Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[C:2]1[CH2:20][CH2:19][C:5]2[C:6]3[CH:18]=[CH:17][CH:16]=[CH:15][C:7]=3[O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:4]=2[CH2:3]1.C1C=CC=CC=1.[O-]CC.[Na+].[C:31](#[N:33])[CH3:32]>>[C:31]([CH:32]=[C:2]1[CH2:20][CH2:19][C:5]2[C:6]3[CH:18]=[CH:17][CH:16]=[CH:15][C:7]=3[O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:4]=2[CH2:3]1)#[N:33]
Reactant: CC#N
Reactant: O=C1CCC2=C(C1)c1ccccc1Oc1ccccc12
Agent: CC[O-]
Agent: [Na+]
Solvent: c1ccccc1
Product: N#CC=C1CCC2=C(C1)c1ccccc1Oc1ccccc12

Procedure:
1 g of 2-keto-1,2,3,4-tetrahydro-tribenzo(b,d,f)-oxepine is mixed with 1 ml of benzene, 15 ml of acetonitrile and 0.5 g of molecular sieve (4 A). 50 mg of sodium-ethoxide are added and the mixture is heated for 3 hours (90°-100° C.). After cooling the mixture the molecular sieve is filtered off and the filtrate evaporated.
Reaction SMILES: C(O[CH:4]=[C:5]1[C:16]2[C:8](=[CH:9][CH:10]=[C:11]3[C:15]=2[S:14][CH:13]=[N:12]3)[NH:7][C:6]1=[O:17])C.[CH:18]1[CH:19]=[CH:20][N:21]=[C:22]([NH:24][S:25]([C:28]2[CH:29]=[CH:30][C:31]([NH2:34])=[CH:32][CH:33]=2)(=[O:27])=[O:26])[CH:23]=1.C(O)C>O>[O:17]=[C:6]1[C:5](=[CH:4][NH:34][C:31]2[CH:30]=[CH:29][C:28]([S:25]([NH:24][C:22]3[CH:23]=[CH:18][CH:19]=[CH:20][N:21]=3)(=[O:27])=[O:26])=[CH:33][CH:32]=2)[C:16]2[C:8](=[CH:9][CH:10]=[C:11]3[C:15]=2[S:14][CH:13]=[N:12]3)[NH:7]1
Reactant: Nc1ccc(S(=O)(=O)Nc2ccccn2)cc1
Reactant: CCOC=C1C(=O)Nc2ccc3ncsc3c21
Solvent: O
Solvent: CCO
Product: O=C1Nc2ccc3ncsc3c2C1=CNc1ccc(S(=O)(=O)Nc2ccccn2)cc1
Reaction time: 18 h
Yield: 71 %

Procedure:
To a 25 ml round bottom flask was added a stir bar, 246 mg (1.00 mmol) of 8-ethoxymethylene-6,8-dihydro-1-thia-3,6-diaza-as-indacen-7-one. 249 (1.00 mmol) of sulfapyridine and 10 ml of ethanol. The flask was fitted with a water-cooled reflux condenser, and the mixture was heated to reflux using an oil bath with stirring for 18 h. The reaction was allowed to cool and was filtered. The precipitate was washed with excess ethanol and dried under vacuum to yield 321 mg (71%) of the title compound: 1H NMR (DMSO-d6): δ 11.9 (br s, 1H), 11.2 (d, 1H), 10.9 (s, 1H), 9.3 (s, 1H), 8.1 (d, 2H), 7.9 (m 3H) 7.8 (m, 1H), 7.6 (d, 2H), 7.2 (d, 1H), 7.2 (d, 1H), 6.9 (t, 1H); C21H15N5O3S2: APCI−MS m/z 450 (M+H)+.
Reaction SMILES: Cl.Cl.[NH2:3][C@H:4]([C:6](OCCN)=[S:7])C.C[C@@H:13]([OH:19])[C@H:14]([NH2:18])[C:15](O)=O.N>C(O)(C)C>[NH2:18][CH:14]([CH3:15])[C:13]([NH:3][CH2:4][CH2:6][SH:7])=[O:19]
Reactant: C[C@H](N)C(=S)OCCN
Reactant: C[C@@H](O)[C@H](N)C(=O)O
Agent: Cl
Agent: N
Solvent: CC(C)O
Product: CC(N)C(=O)NCCS

Procedure:
To a suspension of 22.1 g of the 2-aminoethyl thioalaninate dihydrochloride (0.1 mole), obtained above, in 50 cm3 of isopropanol, thre are slowly added, under an inert atmosphere, 20.4 cm3 (0.15) mole) of a 2.5% aqueous ammonia solution. The resulting solution is evaporated to dryness under reduced pressure. The residue is taken up in 100 cm3 of ethanol. The insoluble ammonium chloride is separated by filtration on fritted glass. The filtrate is evaporated to dryness and dried under a vacuum at 50° C. 17.5 g of 2-amino N-(2-mercaptoethyl) propionamide in the form of a white solid whose melting point is 141° C. are obtained.
Reaction SMILES: [ClH:1].[C:2]([CH2:5][NH:6][C:7]([CH2:9][C@H:10]1[CH2:21][CH2:20][C:19]2[S:18][C:17]3[N:16]=[CH:15][N:14]=[C:13]([O:22][CH:23]4[CH2:28][CH2:27][CH:26]([N:29](C)[C:30](=O)OC(C)(C)C)[CH2:25][CH2:24]4)[C:12]=3[C:11]1=2)=[O:8])(=[O:4])[NH2:3]>C(Cl)Cl>[ClH:1].[C:2]([CH2:5][NH:6][C:7](=[O:8])[CH2:9][C@H:10]1[CH2:21][CH2:20][C:19]2[S:18][C:17]3[N:16]=[CH:15][N:14]=[C:13]([O:22][CH:23]4[CH2:24][CH2:25][CH:26]([NH:29][CH3:30])[CH2:27][CH2:28]4)[C:12]=3[C:11]1=2)(=[O:4])[NH2:3]
Reactant: CN(C(=O)OC(C)(C)C)C1CCC(Oc2ncnc3sc4c(c23)[C@@H](CC(=O)NCC(N)=O)CC4)CC1
Agent: Cl
Solvent: ClCCl
Product: CNC1CCC(Oc2ncnc3sc4c(c23)[C@@H](CC(=O)NCC(N)=O)CC4)CC1

Procedure:
HCl (gas) was introduced into DCM (50 mL) at 0° C. for 30 min with stirring. Then a solution of tert-butyl N-(4-[[(3R)-3-[[(carbamoylmethyl)carbamoyl]methyl]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]cyclohexyl)-N-methylcarbamate (140 mg, 0.27 mmol, 1.00 equiv) in 5 mL of DCM was added and the resulting solution was stirred overnight at room temperature. The solvent was removed under vacuum to provide 120 mg of N-(carbamoylmethyl)-2-[(3R)-12-[[4-(methylamino)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]acetamide hydrochloride as a yellow solid. The solid was dissolved in methanol (10 mL) and HCHO (37%, 0.5 mL) and acetic acid (0.5 mL) were added at room temperature. After stirring for 20 min at room temperature, NaBH3CN (100 mg) was added and the resulting mixture was stirred for 1 h at ambient temperature. After concentration in vacuo, the residue was purified by preparative HPLC under the following conditions (Waters): column: X-briage C18, 19*150 mm 5 um; mobile phase: CH3CN and water with 20 mM NH4HCO3 (10.0% CH3CN up to 50.0% in 10 min, up to 95% in 2 min, down to 10.0% in 2 min); flow rate: 20 mL/min; UV detection at 254/220 nm. The product-containing fractions were collected and partially evaporated to remove water and CH3CN under reduced pressure. The residue was lyophilized overnight to give the desired N-(2-amino-2-oxoethyl)-2-((R)-4-(((1r,4R)-4-(dimethylamino)cyclohexyl)oxy)-6,7-dihydro-SH-cyclopenta[4,5]thieno[2,3-d]pyrimidin-5-yl)acetamide (154.3 mg, 71%) as a white solid. MS: m/z 432 [M+H]+, 454 [M+Na]+; 1H NMR (400 MHz, CD3OD): δ 8.47 (1H, s), 5.28-5.23 (1H, m), 3.89 (2H, s), 3.86-3.77 (1H, m), 3.15-2.99 (3H, m), 2.74-2.68 (1H, m), 2.44-2.34 (11H, m), 2.06-2.04 (2H, m), 1.73-1.58 (2H, m), 1.57-1.43 (2H, m).
Reaction SMILES: [NH:1]1[CH:9]=[C:7]([CH3:8])[C:5](=[O:6])[NH:4][C:2]1=[O:3].[Br:10][C:11]1[CH:12]=[C:13](B(O)O)[CH:14]=[CH:15][CH:16]=1.CO>O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C.O>[Br:10][C:11]1[CH:16]=[C:15]([N:1]2[CH:9]=[C:7]([CH3:8])[C:5](=[O:6])[NH:4][C:2]2=[O:3])[CH:14]=[CH:13][CH:12]=1
Reactant: Cc1c[nH]c(=O)[nH]c1=O
Reactant: OB(O)c1cccc(Br)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CO
Product: Cc1cn(-c2cccc(Br)c2)c(=O)[nH]c1=O
Reaction time: 48 h

Procedure:
A 500 mL round bottom flask was charged with thymine (0.314 g, 2.49 mmol), 3-bromophenylboronic acid (1.00 g, 4.98 mmol), tetramethylethyldiamine (0.75 mL, 4.98 mmol), copper(II) acetate monohydrate (0.497 g, 2.49 mmol), methanol (200 mL), and H2O (50 mL). The blue reaction mixture was stirred for 48 h, concentrated and purified by CombiFlash (0 to 8% MeOH/CH2Cl2) to give desired product. LCMS-ESI+: calc'd for C11H9BrN2O2: 281.0 (M+H+); Found: 281.1 (M+H+).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[C:8]([OH:10])=O)([CH3:4])([CH3:3])[CH3:2].[SH:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=1.N1C=CC=CC=1>ClCCl>[C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[C:8]([S:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=1)=[O:10])([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1ccc(C(=O)O)cc1C(C)(C)C
Reactant: O=C(O)c1ccc(S)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(C(=O)Sc2ccc(C(=O)O)cc2)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 32 %

Procedure:
Crude 3-(tert.butyl)-4-methoxybenzoic acid, prepared starting with 1.04 g (5 mmoles) of 3-(tert.butyl)-4-methoxybenzoic acid, described in Example 35 of French Patent No. 85 13747 (2.570.377), is dissolved in 15 ml of dichloromethane. The solution is slowly added to a mixture of 771 mg (5 mmoles) of 4-mercaptobenzoic acid and 8 ml of pyridine. The reaction mixture is stirred at ambient temperature for 8 hours, evaporated to dryness, taken up in water, acidified to pH 5 with 1N HCl and extracted with ethyl ether. The organic phase is decanted, washed with water, dried over magnesium sulfate and evaporated to dryness. The resulting residue is purified by chromatography on a silica column (eluant: ethyl ether). The solvent is evaporated and 530 mg (32% yield) of 4-[3-tert.butyl-4-methoxybenzoylthio] benzoic acid whose melting point is 220°-221° C. are obtained.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].Cl.Cl.[NH:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][C:23]=2[O:24][CH3:25])[N:20]=[CH:19][N:18]=[C:17]3[NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:28]=2[F:34])[CH2:9][CH2:8]1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[C:1]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][C:23]=2[O:24][CH3:25])[N:20]=[CH:19][N:18]=[C:17]3[NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:28]=2[F:34])[CH2:9][CH2:8]1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCNCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCN(C(C)=O)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
Acetyl chloride (179 mg) was added to a solution of 6-(piperidin-4-yloxy)-4-(3-chloro-2-fluoroanilino)-7-methoxyquinazoline dihydrochloride (1 g) and diisopropylethylamine (735 mg) in methylene chloride that was cooled at 0° C. and the mixture was stirred for 2 hours and allowed to warm to room temperature. The reaction mixture was adsorbed onto silica and the residue was purified by column chromatography eluting with increasingly polar mixtures of methylene chloride/methanol (100/0 to 90/10). The fractions containing the desired product were combined and evaporated under vacuum to give the title product as a colourless foam (0.655 g); 1H NMR Spectrum: (DMSO d6) 1.54-1.78 (m, 2H), 1.91-2.10 (m, 5H), 3.29-3.41 (m, 2H), 3.66-3.76 (m, 1H), 3.78-3.88 (m, 1H), 3.93 (s, 3H), 4.74 (m, 1H), 7.20 (s, 1H), 7.27 (t, 1H), 7.44-7.55 (m, 2H), 7.87 (s, 1H), 836 (s, 1H), 9.54 (s, 1H); Mass Spectrum: (M+H)+ 445.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[C:10]1[O:14][CH:13]=[N:12][CH:11]=1)[NH2:6].[C:15](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:16]>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:6]=[C:15]=[S:16])[CH:7]=[CH:8][C:9]=1[C:10]1[O:14][CH:13]=[N:12][CH:11]=1
Reactant: COc1cc(N)ccc1-c1cnco1
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Solvent: ClCCl
Product: COc1cc(N=C=S)ccc1-c1cnco1
Yield: 94 %

Procedure:
3-Methoxy-4-(5-oxazolyl)aniline, 1D, (3.50 g, 18.4 mmol) and 1,1′-thiocarbonyldi-2(2H)-pyridone (4.41 g, 18.4 mmol) in dichloromethane (100 mL) were stirred at rt for 3 h. The solvent was evaporated under vacuum, and the residue was subjected to a short column (30% AcOEt/hexane) to afford 34A (4.02 g, 94% yield) as white flakes.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8](CC2SC(N)=NC=2)=[CH:7][CH:6]=[CH:5][N:4]=1.ClC(CC1C=[N:23]C=CC=1)C=O.NC(N)=S>C(O)C>[CH3:1][O:2][C:3]1[C:8]([NH2:23])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: COc1ncccc1Cc1cnc(N)s1
Reactant: O=CC(Cl)Cc1cccnc1
Agent: NC(N)=S
Solvent: CCO
Product: COc1ncccc1N

Procedure:
5-(2-Methoxy-pyridin-3-ylmethyl)-thiazol-2-ylamine A mixture of 2-chloro-3-pyridin-3-yl-propionaldehyde (crude from above) and thiourea (14.8 g, 0.194 mol) in ethanol (200 mL) was heated to reflux overnight. The solvent was removed and the residue was diluted with dichoromethane (1.2 L) and then washed with sodium hydroxide (10% aqueous solution, 400 mL) and water (200 mL). The organic layer was extracted three times with hydrochloric acid (5% aqueous solution, 400 mL) and the combined aqueous layer was brought to between pH 9 and 10 with sodium hydroxide (10% aqueous solution). The resulting precipitate was filtered to give the crude product, which was recrystallized, from ethyl acetate and hexanes to give the pure product (5.1 g, 0.023 mol, 5.6% from 2-methoxy-pyridin-3-ylamine). ESI-MS m/z calc. 221.1, found 222.2 (M+1)+.
Reaction SMILES: Cl[CH:2]([O:4][C:5](=[O:32])[N:6]([C:29](=[O:31])[CH3:30])[CH2:7][C@@H:8]1[O:12][C:11](=[O:13])[N:10]([C:14]2[CH:19]=[CH:18][C:17]([CH:20]3[CH2:25][CH2:24][S:23](=[O:27])(=[O:26])[CH2:22][CH2:21]3)=[C:16]([F:28])[CH:15]=2)[CH2:9]1)[CH3:3].[C:33]([OH:36])(=[O:35])[CH3:34].CCOCC>C([O-])(=O)C.[Hg+2].C([O-])(=O)C.O>[C:29]([N:6]([CH2:7][C@@H:8]1[O:12][C:11](=[O:13])[N:10]([C:14]2[CH:19]=[CH:18][C:17]([CH:20]3[CH2:25][CH2:24][S:23](=[O:27])(=[O:26])[CH2:22][CH2:21]3)=[C:16]([F:28])[CH:15]=2)[CH2:9]1)[C:5]([O:4][CH:2]([O:36][C:33](=[O:35])[CH3:34])[CH3:3])=[O:32])(=[O:31])[CH3:30]
Reactant: CC(=O)N(C[C@H]1CN(c2ccc(C3CCS(=O)(=O)CC3)c(F)c2)C(=O)O1)C(=O)OC(C)Cl
Reactant: CC(=O)O
Agent: CC(=O)[O-]
Agent: [Hg+2]
Solvent: CCOCC
Solvent: O
Product: CC(=O)OC(C)OC(=O)N(C[C@H]1CN(c2ccc(C3CCS(=O)(=O)CC3)c(F)c2)C(=O)O1)C(C)=O
Yield: 43 %

Procedure:
Acetyl-{3-[4-(1,1-dioxo-hexahydro-1λ6-thiopyran-4-yl)-3-fluoro-phenyl]-2-oxo-oxazolidin 5(R)-ylmethyl}-carbamic acid 1(R,S)-chloro-ethyl ester (11) (0.49 g, 1 mmol), mercury(II) acetate (0.37 g, 1.175 mmol), and acetic acid (6.3 mL, 109 mmol) are stirred at RT overnight. Ether and water are added and the layers are separated. The organic layer is washed several times with water, brine, dried over Na2SO4 and conc in vacuo. After purification by silica gel chromatography, the product is re-dissolved in CH2Cl2 and washed with several portions of sat NaHCO3, water, dried over Na2SO4 and conc in vacuo to give the title compound in 43% yield (0.51 g) as a mixture of two diastereomers in a 1:1 ratio. 1H NMR (400 MHz, CDCl3): δ 7.46 (dt, 1H), 7.21 (m, 1H), 7.13 (m, 1H), 6.88 (q, 1H), 4.82 (m, 0.5H), 4.75 (m, 0.5H), 4.13 (m, 1H), 4.04 (m, 2H), 3.73 (dd, 0.5H), 3.67 (dd, 0.5H), 3.12 (m, 5H), 2.55 (s, 1.5H), 2.53 (s, 1.5H), 2.38 (m, 2H), 2.17 (m, 2H), 2.13 (s, 1.5H), 2.06 (s, 1.5H), 1.57 (d, 1.5H), 1.54 (d, 1.5H). MS-APCI (m/z+): 341, 385, 427, 515.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:11]1[CH:12]=[N:13][CH:14]=[CH:15][C:16]=1N.[F:18][B-](F)(F)F.[H+].N([O-])=O.[Na+].[OH-].[Na+]>>[F:18][C:16]1[CH:15]=[CH:14][N:13]=[CH:12][C:11]=1[C:3]1[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[CH3:1]
Reactant: Cc1cc([N+](=O)[O-])ccc1-c1cnccc1N
Reactant: F[B-](F)(F)F
Agent: O=N[O-]
Agent: [H+]
Agent: [Na+]
Product: Cc1cc([N+](=O)[O-])ccc1-c1cnccc1F
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 17.4 %

Procedure:
To a solution of Intermediate 19A (340 mg, 1.483 mmol) in tetrafluoroboric acid (1 mL, 7.65 mmol) at −10° C. was added sodium nitrite (179 mg, 2.60 mmol) in small portions, keeping the temperature below −5° C. After the addition was complete, the mixture was stirred at 0° C. for 45 min and then warmed slowly to room temperature over a period of 30 min to decompose the preparation of diazonium salt. The temperature of the mixture was rose to 30-35° C. and nitrogen was evolved for about 30 min. The resulting mixture was cooled to −10° C. and neutralized with 1M sodium hydroxide precooled to 0-5° C. The mixture was extracted with ethyl acetate (2×25 mL), washed with cooled water (25 mL), and dried over magnesium sulfate. The crude material was purified by silica gel chromatography (40 g ISCO column, eluting with 100% hexanes to 100% CH2Cl2) to provide Intermediate 19B (60 mg, 0.258 mmol, 17.42% yield) as a yellow solid. MS (ES): m/z=233.0 [M+H]+. 1H NMR (400 MHz, MeOD) δ ppm 2.34 (s, 3 H) 7.44 (dd, J=9.66, 5.65 Hz, 1 H) 7.55 (d, J=8.28 Hz, 1 H) 8.20 (dd, J=8.16, 2.13 Hz, 1 H) 8.28 (d, J=2.26 Hz, 1 H) 8.57 (d, J=9.79 Hz, 1 H) 8.70 (dd, J=7.65, 5.65 Hz, 1 H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5](=[O:17])[CH2:6][C:7]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1)([CH3:9])[CH3:8])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[F:25][C:26]([Si](C)(C)C)([F:28])[F:27].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.S(=O)(=O)(O)O>CN(C)C=O.O1CCCC1.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:18])[C:5]([OH:17])([C:26]([F:28])([F:27])[F:25])[CH2:6][C:7]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1)([CH3:9])[CH3:8])[CH3:2]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: CCOC(=O)C(=O)CC(C)(C)c1cccc(F)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C(O)(CC(C)(C)c1cccc(F)c1)C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
5.3 g of 4-(3-fluorophenyl)-4-methyl-2-oxovaleric acid-ethyl ester in 60 ml of dimethylformamide is combined at 0° C. with 3.25 g of cesium carbonate and 4.63 ml of trifluoromethyl(trimethyl)-silane. After 1 hour at 0° C. and 16 hours at room temperature, it is cooled again to 0° C. and mixed with 20 ml of a 1 M tetrabutylammonium fluoride solution in tetrahydrofuran. After 30 minutes at 0° C., 2N sulfuric acid and ethyl acetate are added to it, the ethyl acetate phase is washed with water, dried (Na2SO4) and concentrated by evaporation. After chromatography on silica gel hexane-ethyl acetate (20:1) and bulb tube distillation, 4.45 g of 4-(3-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleric acid-ethyl ester is obtained (boiling point 100° C./0.04 hPa).
Reaction SMILES: C([O:3][P:4]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][N:14]2[C:23]3[C:18](=[CH:19][C:20]([N+:24]([O-:26])=[O:25])=[CH:21][CH:22]=3)[NH:17][C:16](=[O:27])[C:15]2=[O:28])=[CH:9][CH:8]=1)(=[O:6])[OH:5])C.O>Cl>[N+:24]([C:20]1[CH:19]=[C:18]2[C:23](=[CH:22][CH:21]=1)[N:14]([CH2:13][C:10]1[CH:9]=[CH:8][C:7]([P:4](=[O:3])([OH:5])[OH:6])=[CH:12][CH:11]=1)[C:15](=[O:28])[C:16](=[O:27])[NH:17]2)([O-:26])=[O:25]
Reactant: CCOP(=O)(O)c1ccc(Cn2c(=O)c(=O)[nH]c3cc([N+](=O)[O-])ccc32)cc1
Agent: Cl
Solvent: O
Product: O=c1[nH]c2cc([N+](=O)[O-])ccc2n(Cc2ccc(P(=O)(O)O)cc2)c1=O
Yield: 47.9 %

Procedure:
582 mg (1.4 mmol) of 4-(6-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-ylmethyl)phenylphosphonic acid ethyl ester is refluxed in 6 ml of concentrated hydrochloric acid for 2 hours. After cooling, the batch is combined with water and suctioned off. The filter cake is dried, thus obtaining 253 mg of 4-(6-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-ylmethyl)phenylphosphonic acid, mp: 253-265° C. with decomposition.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[C:20]([CH3:21])=[CH:19][C:13]2[N:14]=[C:15]([NH2:18])[N:16]=[N:17][C:12]=2[CH:11]=1.Br[C:23]1[CH:36]=[CH:35][C:26]([O:27][CH2:28][CH2:29][N:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)=[CH:25][CH:24]=1.C([O-])([O-])=O.[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[C:20]([CH3:21])=[CH:19][C:13]2[N:14]=[C:15]([NH:18][C:23]3[CH:24]=[CH:25][C:26]([O:27][CH2:28][CH2:29][N:30]4[CH2:31][CH2:32][CH2:33][CH2:34]4)=[CH:35][CH:36]=3)[N:16]=[N:17][C:12]=2[CH:11]=1
Reactant: COc1ccc(Cl)c(-c2cc3nnc(N)nc3cc2C)c1
Reactant: Brc1ccc(OCCN2CCCC2)cc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: COc1ccc(Cl)c(-c2cc3nnc(Nc4ccc(OCCN5CCCC5)cc4)nc3cc2C)c1
Temperature: 100 °C

Procedure:
7-(2-chloro-5-methoxy-phenyl)-6-methyl-benzo[1,2,4]triazin-3-ylamine (0.67 mmol, 1.0 equiv), 1-[2-(4-bromophenoxy)-ethyl]pyrrolidine (0.005 mmol, 1.5 equiv), Cs2CO3 (2.01 mmol, 3.0 equiv), Pd2(dba)3 (0.067 mmol, 0.1 equiv), and Xantphos (0.134 mmol, 0.2 equiv) were dissolved in 20 mL dioxane, placed under an argon atmosphere and refluxed at 100° C. for 18 h. The reaction was cooled to room temperature and filtered. The filtrate was dissolved in EtOAc, washed with saturated NaHCO3 and brine and organic phase was dried (Na2SO4). The organics were concentrated under reduced pressure to afford residue that was precipitated out using EtOAc/hexanes (1:5 v/v) to give [7-(2-chloro-5-methoxy-phenyl)-6-methyl-benzo[1,2,4]triazin-3-yl]-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-amine, as an orange solid (271.2 mg, 83% yield). Rf=0.56 (9:1 DCM/MeOH). MS (ES+) m/z=491. LC retention time 2.72 min.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10](=[O:17])[C:11]3[N:12]([CH:14]=[CH:15][CH:16]=3)[CH:13]=2)=[CH:4][CH:3]=1.[O:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]1[O:24][CH2:25][CH2:26][N:27]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[N:28]1.C(=O)([O-])O.[Na+]>CN(C=O)C.O>[O:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]1[O:24][CH2:25][CH2:26][N:27]1[CH:31]=[C:30]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[NH:9][C:10](=[O:17])[C:11]4[N:12]([CH:14]=[CH:15][CH:16]=4)[CH:13]=3)=[CH:4][CH:3]=2)[CH:29]=[N:28]1
Reactant: CC1(C)OB(c2cnn(CCOC3CCCCO3)c2)OC1(C)C
Reactant: O=c1[nH]c(-c2ccc(Br)cc2)cn2cccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1[nH]c(-c2ccc(-c3cnn(CCOC4CCCCO4)c3)cc2)cn2cccc12
Temperature: 40 °C
Reaction time: 20 h

Procedure:
Under nitrogen, a suspension of 145 mg (0.50 mmol) 3-(4-bromo-phenyl)-2H-pyrrolo[1,2-a]pyrazin-1-one, 177 mg (0.55 mmol) 1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole and 50 mg (0.60 mmol) sodium hydrogen carbonate in 1 ml DMF and 0.5 ml water is heated to 40° C. Then 7.0 mg (0.010 mmol) bis(triphenylphosphine)palladium(II)-chloride is added. The reaction mixture is heated to 80° C. and stirred at this temperature for 20 hours. The reaction mixture is cooled to room temperature and excess water is added. The resulting precipitate is filtered off and washed with water. The residue is chromatographed on a silica gel column with methanol/dichloromethane as eluent to give 3-(4-{1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-1H-pyrazol-4-yl}-phenyl)-2H-pyrrolo[1,2-a]pyrazin-1-one as white powder; HPLC/MS 2.39 min (B), [M+H] 405;
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:15]([O:17][CH3:18])=[O:16])[S:5][C:6]=1[NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].C(N(CC)CC)C.Br[CH2:27][C:28]([O:30][CH3:31])=[O:29]>C(Cl)Cl>[C:11]([O:10][C:8]([NH:7][C:6]1[S:5][C:4]([C:15]([O:17][CH3:18])=[O:16])=[CH:3][C:2]=1[NH:1][CH2:27][C:28]([O:30][CH3:31])=[O:29])=[O:9])([CH3:12])([CH3:13])[CH3:14]
Reactant: COC(=O)CBr
Reactant: COC(=O)c1cc(N)c(NC(=O)OC(C)(C)C)s1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CNc1cc(C(=O)OC)sc1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 78.5 %

Procedure:
To a solution of methyl 4-amino-5-(tert-butoxycarbonylamino)thiophene-2-carboxylate 89 (0.037 mmol, 10 mg) in CH2Cl2 (1 mL), triethylamine (0.367 mmol, 51.2 μL) and methyl bromoacetate (0.184 mmol, 17.45 μL) were added and stirred at rt for 3 h. The reaction was quenched in water and extracted with CH2Cl2. The organic layer was dried with phaseseparator whereafter and concentrated under reduced pressure to give methyl 5-(tert-butoxycarbonylamino)-4-(2-methoxy-2-oxoethylamino)thiophene-2-carboxylate 90 (10 mg, 79%). NMR (400 MHz, CDCl3) 1.54 (s, 9H), 3.31 (br s, 1H), 3.77 (s, 3H), 3.79 (d, J=6.3 Hz, 2H), 3.82 (s, 3H), 7.38 (s, 1H), 7.54 (br s, 1H). (m/z)=345 (M+H)+.
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15]O)[N:10]=[CH:9]2)C=CC=CC=1.[OH:29][C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][CH:39]=1)[C:36](=[O:40])[CH2:35][CH2:34][CH2:33]2>>[NH:8]1[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][O:29][C:30]2[CH:31]=[C:32]3[C:37](=[CH:38][CH:39]=2)[C:36](=[O:40])[CH2:35][CH2:34][CH2:33]3)[N:10]=[CH:9]1
Reactant: OCCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: O=C1CCCc2cc(O)ccc21
Product: O=C1CCCc2cc(OCCCc3c[nH]cn3)ccc21

Procedure:
5 mmol of 3-(1-triphenylmethyl-1H-imidazol-4-yl)propanol and 6 mmol of 3,4-dihydro-6-hydroxy-2H-naphthalen-1-one are treated as described in Example 56.
Reaction SMILES: [CH3:1][NH:2][C:3](=O)[C:4]([CH3:7])([CH3:6])[CH3:5].[NH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>C1C=CC=CC=1.P(Cl)(Cl)(Cl)=O>[CH3:1][NH:2][C:3](=[N:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[C:4]([CH3:7])([CH3:6])[CH3:5]
Reactant: Nc1ccccc1N1CCCCC1
Reactant: CNC(=O)C(C)(C)C
Solvent: c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: CNC(=Nc1ccccc1N1CCCCC1)C(C)(C)C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of N-methylpivalamide (11.5 g) in benzene (120 ml) and phosphorus oxychloride (9.2 ml) was stirred at room temperature for 3 days. A solution of 1-(2-aminophenyl)piperidine (14 g) in benzene (80 ml) was added and the mixture heated at 65°-70° C. for four days to give N-methyl-N'-(2-piperidinophenyl)pivalamidine (m.p. 78° C.) which was recrystallised from hexane. The product was obtained as a 0.25 hydrate.