with ethyl acetate and water. The organic layer was washed with water several times, dried with anhydrous magnesium sulfate, filtered and solvent-evaporated. The residual oil was chromatographed on silica gel to afford 5-(4-(benzyloxy)benzyl)thiazolidine-2,4-dione (Derivative 116 of the above formula) as white solid (0.8 g, yield: 79%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[N:12]=[C:11]([C:13]3[S:14][CH:15]=[CH:16][N:17]=3)[N:10]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])[N:9]=2)[CH:3]=1.[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>C(O)CO.O1CCOCC1.[Cl-].[Na+].O.[Cu-]=O>[F:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][N:10]1[C:11]([C:13]2[S:14][CH:15]=[CH:16][N:17]=2)=[N:12][C:8]([C:4]2[CH:3]=[C:2]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[CH:7]=[CH:6][N:5]=2)=[N:9]1
Reactant: Fc1ccccc1Cn1nc(-c2cc(Br)ccn2)nc1-c1nccs1
Reactant: C1COCCN1
Agent: O=[Cu-]
Agent: [Cl-]
Agent: [Na+]
Solvent: OCCO
Solvent: C1COCCO1
Solvent: O
Product: Fc1ccccc1Cn1nc(-c2cc(N3CCOCC3)ccn2)nc1-c1nccs1
Temperature: 100 °C
Yield: 79 %

Procedure:
To a stirring suspension of 2-(3-(4-bromopyridin-2-yl)-1-(2-fluorobenzyl)-1H-1,2,4-triazol-5-yl)thiazole (I-36, 1 eq) and copper(I) oxide (1 eq) in ethylene glycol-dioxane (approx. 4:1) in a sealed tube is added morpholine (30 eq). The resultant reaction mixture was heated at 100° C. for 12 hr. The reaction was cooled to room temperature and treated with brine and then extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, concentrated and purified using SiO2 chromatography (methylene chloride/acetonitrile/methanol) to afford 4-(2-(1-(2-fluorobenzyl)-5-(thiazol-2-yl)-1H-1,2,4-triazol-3-yl)pyridin-4-yl)morpholine as a solid in 79% yield.