Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][C:3]=1[CH2:9]O.S(Cl)([Cl:13])=O>>[Cl:8][C:6]1[CH:7]=[C:2]([Cl:1])[C:3]([CH2:9][Cl:13])=[CH:4][N:5]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cnc(Cl)cc1Cl
Product: ClCc1cnc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
(4,6-Dichloro-pyridin-3-yl)-methanol (2.21 g, 12.41 mmol) is cooled under an atmosphere of argon to 0° C. Thionyl chloride (8 ml) is carefully added. After 5 minutes at 0° C., the solution is heated to reflux. After 10 minutes, TLC analysis indicated complete conversion of the starting material. After cooling to RT, excess thionyl chloride is removed via a membrane pump. The remaining oil is dissolved in EtOAc. The solution is poured into a concentrated aqueous solution of NaHCO3. The organic layer is separated and washed twice with a concentrated aqueous solution of NaCl. After drying over Na2SO4, the organic solvent is removed to afford the title compound of adequate purity for immediate further use. 1H NMR (CDCl3, 400 MHz): δ 4.65 (s, 2H), 7.42 (s, 1H), 8.44 (s,1H). ES+−MS: 195, 197, 199 (3 Cl) [M+H]+.
Reaction SMILES: C([N:8]1[C:17](=[O:18])[C:16]([CH3:19])=[C:11]2[S:12][CH2:13][CH2:14][CH2:15][N:10]2[C:9]1=[O:20])C1C=CC=CC=1.B(Br)(Br)Br.CO>C1(C)C=CC=CC=1>[CH3:19][C:16]1[C:17](=[O:18])[NH:8][C:9](=[O:20])[N:10]2[CH2:15][CH2:14][CH2:13][S:12][C:11]=12
Reactant: Cc1c2n(c(=O)n(Cc3ccccc3)c1=O)CCCS2
Agent: BrB(Br)Br
Solvent: Cc1ccccc1
Solvent: CO
Product: Cc1c2n(c(=O)[nH]c1=O)CCCS2
Reaction time: 0.5 h

Procedure:
To a solution of 7.21 g (25 mmol) of 7-benzyl-9-methyl-3,4-dihydro-2H,6H-pyrimido[6,1-b][1,3]thiazine-6,8(7H)-dione in 200 ml of toluene, 12.5 g (50 mmol) of boron tribromide was added under ice cooling conditions, followed by refluxing for 16 hours. After the reaction mixture was cooled, 50 ml of methanol was added, followed by stirring for 30 minutes. After this mixture was concentrated to dryness, methanol-diethyl ether was added to the residue. The resulting precipitate was collected by filtration, washed with diethyl ether and dried to yield 3.97 g (80.1%, light white crystal) of the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:28][CH3:29])[C:12]([NH:17][C@@H:18]2C3C(=CC=CC=3)[CH2:20][C@@H:19]2[OH:27])=[N:13][C:14]=1[CH2:15][CH3:16].BrC1N=C(CC)C(N[C@H]2[C@H](O)C[N:42]([C:46]([O:48][CH2:49][C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)=[O:47])[CH2:41]2)=NC=1CC>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:28][CH3:29])[C:12]([NH:17][C@H:18]2[C@H:19]([OH:27])[CH2:20][N:42]([C:46]([O:48][CH2:49][C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)=[O:47])[CH2:41]2)=[N:13][C:14]=1[CH2:15][CH3:16]
Reactant: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@@H]1c2ccccc2C[C@@H]1O
Reactant: CCc1nc(N[C@@H]2CN(C(=O)OCc3ccccc3)C[C@H]2O)c(CC)nc1Br
Product: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@@H]1CN(C(=O)OCc2ccccc2)C[C@H]1O

Procedure:
Following the procedure for the preparation of (1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol but substituting benzyl(trans)-3-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]-4-hydroxypyrrolidine-1-carboxylate and making non-critical variations provided the title compound as a oil: 1H NMR (300 MHz, CDCl3) δ) 7.49–7.11, 5.97, 5.17, 4.78, 4.67, 4.33–4.26, 4.16–3.96, 3.46, 2.69, 2.49, 1.46–1.24, 1.14; HRMS (FAB) calcd for C26H28Cl2N4O3+H 515.1616, found 515.1606.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39]O)=[CH:33][C:32]=2[CH3:41])=[C:28]([CH:42]([CH3:44])[CH3:43])[NH:27][N:26]=1)(=O)C.[NH2:45][C:46]([CH3:51])([CH2:49][OH:50])[CH2:47][OH:48].NC(C)(C)CO>>[C@@H:6]1([O:24][C:25]2[C:29]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][NH:45][C:46]([CH2:49][OH:50])([CH3:51])[CH2:47][OH:48])=[CH:33][C:32]=3[CH3:41])=[C:28]([CH:42]([CH3:43])[CH3:44])[NH:27][N:26]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: CC(N)(CO)CO
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCO)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CC(C)(N)CO
Product: Cc1cc(OCCNC(C)(CO)CO)ccc1Cc1c(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)n[nH]c1C(C)C

Procedure:
The title compound was prepared in a similar manner to that described in Example 57 using 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(2-hydroxyethoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazole and 2-amino-2-methyl-1,3-propanediol instead of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-hydroxypropoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazole and 2-amino-2-methyl-1-propanol, respectively.
Reaction SMILES: [CH:1](OCC)=[O:2].[NH:6]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1>>[CH:1]([N:6]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:2]
Reactant: C1CCCNCC1
Reactant: CCOC=O
Product: O=CN1CCCCCC1
Reaction time: 8 h
Yield: 84 %

Procedure:
Ethyl formate (22.2 G, 0.3M) was added dropwise under nitrogen to hexahydro-1H-azepine (19.8 G, 0.2M) in such a way that a gentle reflux is maintained during the addition. The reaction mixture was then allowed to stir overnight. The volatile materials were evaporated at room temperature and ~20 mm. The residue was distilled in vacuo to give 1-(Formyl)-Hexahydro-1H-Azepine (bp. 56°-8°/3-4 mm; 84%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:14]([F:15])=[CH:13][C:12]([NH2:16])=[C:11]([F:17])[CH:10]=1.C(N(CC)CC)C.[F:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH:37]=[CH:36][CH:35]=[C:34]([C:38](Cl)=[O:39])[C:33]2=[O:41])=[CH:28][CH:27]=1>C1COCC1>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:14]([F:15])=[CH:13][C:12]([NH:16][C:38]([C:34]2[C:33](=[O:41])[N:32]([C:29]3[CH:28]=[CH:27][C:26]([F:25])=[CH:31][CH:30]=3)[CH:37]=[CH:36][CH:35]=2)=[O:39])=[C:11]([F:17])[CH:10]=1
Reactant: O=C(Cl)c1cccn(-c2ccc(F)cc2)c1=O
Reactant: Nc1cc(F)c(Oc2ccncc2Br)cc1F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1cc(F)c(Oc2ccncc2Br)cc1F)c1cccn(-c2ccc(F)cc2)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.2 %

Procedure:
A solution of Example A2 (0.100 g, 0.332 mmol) in THF (1 mL) was treated with triethylamine (0.069 ml, 0.498 mmol) and a suspension of 1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carbonyl chloride (0.125 g, 0.498 mmol) in THF (2 mL). The mixture was blanketed with argon and stirred overnight at room temperature. The solids were removed via filtration, rinsed with THF and the filtrate was concentrated to dryness. The crude material was purified by silica gel chromatography (10-100% EtOAc/Hex) to afford N-(4-(3-bromopyridin-4-yloxy)-2,5-difluorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (122 mg, 71% yield) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 12.45 (s, 1H); 8.74 (s, 1H); 8.58 (m, 2H); 8.38 (d, J=5.6 Hz, 1H); 8.15 (dd, J=6.6, 2.2 Hz, 1H); 7.67 (dd, J=11.0, 7.3 Hz, 1H); 7.60 (dd, J=8.8, 4.9 Hz, 2H); 7.41 (t, J=8.7 Hz, 2H); 6.89 (d, J=5.6 Hz, 1H); 6.74 (t, J=7.0 Hz, 1H); MS (ESI) m/z: 516.0, 518.0 (M+H+).
Reaction SMILES: [I-].C[S+](C)C.[Li][CH2:7]CCC.[F:11][C@H:12]1[C@@H:16]2[O:17][Si:18]([CH:32]([CH3:34])[CH3:33])([CH:29]([CH3:31])[CH3:30])[O:19][Si:20]([CH:26]([CH3:28])[CH3:27])([CH:23]([CH3:25])[CH3:24])[O:21][CH2:22][C@H:15]2[C@H:14]2[O:35][C@@H:13]12>C1COCC1>[F:11][C@H:12]1[C@@H:22]2[O:21][Si:20]([CH:23]([CH3:25])[CH3:24])([CH:26]([CH3:28])[CH3:27])[O:19][Si:18]([CH:29]([CH3:31])[CH3:30])([CH:32]([CH3:33])[CH3:34])[O:17][CH2:16][C@H:15]2[C:14](=[CH2:7])[C@H:13]1[OH:35]
Reactant: CC(C)[Si]1(C(C)C)OC[C@H]2[C@H]3O[C@H]3[C@@H](F)[C@@H]2O[Si](C(C)C)(C(C)C)O1
Reactant: [Li]CCCC
Agent: C[S+](C)C
Agent: [I-]
Solvent: C1CCOC1
Product: C=C1[C@@H](O)[C@@H](F)[C@@H]2O[Si](C(C)C)(C(C)C)O[Si](C(C)C)(C(C)C)OC[C@@H]12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 81.3 %

Procedure:
To a suspension of trimethylsulfonium iodide (30.5 g, 138.4 mmol) in THF (150 mL) at −20° C., n-BuLi (2.5 M solution in hexane) (55.3 mL, 138.4 mmol) was added. After 30 min, the epoxide 13 (6.0 g, 15.5 mmol) in THF (30 mL) was introduced at −20° C. and the reaction mixture allowed slowly to warm to 0° C. over 1 h. The mixture was then stirred at ambient temperature for 2 h, quenched with water and then extracted with ethyl acetate (3×200 ml). The combined organic layer was washed with brine, dried over Na2SO4 and concentrated reduced under pressure. The residues were purified on silica gel column chromatography (10% EtOAc/Hexane) to give the allylic alcohol 14 (5.1 g, 81%) as oil. [α]26D −0.54° (c 0.5, MeOH); 1H NMR (500 MHz, CDCl3) δ 0.93-1.12 (m, 28H), 1.99 (dd, J=2.5, 5.5 Hz, 1H, OH), 2.58 (m, 1H), 3.85 (dd, J=9.5, 11.5 Hz, 1H), 4.08 (dd, J=5.0, 12.0 Hz, 1H), 4.44 (m, 1H) 4.48 (m, 1H), 4.73 (dt, J=5.0, 9.0 Hz, 1H), 5.09 (s, 1H), 5.35-5.34 (m, 1H); 19F NMR (500 MHz, CDCl3) δ −203.0 (m); 13C NMR (125 MHz, CDCl3) δ 12.5, 12.9, 13.4, 13.5, 17.0, 17.03, 17.41, 17.46, 17.5, 17.6, 48.5, 50.2, 65.5, 72.6, 97.4 (d, J=185.0 Hz), 111.8, 146.8; HR-MS Calcd. For (C19H37FO4Si2+H)+ 405.2214. found 405.2202.
Reaction SMILES: C(=O)([O-])[O-].[Ca+2].[NH2:6][C:7]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10].Cl.[C:20](Cl)(Cl)=[S:21]>O.ClC(Cl)Cl>[OH:18][C:15]1[CH:16]=[CH:17][C:7]([N:6]=[C:20]=[S:21])=[C:8]([CH:14]=1)[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: S=C(Cl)Cl
Reactant: CCOC(=O)c1cc(O)ccc1N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCOC(=O)c1cc(O)ccc1N=C=S
Temperature: 10 °C
Reaction time: 0.25 h
Yield: 67.1 %

Procedure:
To a stirred mixture of 5 parts of calcium carbonate, 18.75 parts of trichloromethane and 12.5 parts of water were added 3.6 parts of ethyl 2-amino-5-hydroxybenzoate. 3 Parts of concentrate hydrochloric acid and 10 parts of water were added and the whole was stirred for 15 minutes under nitrogen atmosphere. After cooling in an ice bath at 10° C., 2.6 parts of carbonothioic dichloride were added dropwise, during a period of 20 minutes, at 10°-15° C. The whole was allowed to reach room temperature and stirring was continued for 2 hours. 300 Parts of trichloromethane and 200 parts of water were added. The organic layer was separated, washed with a hydrochloric acid solution 1N and with a sodium hydrogen carbonate solution 10%, dried, filtered and evaporated. The residue was crystallized from 45 parts of benzene. The product was filtered off and dried, yielding 3.0 parts (67.1%) of ethyl 5-hydroxy-2-isothiocyanatobenzoate (18).
Reaction SMILES: [C:1]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:10]=1[NH:16][C:17]([C:19]1[S:23][C:22]([NH2:24])=[N:21][CH:20]=1)=[O:18])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[Cl:25][C:26]1[CH:31]=[C:30](Cl)[N:29]=[C:28]([CH3:33])[N:27]=1.Cl>C1COCC1>[C:1]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:10]=1[NH:16][C:17]([C:19]1[S:23][C:22]([NH:24][C:30]2[CH:31]=[C:26]([Cl:25])[N:27]=[C:28]([CH3:33])[N:29]=2)=[N:21][CH:20]=1)=[O:18])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)C(=O)OCc1cccc(Cl)c1NC(=O)c1cnc(N)s1
Reactant: Cc1nc(Cl)cc(Cl)n1
Agent: Cl
Solvent: C1CCOC1
Product: Cc1nc(Cl)cc(Nc2ncc(C(=O)Nc3c(Cl)cccc3COC(=O)C(C)(C)C)s2)n1
Temperature: 18 °C
Reaction time: 1.5 h
Yield: 65.7 %

Procedure:
To a solution of compound 10a (2.21 g, 6 mmol) and 4,6-dichloro-2-methylpyrimidine (11a, 1.18 g, 7.2 mmol) in THF (30 mL) was added a solution of NaOBu-t in THF (30% w/w, 7.4 mL) at temperature between 10° C. to 18° C. The reaction mixture was stirred at 18° C. for 1.5 h. It was then cooled to 0° C. A solution of 1N HCl (14.0 mL) was added. The mixture then was partitioned between EtOAc and H2O (1:1, 200 mL). The organic phase was separated, and the aqueous layer was extracted with EtOAc (100 mL). The combined extracts were concentrated in vacuo. The residue was subjected to a flash column using 50% EtOAc in hexane to give crude compound 12a which was triturated with 10% EtOAc in hexane to give compound 12a (1.95 g, 66% yield). 1H NMR (500 MHz, CDCl3) δ 1.19 (s, 9H), 2.73 (s, 3H), 5.12 (s, 2H), 6.93 (s, 1H), 7.21-7.49 (m, 3H), 8.21 (s, 1H), 8.98 (s, 1H).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH2:7])[CH3:3].C([O-])([O-])=O.[K+].[K+].[Br:15][CH2:16][C:17](Br)=[O:18].O>C(Cl)Cl>[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH:7][C:17](=[O:18])[CH2:16][Br:15])[CH3:3]
Reactant: CCOC(=O)CN
Reactant: O=C(Br)CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)CNC(=O)CBr
Yield: 37.5 %

Procedure:
To a mixture of glycine ethyl ester hydrochloride (2.0 g, 14.3 mmol) and K2CO3 (2.1 g, 15.2 mmol) in CH2Cl2 (35 ml) cooled at 0-5° C. bromoacetyl bromide (1.36 ml, 15.6 mmol) was added dropwise. The suspension was stirred at room temperature and after 3 h H2O (20 ml) was added. The phases were separated and the organic one was washed with a saturated solution of NaHCO3 (20 ml) and H2O (20 ml) and dried over Na2SO4. The solvent was evaporated obtaining 39 as white solid (1.2 g, 40%). ESI+MS: calcd for C6H10BrNO3: 224.06; found: 224.0 and 226.0 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:13](=[O:19])[C:14]([N:16]([CH3:18])[CH3:17])=[O:15])=[CH:8][N:9]2[CH3:12])=[CH:5][C:4]=1[C:20]([CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)=[O:21].[F:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33]Br)=[CH:31][CH:30]=1>CCO>[F:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33][N:25]2[CH2:24][CH2:23][CH:22]([C:20]([C:4]3[CH:5]=[C:6]4[C:10](=[CH:11][C:3]=3[O:2][CH3:1])[N:9]([CH3:12])[CH:8]=[C:7]4[C:13](=[O:19])[C:14]([N:16]([CH3:18])[CH3:17])=[O:15])=[O:21])[CH2:27][CH2:26]2)=[CH:31][CH:30]=1
Reactant: COc1cc2c(cc1C(=O)C1CCNCC1)c(C(=O)C(=O)N(C)C)cn2C
Reactant: Fc1ccc(CBr)cc1
Solvent: CCO
Product: COc1cc2c(cc1C(=O)C1CCN(Cc3ccc(F)cc3)CC1)c(C(=O)C(=O)N(C)C)cn2C
Temperature: 25 °C
Yield: 71.1 %

Procedure:
144 mg of 2-[6-Methoxy-1-methyl-5-(piperidine-4-carbonyl)-1H-indol-3-yl]-N,N-dimethyl-2-oxo-acetamide (0.39 mMol) is dissolved in 10 ml EtOH followed by the addition of 0.05 ml of 4-fluorobenzyl bromide (0.4 mMol). The reaction mixture is stirred at room temperature over night. After removing the solvent, residue is taken up in CH2Cl2 and washed with H2O, brine, dried over anhydrous sodium sulfate and concentrated. Silica gel column separation (2% MeOH in CH2Cl2) then gives 133 mg of product.
Reaction SMILES: [O-]CC.[Na+].[CH2:5]([O:12][C:13]1[CH:18]=[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:16]([C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:15][C:14]=1[C:31](=[O:33])[CH3:32])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:34](OCC)(=[O:40])[C:35]([O:37][CH2:38][CH3:39])=[O:36].Cl>C(O)C.O>[CH2:38]([O:37][C:35](=[O:36])[C:34]([OH:40])=[CH:32][C:31]([C:14]1[CH:15]=[C:16]([C:27]([CH3:29])([CH3:28])[CH3:30])[C:17]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[CH:18][C:13]=1[O:12][CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:33])[CH3:39]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)c1cc(C(C)(C)C)c(OCc2ccccc2)cc1OCc1ccccc1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(O)=CC(=O)c1cc(C(C)(C)C)c(OCc2ccccc2)cc1OCc1ccccc1
Yield: 93.1 %

Procedure:
Sodium ethoxide (2.8 g, 41 mmol) was added to a suspension of the 1-(2,4-bis-benzyloxy-5-tert-butyl-phenyl)-ethanone (7.8 g, 20 mmol) in ethanol (40 ml). Diethyl oxalate (4 ml, 29.5 mmol) was added and the resulting suspension heated under reflux for ˜2 hrs. to give a pale red solution. The solution was allowed to cool and poured into water (200 ml), the mixture was acidified with hydrochloric acid (50 ml, 1M) and extracted with dichloromethane (150 ml). The extracts were washed with water (2×200 ml) and saturated aqueous sodium chloride solution (100 ml). The solution was dried over anhydrous sodium sulphate and concentrated to a yellow gum. Trituration with hexane gave a yellow solid. Solids were removed by filtration and washed with hexane and dried in vacuo (40° C.), to give 4-(2,4-Bis-benzyloxy-5-tert-butyl-phenyl)-2-hydroxy-4-oxo-but-2-enoic acid ethyl ester as a yellow powder (9.1 g, 93%).
Reaction SMILES: C(OC(=O)[NH:10][CH:11]([C:13]1[N:14]=[C:15]2[CH:20]=[CH:19][CH:18]=[N:17][N:16]2[C:21]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1)[CH3:12])C1C=CC=CC=1.CSC>C(O)(C(F)(F)F)=O>[N:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:21]1[N:16]2[N:17]=[CH:18][CH:19]=[CH:20][C:15]2=[N:14][C:13]=1[CH:11]([NH2:10])[CH3:12]
Reactant: CC(NC(=O)OCc1ccccc1)c1nc2cccnn2c1-c1ccccn1
Solvent: O=C(O)C(F)(F)F
Solvent: CSC
Product: CC(N)c1nc2cccnn2c1-c1ccccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 117.5 %

Procedure:
The mixture of [1-(3-pyridin-2-yl-imidazo[1,2-b]pyridazin-2-yl)-ethyl]-carbamic acid benzyl ester (600 mg, 1.6 mmol) and dimethylsulfide (1.2 mL) in TFA (7.5 mL)) was stirred at rt overnight. The mixture was concentrated in vacuo. The residue was dissolved in EtOAc. The organic layer was washed with satd. sodium bicarbonate solution, dried over sodium sulfate, filtered and concentrated in vacuo to provide 1-(3-pyridin-2-yl-imidazo[1,2-b]pyridazin-2-yl)-ethylamine (450 mg): LC-MS (ESI) m/z 240.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:10]1[C:11]([CH:16]=[C:17](O)[C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[N:12][CH:13]=[CH:14][CH:15]=1)=[O:9].[N:25]([CH2:28][C:29]1[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[C:31]([C:39]([F:42])([F:41])[F:40])[CH:30]=1)=[N+:26]=[N-:27].C(=O)([O-])[O-].[K+].[K+].O>C(O)(C)C>[F:36][C:35]([F:37])([F:38])[C:33]1[CH:34]=[C:29]([CH:30]=[C:31]([C:39]([F:42])([F:40])[F:41])[CH:32]=1)[CH2:28][N:25]1[C:17]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[C:16]([C:11]2[C:10]([C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])=[O:9])=[CH:15][CH:14]=[CH:13][N:12]=2)[N:27]=[N:26]1
Reactant: O=C(c1ccccc1Cl)c1cccnc1C=C(O)c1ccncc1
Reactant: [N-]=[N+]=NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)O
Product: O=C(c1ccccc1Cl)c1cccnc1-c1nnn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1-c1ccncc1
Temperature: 20 °C
Reaction time: 16 h

Procedure:
The reaction can also be carried out using (2-chlorophenyl)-[2-(2-hydroxy-2-pyridin-4-yl-vinyl)pyridin-3-yl]methanone (30.0 g; 72.3 mmol; 1.0 equiv) in isopropanol (225 mL). 1-azidomethyl-3,5-bistrifluoromethylbenzene (20.43 g; 76 mmol; 1.05 equiv) and potassium carbonate (5.0 g; 36.2 mmol; 0.5 equiv) are added, and the reaction mixture is heated to reflux for 21-24 hours. Cool the reaction mixture to 20° C., add water (120 mL), and stir for approximately 16 hours. Filter, wash with 120 mL isopropanol/water (1:1 v/v), and dry under reduced pressure at 50° C. to yield the title compound, which may be recrystallized as described above.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:11])[CH3:10].[CH:12]1([N:15]=[C:16]=[O:17])[CH2:14][CH2:13]1>O1CCCC1>[CH:12]1([NH:15][C:16](=[O:17])[N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[C:9](=[O:11])[CH3:10])[CH2:14][CH2:13]1
Reactant: O=C=NC1CC1
Reactant: CC(=O)Nc1ccccc1F
Solvent: C1CCOC1
Product: CC(=O)N(C(=O)NC1CC1)c1ccccc1F
Temperature: 100 °C

Procedure:
A mixture of 5.8 g of 3A, 50 ml of tetrahydrofuran and 5.0 g of 1A was heated in a sealed glass cylinder for 12 hours at 100° C. Then the solvent was evaporated, and the residue was recrystallized from ether/hexane to give 3, as a white solid, m.p.: 43°-45° C.
Reaction SMILES: [Cu]C#N.C[Li].B(F)(F)F.CCOCC.[OH:15][C@H:16]1[C@H:20]([CH3:21])[CH2:19][C@@H:18]([C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[CH2:17]1>C1COCC1>[OH:15][C@@H:16]1[C@@H:20]([CH3:21])[CH2:19][C@H:18]([C:22]([O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[O:23])[CH2:17]1
Reactant: C[C@@H]1C[C@@H](C(=O)OCc2ccccc2)C[C@H]1O
Agent: N#C[Cu]
Agent: FB(F)F
Agent: [Li]C
Solvent: CCOCC
Solvent: C1CCOC1
Product: C[C@H]1C[C@H](C(=O)OCc2ccccc2)C[C@@H]1O
Temperature: -78 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
A 50 mL three neck round bottom flask equipped with a magnetic stirrer and two addition funnels, which had been flame dried under argon, charged with COPPER(I) CYANIDE (226 mg, 2.52 mmol), and evacuated under high vacuum overnight, was charged with THF (5 mL), and the suspension was cooled to −78° C. The mixture was treated with the dropwise addition of methyllithium (1.6 M in diethylether) (3.15 mL, 5.04 mmol). When the addition was complete, the cooling bath was removed, and the suspension was allowed to slowly warm, until a homogeneous solution was observed. The solution was cooled to −78° C., then treated with the slow dropwise addition of a solution of trans-benzyl 6-oxabicyclo[3.1.0]hexane-3-carboxylate (250 mg, 1.145 mmol) in THF (5 mL) followed by boron trifluoride etherate (0.581 mL, 4.58 mmol) in one portion. The mixture was stirred at −78° C. for 2 h, at which point a precipitate was observed, and the color quickly changed to bright yellow. The reaction was allowed to slowly come to room temperature, during which the color began to turn grey. The reaction was quenched with 30 mL of a 9:1 aqueous solution of saturated NH4Cl and 10% NH4OH, and the mixture was stirred for 30 minutes. The resulting deep blue mixture was filtered to remove a small amount of precipitate, and extracted 3× with ethyl acetate. The combined organic phases were washed with water followed by brine, then dried over sodium sulfate and concentrated in-vacuo. The residue was purified over a 2×15 cm silica gel column, eluting with ethyl acetate/hexanes (25%-50% EtOAc), to yield a racemic mixture of (1R,3R,4R)-benzyl 3-hydroxy-4-methylcyclopentanecarboxylate and (1S,3S,4S)-benzyl 3-hydroxy-4-methylcyclopentanecarboxylate (225 mg, 0.480 mmol, 84% yield) as a colorless oil.
Reaction SMILES: C(NC(C)CNC(=S)SC)(=O)C.[C:13]([NH:16][CH2:17][CH:18]([NH:20][C:21](=[S:24])SC)[CH3:19])(=[O:15])[CH3:14].[N-:25]=[N+:26]=[N-:27].[Na+]>O1CCOCC1.O>[C:13]([NH:16][CH2:17][CH:18]([N:20]1[C:21]([SH:24])=[N:27][N:26]=[N:25]1)[CH3:19])(=[O:15])[CH3:14]
Reactant: CSC(=S)NC(C)CNC(C)=O
Reactant: [N-]=[N+]=[N-]
Agent: CSC(=S)NCC(C)NC(C)=O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)NCC(C)n1nnnc1S
Yield: 27 %

Procedure:
A mixture of methyl N-(2-acetamidopropyl)dithiocarbamate and methyl N-[1-(acetamidomethyl)ethyl]dithiocarbamate (100 g) in dioxane (300 ml) and a solution of sodium azide (41 g) in water (270 ml) were stirred for 4.5 hours under reflux. The reaction mixture was concentrated to half volume under reduced pressure, washed with diethyl ether and acidified with concentrated hydrochloric acid. The resulting precipitate was collected by filtration and washed with diethyl ether to give pale yellow powder of 1-[1-(acetamidomethyl)ethyl]-1H-tetrazole-5-thiol (26.32 g), mp 176° to 178° C.