Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([CH3:14])=[N:4][C:5]([N:8]2[CH:12]=[C:11]([CH3:13])[N:10]=[N:9]2)=[CH:6][CH:7]=1.[F:15][C:16]1[CH:17]=[C:18]([N:31]2[CH2:35][C@H:34]([CH2:36][N:37]3[CH:41]=[CH:40][N:39]=[N:38]3)[O:33][C:32]2=[O:42])[CH:19]=[CH:20][C:21]=1B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O.C1(P([Pd-4](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)C=CC=CC=1>[F:15][C:16]1[CH:17]=[C:18]([N:31]2[CH2:35][C@H:34]([CH2:36][N:37]3[CH:41]=[CH:40][N:39]=[N:38]3)[O:33][C:32]2=[O:42])[CH:19]=[CH:20][C:21]=1[C:2]1[C:3]([CH3:14])=[N:4][C:5]([N:8]2[CH:12]=[C:11]([CH3:13])[N:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: Cc1cn(-c2ccc(Br)c(C)n2)nn1
Reactant: CC1(C)OB(c2ccc(N3C[C@H](Cn4ccnn4)OC3=O)cc2F)OC1(C)C
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd-4]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cn(-c2ccc(-c3ccc(N4C[C@H](Cn5ccnn5)OC4=O)cc3F)c(C)n2)nn1
Temperature: 80 °C

Procedure:
3-Bromo-2-methyl-6-(4-methyl-1H-1,2,3-triazol-1-yl)pyridine (196 mg, 0.773 mmol), (5R)-3-[3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one (300 mg, 0.773 mmol), potassium carbonate (320 mg, 2.31 mmol), and tetrakis(triphenylphosphino) palladium(0) (89 mg, 0.077 mmol) were combined and suspended in DMF (3 ml) and water (0.3 ml). The mixture was heated at 80° C. for 2 hours, then diluted with water to 7 ml. The solids were collected, rinsed with water and resuspended in warm DMSO (3 ml). The suspension was diluted with dichloromethane (5 ml) and ether (4 ml). The solid was collected, rinsed with ether and methanol, and dried in vacuo to give the pure product as a white solid, 110 mg.
Reaction SMILES: [C:1]([O:7][CH2:8][CH:9]([CH2:14][O:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])OCOC)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[C:22]([O:25][C:26](=[O:28])[CH3:27])(=[O:24])C.B(F)(F)F.CCOCC>C(Cl)Cl>[C:1]([O:7][CH2:8][CH:9]([CH2:14][O:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])[O:24][CH2:22][O:25][C:26](=[O:28])[CH3:27])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(=O)OC(C)=O
Reactant: COCOC(COC(=O)C(C)(C)C)COC(=O)C(C)(C)C
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: CC(=O)OCOC(COC(=O)C(C)(C)C)COC(=O)C(C)(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
50 g of 1,3-dipivaloyl-2-methoxymethyl glycerol, 150 ml of methylene chloride, and 17 ml of acetic anhydride was cooled to about -5° C. Then 0.3 ml of boron trifluoride etherate was added and the mixture was stirred for an additional 1 hr at about 0° C. then allowed to warm to 25° C. over an additional 1.5 hr. After this period, 100 ml saturated aqueous Na2Cl3 was added to the mixture followed by 100 ml CH2Cl2. After vigorous stirring for 5 min, the organic layer was separated and washed once with 100 ml H2O, once with aqueous NaCl, dried over anhydrous magnesium sulfate and concentrated in vacuo to afford 1,3-dipivaloyl-2-acetoxymethyl glycerol as a faintly colored oil.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:5][CH:4]([C:14]([OH:16])=O)[CH2:3]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:29]([NH2:32])[CH2:30][CH3:31]>C(#N)C>[O:1]=[C:2]1[N:6]([CH2:7][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:5][CH:4]([C:14]([NH:32][CH2:29][CH2:30][CH3:31])=[O:16])[CH2:3]1
Reactant: CCCN
Reactant: O=C(O)C1CC(=O)N(Cc2ccccc2)C1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Product: CCCNC(=O)C1CC(=O)N(Cc2ccccc2)C1
Temperature: 60 °C
Reaction time: 2 h
Yield: 92.2 %

Procedure:
To a solution of 10.96 g (50 mmole) of 5-oxo-1-(phenylmethyl)-3-pyrrolidinecarboxylic acid in 150 mL of acetonitrile was added 9.73 g (60 mmole) of 1,1'-carbonyldiimidazole. The reaction was heated to 60° C. for one hour, cooled to room temperature and treated with 4.13 g (70 mmole) of n-propylamine. After stirring for two hours, the solvent was removed in vacuo and the residue partitioned between ether and water. The organic layer was washed with water, 1N hydrochloric acid, dried over magnesium sulfate, filtered, and evaporated in vacuo to give 12.0 g of 5-oxo-1-(phenylmethyl)-N-propyl-3-pyrrolidinecarboxamide, mp 86°-87° C.
Reaction SMILES: [Na].C([NH:4][C:5]([NH:10]C)=[N:6][CH2:7][CH2:8][SH:9])#N.Cl.[CH3:13][C:14]1[NH:18][CH:17]=[N:16][C:15]=1[CH2:19]Cl>C(O)C>[CH3:13][C:14]1[NH:18][CH:17]=[N:16][C:15]=1[CH2:19][S:9][CH2:8][CH2:7][NH:6][C:5]([NH2:10])=[NH:4]
Reactant: Cc1[nH]cnc1CCl
Reactant: CNC(=NCCS)NC#N
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: Cc1[nH]cnc1CSCCNC(=N)N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium (1.43 g) was added, with stirring under nitrogen, to dry ethanol (100 ml). After the sodium had dissolved a solution of N-cyano-N'-methyl-N"-(2-mercaptoethyl)guanidine (4.90 g) in dry ethanol (50 ml) was added and the mixture was stirred at room temperature for one hour. 5-Methyl-4-chloromethylimidazole hydrochloride (5.18 g) was added in batches over a period of one hour at room temperature. The mixture was then stirred at room temperature, for a further hour and heated at reflux temperature for 1/2 hour. After cooling the mixture was filtered and the filtrate was evaporated to a glassy solid (8.8 g). This crude product was chromatographed on silica gel with acetonitrile as eluant and the solid product obtained (3.60 g) was recrystallised from acetonitrile to give N-cyano-N'-methyl-"-[2-(5-methyl-4-imidazolylmethylthio)ethyl]guanidine, m.p.=140°-142° C.
Reaction SMILES: [C:1]([OH:12])(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].C(O)C.C(=O)([O-])[O-].[Ca+2:20]>O>[C:1]([O-:12])(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[Ca+2:20].[C:1]([O-:12])(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCC(=O)O
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Solvent: CCO
Product: CCCCCCCCCC(=O)[O-]
Reaction time: 0.08 h

Procedure:
To a one-liter three-necked flask equipped with a thermometer, mechanical stirrer, and a reflux condenser, were added decanoic acid (20.0 g, 116 mmole) and absolute ethanol (0.19 L). The mixture was stirred vigorously for 5 minutes. The clear solution was then diluted with water (30 ml). Solid calcium carbonate (5.5 g, 55 mmole) was added in one portion and the resulting white suspension heated under reflux for 12 days. Water (10 ml) was added to the reaction each day except the last one. On the last day, excess water (100 ml) was added to complete the reaction. The mixture was cooled to 45° C. (water bath) and filtered through a coarse glass funnel. This gave a white solid which was washed with absolute ethanol (50 ml), tert-butyl methyl ether (2×50 ml) and air-dried for 2 hours. The solid was then dissolved in boiling methanol (1.3 L) and the cloudy solution filtered on a Celite pad. The clear filtrate was cooled and concentrated to 300 ml. The white precipitate was filtered under suction (water aspirator) using a coarse glass funnel (1 L) and air-dried for 3 hours. The resulting solid was kept under high vacuum at 20° C. for 18 hours. The pure acid calcium salt was isolated as a snow-white solid. Yield of product: 14.0 g (63%); mp=172-76° C., 1H NMR (CD3OD, 400 MHz) δ: 2.18 (t, J=7.63 Hz, 4H); 1.61 (m, 4H); 1.30 (m, 24H); 0.91 (t, J=7.04 Hz, 6H); 13C NMR (D2O, 400 MHz) δ: 183.0, 38.0, 32.4, 30.2, 30.1, 30.0, 29.8, 26.9, 23,1, 13.9.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:24]=[CH:23][C:8]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[CH:13][N:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(=O)([O-])O.[Na+].[N:30]#[C:31]Br>ClCCl.O>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]3[CH2:22][CH2:21][N:20]([C:31]#[N:30])[CH2:19][CH2:18]3)=[CH:13][N:12]=2)=[CH:23][CH:24]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(OCc2ccc(C3CCNCC3)cn2)cc1
Reactant: N#CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)c1ccc(OCc2ccc(C3CCN(C#N)CC3)cn2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 85.7 %

Procedure:
To a solution of 4-[2-(4-methanesulfonylphenoxymethyl)pyridin-5-yl]piperidine (124 mg, 0.358 mmol) in dichloromethane (1 mL) was added a solution of sodium hydrogen carbonate (60 mg, 0.716 mmol) in water (0.5 mL). The mixture was cooled in an ice bath followed by the addition of a solution of cyanogen bromide (45 mg, 0.430 mmol) in dichloromethane (1 mL). The mixture was stirred at 0° C. for 30 minutes and then stirred at room temperature for an additional 1 hour. The mixture was poured into saturated aqueous sodium hydrogen carbonate solution and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to give the title compound (114 mg, yield 86%).
Reaction SMILES: [C:1]([NH:4][C:5]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21]Cl)=[CH:17][CH:16]=1)(C([O-])=O)[C:6]([O:8]CC)=[O:7])(=[O:3])[CH3:2].[S:23]([O-:26])([O-:25])=[O:24].[Na+:27].[Na+].[OH-].[Na+].Cl>O.C(O)C>[C:1]([NH:4][C@H:5]([C:6]([OH:8])=[O:7])[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][S:23]([O-:26])(=[O:25])=[O:24])=[CH:17][CH:16]=1)(=[O:3])[CH3:2].[Na+:27]
Reactant: O=S([O-])[O-]
Reactant: CCOC(=O)C(Cc1ccc(CCl)cc1)(NC(C)=O)C(=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(=O)N[C@@H](Cc1ccc(CS(=O)(=O)[O-])cc1)C(=O)O
Temperature: 120 °C
Yield: 39 %

Procedure:
1.1 g of ethyl 2-acetamido-2-(4-chloromethylbenzyl)malonate are added to a solution of 3.31 g of sodium sulfite in 20 cm3 of distilled water, and 8 cm3 of a 10% aqueous solution of caustic soda, and the reaction mixture is heated for 3 hours to a temperature of about 120° C. After cooling to a temperature of about 20° C., the reaction mixture is taken to pH=1 by means of a 1N aqueous solution of hydrochloric acid, and the mixture is again heated to 120° C. for 1 hour. The reaction mixture is cooled to a temperature of about 20° C., and taken up in 150 cm3 of ethanol; the inorganic salts are separated off by filtration and the filtrate is concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at 30° C. The residue obtained is passed through a 2.5 cm diameter chromatography column packed with 100 g of silica gel, eluting with a mixture of dichloromethane, methanol, water and acetic acid (respectively 70-30-6-3 by volume). 424 mg of monosodium N-acetyl-4-sulfonatomethylphenylalanine are thus obtained.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:16]2[C:15]3[CH:14]=[CH:13][C:12]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)=[CH:11][C:10]=3[N:9]=[C:8]([NH2:23])[C:7]=2[N:6]=[C:5]1[CH2:24][O:25][CH2:26][CH3:27].C(N(CC)CC)C.[C:35](Cl)(=[O:39])[CH:36]([CH3:38])[CH3:37]>>[NH2:23][C:8]1[C:7]2[N:6]=[C:5]([CH2:24][O:25][CH2:26][CH3:27])[N:4]([CH2:3][CH2:2][NH:1][C:35](=[O:39])[CH:36]([CH3:38])[CH3:37])[C:16]=2[C:15]2[CH:14]=[CH:13][C:12]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:11][C:10]=2[N:9]=1
Reactant: CC(C)C(=O)Cl
Reactant: CCOCc1nc2c(N)nc3cc(-c4cccnc4)ccc3c2n1CCN
Solvent: CCN(CC)CC
Product: CCOCc1nc2c(N)nc3cc(-c4cccnc4)ccc3c2n1CCNC(=O)C(C)C
Yield: 32.8 %

Procedure:
1-(2-Aminoethyl)-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine (2.00 g, 5.50 mmol) was treated with triethylamine (1.00 mL, 7.20 mmol) and isobutyryl chloride (0.64 mL, 6.10 mmol) according to the method described in Part B of Examples 372-376. The crude product was recrystallized from 93:7 acetonitrile:water and then from isopropanol (7.3 mL/g) and dried for two hours in a drying oven to provide 0.78 g of N-{2-[4-amino-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]ethyl}-2-methylpropanamide as a white solid, mp 213-215° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][CH:11]=[N:10][CH:9]=2)=[C:4]([O:13][CH3:14])[CH:3]=1.C(N(CC)CC)C.[Cl:22][CH2:23][C:24](Cl)=[O:25]>ClCCl>[Cl:22][CH2:23][C:24]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][CH:11]=[N:10][CH:9]=2)=[C:4]([O:13][CH3:14])[CH:3]=1)=[O:25]
Reactant: O=C(Cl)CCl
Reactant: COc1cc(N)ccc1-c1cnco1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(NC(=O)CCl)ccc1-c1cnco1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of 1D (500 mg, 2.63 mmol) and triethylamine (370 μL, 2.89 mmol) in dichloromethane (13.0 mL), was added chloroacetyl chloride (0.23 mL, 2.89 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 10 min. and then at RT for 4 h. The mixture was diluted with dichloromathane, washed with water, brine, and dried over Na2SO4. The mixture was filtered through celite and concentrated in vacuo to give 2A as a yellow solid. LC/MS: ret. timeA=3.123 min., MS (M+H)+=267.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([S:20][CH3:21])=[CH:16][CH:15]=3)=[CH:12][C:11]([C:22]([O:24]CC)=[O:23])=[N:10]2)=[CH:5][CH:4]=1)#[N:2].[OH-].[Na+]>C(O)C.O1CCCC1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([N:9]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([S:20][CH3:21])=[CH:16][CH:15]=3)=[CH:12][C:11]([C:22]([OH:24])=[O:23])=[N:10]2)=[CH:7][CH:8]=1)#[N:2]
Reactant: CCOC(=O)c1cc(-c2ccc(SC)cc2)n(-c2ccc(C#N)cc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CSc1ccc(-c2cc(C(=O)O)nn2-c2ccc(C#N)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.8 %

Procedure:
A mixture of ethyl 1-(4-cyanophenyl)-5-[4-(methylthio)phenyl]pyrazole-3-carboxylate (2.8 g) and 1N sodium hydroxide (10 ml) in ethanol (50 ml) and tetrahydrofuran (20 ml) was stirred at ambient temperature for 3 hours. The solvent was evaporated, and the residue was dissolved in water, acidified with hydrochloric acid, and extracted with ethyl acetate. The extract was washed with water, dried, and evaporated to give 1-(4-cyanophenyl)-5-[4-(methylthio)phenyl]pyrazole-3-carboxylic acid (2.5 g).
Reaction SMILES: Br.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]#[C:9][CH2:10]Br.[F:12][C:13]1[CH:14]=[C:15]([OH:28])[CH:16]=[C:17]([C:19]2([O:26][CH3:27])[CH2:23][CH2:22][CH2:21][CH:20]2[O:24][CH3:25])[CH:18]=1>>[F:12][C:13]1[CH:14]=[C:15]([O:28][CH2:10][C:9]#[C:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][N:2]=2)[CH:16]=[C:17]([C:19]2([O:26][CH3:27])[CH2:23][CH2:22][CH2:21][CH:20]2[O:24][CH3:25])[CH:18]=1
Reactant: BrCC#Cc1ccccn1
Reactant: COC1CCCC1(OC)c1cc(O)cc(F)c1
Agent: Br
Product: COC1CCCC1(OC)c1cc(F)cc(OCC#Cc2ccccn2)c1
Yield: 83 %

Procedure:
Using the procedure described in Example 1, 3-(2-pyridyl)prop-2-yn-1-yl bromide hydrobromide was reacted with (1RS,2SR)-1-(5-fluoro-3-hydroxyphenyl)-1,2-dimethoxycyclopentane to give (1RS,2SR)-1-[5-fluoro-3-(3-(2-pyridyl)prop-2-yn-1-yloxy)phenyl]-1,2-dimethoxycyclopentane in 83% yield, as an oil. NMR Spectrum (CDCl3, delta values) 1.6-2.25(m, 6H), 2.94(s, 3H), 2.97(s, 3H), 3.55(m, 1H), 5.21(s, 2H), 6.55-8.0(m, 10H).
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]3[CH:17]=[C:16]([C:18]4[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=4)[N:15]=[CH:14][N:13]=3)[C:5]=2[N:6]=1.[CH2:28]([CH2:30][NH2:31])[OH:29]>O1CCOCC1>[F:25][C:24]([F:27])([F:26])[C:21]1[CH:22]=[CH:23][C:18]([C:16]2[N:15]=[CH:14][N:13]=[C:12]([O:11][C:7]3[C:5]4[N:6]=[C:2]([NH:31][CH2:30][CH2:28][OH:29])[S:3][C:4]=4[CH:10]=[CH:9][CH:8]=3)[CH:17]=2)=[CH:19][CH:20]=1
Reactant: NCCO
Reactant: FC(F)(F)c1ccc(-c2cc(Oc3cccc4sc(Br)nc34)ncn2)cc1
Solvent: C1COCCO1
Product: OCCNc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4)ncn3)cccc2s1
Temperature: 200 °C

Procedure:
To 2-bromo-4-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazole, (Example 86), (90 mg, 0.2 mmol) dissolved in dioxane (1 mL) was added ethanolamine (0.06 mL, 1 mmol, Aldrich). The reaction mixture was heated in microwave synthesizer at 200° C. for 10 min, allowed to cool to room temperature and evaporated in vacuum. Purification of the residue by silica gel chromatography (1:1 of EtOAc/hexanes) provided the title compound as a white solid. MS (ESI, pos. ion) m/z: 433 (M+1).
Reaction SMILES: Br[CH2:2][C:3]1[N:8]=[CH:7][N:6]2[N:9]=[CH:10][N:11]=[C:5]2[C:4]=1[CH2:12][CH2:13][CH3:14].[NH:15]1[CH:19]=[CH:18][N:17]=[C:16]1[C:20]1[N:27]=[CH:26][CH:25]=[CH:24][C:21]=1[C:22]#[N:23].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:12]([C:4]1[C:5]2[N:6]([N:9]=[CH:10][N:11]=2)[CH:7]=[N:8][C:3]=1[CH2:2][N:15]1[CH:19]=[CH:18][N:17]=[C:16]1[C:20]1[N:27]=[CH:26][CH:25]=[CH:24][C:21]=1[C:22]#[N:23])[CH2:13][CH3:14]
Reactant: CCCc1c(CBr)ncn2ncnc12
Reactant: N#Cc1cccnc1-c1ncc[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCc1c(Cn2ccnc2-c2ncccc2C#N)ncn2ncnc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 169 (56 mg, 0.22 mmol), 170 (42 mg, 0.25 mmol) and K2CO3 (138 mg) in DMF (4 mL) is stirred at room temperature overnight. Solvent is removed in vacuo. Water (10 mL) is added and the mixture is extracted with ethyl acetate (3×25 mL). The combined organic layers are dried and solvent removed. The crude is purified by PTLC (5% MeOH in methylene chloride) to give the title product (167) as a solid. 1H NMR 9.13 (s, 1H), 8.64–8.66 (m, 1H), 8.36 (s, 1H), 8.07–8.10 (m, 1H), 7.29–7.34 (m, 1H), 7.32 (s, 1H), 7.23 (s, 1H), 5.94 (s, 2H), 3.02–3.08 (m, 2H) 1.66–1.74 (m, 2H), 1.00 (t, 3H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][C:7]([NH:9][NH2:10])=[O:8])=[CH:2]1.[F:11][C:12]([F:23])([F:22])[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][C:14]=1[C:19](O)=O.N>P(Cl)(Cl)(Cl)=O>[S:1]1[CH:5]=[CH:4][C:3]([CH2:6][C:7]2[O:8][C:19]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][C:13]=3[C:12]([F:23])([F:11])[F:22])=[N:10][N:9]=2)=[CH:2]1
Reactant: O=C(O)c1cnccc1C(F)(F)F
Reactant: NNC(=O)Cc1ccsc1
Agent: N
Solvent: O=P(Cl)(Cl)Cl
Product: FC(F)(F)c1ccncc1-c1nnc(Cc2ccsc2)o1
Temperature: 0 °C
Yield: 39.9 %

Procedure:
880 mg of thiophene-3-acetic hydrazide were added to a solution of 960 mg of 4-trifluoromethylpyridine-3-carboxylic acid in 5 ml of phosphorus oxychloride, and the mixture was heated at reflux for 2 hours. The reaction mixture was subsequently added dropwise to ice-water, made neutral using concentrated ammonia solution and extracted with ethyl acetate. Drying (Na2SO4), concentration and chromatographic purification gave 624 mg of the desired product as a slightly brown oil.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[C@H:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=2)[O:8][CH2:7][CH2:6][N:5]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:4]1.C(N(CC)CC)C.[CH3:32][O:33][CH2:34][C:35](Cl)=[O:36]>C1COCC1>[Cl:17][C:12]1[CH:11]=[C:10]([C@@H:9]2[O:8][CH2:7][CH2:6][N:5]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:4][C@H:3]2[CH2:2][NH:1][C:35](=[O:36])[CH2:34][O:33][CH3:32])[CH:15]=[CH:14][C:13]=1[Cl:16]
Reactant: COCC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](CN)C1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COCC(=O)NC[C@@H]1CN(C(=O)OC(C)(C)C)CCO[C@H]1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.9 %

Procedure:
To a solution of tert-butyl (6R,7R)-6-(aminomethyl)-7-(3,4-dichlorophenyl)-1,4-oxazepane-4-carboxylate (165 mg) in THF (2.5 mL) were added triethylamine (89 mg) and methoxyacetyl chloride (71.6 mg), and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, distilled water was added to the residue, and the mixture was extracted twice with ethyl acetate. The combined organic layers were washed with brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (161 mg).
Reaction SMILES: [C:1]([CH2:3][C:4]1([N:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[N:17][N:16]4[C:19]([C:22]5[CH:23]=[C:24]([NH:28][C:29]([NH:31][CH2:32][C:33]([F:36])([F:35])[F:34])=[O:30])[CH:25]=[CH:26][CH:27]=5)=[CH:20][N:21]=[C:15]4[CH:14]=3)[CH:10]=[N:9]2)[CH2:7][NH:6][CH2:5]1)#[N:2].[O:37]1[CH2:41][CH2:40][CH:39]([C:42](O)=[O:43])[CH2:38]1>>[C:1]([CH2:3][C:4]1([N:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[N:17][N:16]4[C:19]([C:22]5[CH:23]=[C:24]([NH:28][C:29]([NH:31][CH2:32][C:33]([F:35])([F:36])[F:34])=[O:30])[CH:25]=[CH:26][CH:27]=5)=[CH:20][N:21]=[C:15]4[CH:14]=3)[CH:10]=[N:9]2)[CH2:5][N:6]([C:42]([CH:39]2[CH2:40][CH2:41][O:37][CH2:38]2)=[O:43])[CH2:7]1)#[N:2]
Reactant: O=C(O)C1CCOC1
Reactant: N#CCC1(n2cc(-c3cnn4c(-c5cccc(NC(=O)NCC(F)(F)F)c5)cnc4c3)cn2)CNC1
Product: N#CCC1(n2cc(-c3cnn4c(-c5cccc(NC(=O)NCC(F)(F)F)c5)cnc4c3)cn2)CN(C(=O)C2CCOC2)C1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 77 starting from N-[3-(7-{1-[3-(cyanomethyl)azetidin-3-yl]-1H-pyrazol-4-yl}imidazo[1,2-b]pyridazin-3-yl)phenyl]-N′-(2,2,2-trifluoroethyl)urea and tetrahydrofuran-3-carboxylic acid. LCMS (M+H)+: m/z=594.2.
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][N:15]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[S:17][C:16]3=[O:24])[CH2:8][CH2:7]2)[N:5]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:4][N:3]1[CH2:31][C:32]1[CH:33]=[C:34]([CH:39]=[CH:40][CH:41]=1)[C:35]([O:37]C)=[O:36].O.[OH-].[Li+]>CO.O>[O:1]=[C:2]1[C:6]2([CH2:7][CH2:8][N:9]([CH2:12][CH2:13][CH2:14][N:15]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[S:17][C:16]3=[O:24])[CH2:10][CH2:11]2)[N:5]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:4][N:3]1[CH2:31][C:32]1[CH:33]=[C:34]([CH:39]=[CH:40][CH:41]=1)[C:35]([OH:37])=[O:36]
Reactant: COC(=O)c1cccc(CN2CN(c3ccccc3)C3(CCN(CCCn4c(=O)sc5ccccc54)CC3)C2=O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cccc(CN2CN(c3ccccc3)C3(CCN(CCCn4c(=O)sc5ccccc54)CC3)C2=O)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 35.9 %

Procedure:
To a solution of methyl 3-((4-oxo-8-(3-(2-oxobenzo[d]thiazol-3(2H)-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (0.17 g, 0.3 mmol) in methanol (3 mL) was added lithium hydroxide monohydrate (0.025 g, 0.6 mmol) in water (1 mL). After stirring at room temperature for 18 h, the reaction mixture was concentrated in vacuo and isolated by preparatory TLC (10% methanol/dichloromethane) to obtain the title compound (0.06 g, 36%); 1H NMR (DMSO-d6): δ 1.60 (d, 2H, J=14 Hz), 1.85 (t, 2H, J=5.6 Hz), 2.48-2.53 (m, 7H), 2.66-2.75 (m, 4H), 4.04 (t, 2H, J=8.4 Hz), 4.59 (d, 2H, J=8.4 Hz), 6.77 (t, 1H, J=7.6 Hz), 6.85 (d, 2H, J=8.4 Hz), 7.18-7.24 (m, 3H), 7.33 (t, 1H, J=7.2 Hz), 7.45-7.51 (m, 3H), 7.64 (d, 1H, J=7.2 Hz), 7.85 (d, 2H, J=8 Hz); MS for C31H32N4O4S m/z 556.95 (M+H)+.
Reaction SMILES: BrBr.[C:3]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)(=[O:5])C.S([O-])([O-])=[O:21].[Na+].[Na+].Cl>O.O1CCOCC1>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([C:9]2[CH:10]=[CH:11][C:6]([C:3]([OH:5])=[O:21])=[CH:7][CH:8]=2)=[CH:13][CH:14]=1
Reactant: O=S([O-])[O-]
Reactant: COc1ccc(-c2ccc(C(C)=O)cc2)cc1
Agent: BrBr
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(-c2ccc(C(=O)O)cc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 93.1 %

Procedure:
A solution of 64.7 g (1.61 mol) of soda in 560 ml water is prepared at 0° C. 69.9 g (0.44 mol) of bromine then 260 ml of 1,4-dioxane are added successively. A yellow solution is obtained which is cooled down to 0° C. and which is added over 10 minutes, without exceeding 10° C., to a suspension of 28 g (0.12 mol) of 4'-acetyl-4-methoxybiphenyl in a mixture of 750 ml of 1,4-dioxane and 510 ml water. The reaction medium is agitated for 1 hour at approximately 20° C., a solution of 15.5 g of sodium sulphite in 160 ml water is added and taken to reflux for 10 minutes. 76 ml of concentrated hydrochloric acid is added and the reaction medium is left under agitation whilst being cooled down, for 1 hour. After drying, washing with water and drying at 50° C., 25.5 g of 4'-methoxy-4-biphenyl carboxylic acid is obtained in the form of a white powder (yield: 93%).