Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)COC([PH2]=C)=O)C=CC=CC=1.Br[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=2)=[CH:32][CH:31]=1)=[O:29].Br[CH2:44][C:45]([O:47][CH2:48][CH3:49])=[O:46].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1C=CC=CC=1>[F:42][C:39]1[CH:40]=[CH:41][C:36]([C:33]2[CH:34]=[CH:35][C:30]([C:28](=[O:29])/[CH:27]=[CH:44]/[C:45]([O:47][CH2:48][CH3:49])=[O:46])=[CH:31][CH:32]=2)=[CH:37][CH:38]=1
Reactant: O=C(CBr)c1ccc(-c2ccc(F)cc2)cc1
Reactant: CCOC(=O)CBr
Agent: C=[PH2]C(=O)OCC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: CCOC(=O)/C=C/C(=O)c1ccc(-c2ccc(F)cc2)cc1
Reaction time: 2 h

Procedure:
A mixture of 18.5 gm (0.0538 mol) of triphenyl-carbethoxy-methylenephosphoran and 260 cc of absolute benzene was heated to boiling, 7.6 gm (0.026 mol) of 2-bromo-4'-(4-fluoro-phenyl)-acetophenone were added, and the mixture was stirred for two hours at the boiling point. Thereafter, the precipitated triphenyl-carbethoxy-methylphosphonium bromide was separated by vacuum filtration, the clear filtrate was admixed with 4.35 gm (0.026 mol) of ethyl bromoacetate to tie up the triphenyl-phosphine, and the mixture was again boiled for two hours. Thereafter, the reaction mixture was allowed to cool, was then filtered, the filtrate was evaporated, and the residue was recrystallized first from methanol and subsequently from cyclohexane, yielding 4.2 gm (54% of theory) of the compound of the formula ##STR9## having a melting point of 115°-117° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[C:7]([CH:11]=1)=[N:8][S:9][N:10]=2.C(O)C.[C-:15]#[N:16].[K+]>O>[N:10]1[S:9][N:8]=[C:7]2[CH:11]=[C:3]([CH2:2][C:15]#[N:16])[CH:4]=[CH:5][C:6]=12
Reactant: [C-]#N
Reactant: BrCc1ccc2nsnc2c1
Agent: [K+]
Solvent: O
Solvent: CCO
Product: N#CCc1ccc2nsnc2c1
Yield: 53.3 %

Procedure:
A mixture of 5-bromomethyl-benzo[1,2,5]thiadiazole [RN65858-50-6](7.0 g, 30 mmol), ethanol (50 ml)and a solution of potassium cyanide (2.3 g, 36 mmol) in water (25 ml) was stirred at 50° C. for 15 hours. The alcoholic solution was concentrated and the residue suspended in water. The solid was collected by filtration, washed with water and dried in vacuo to give benzo[1,2,5]thiadiazol-5-yl-acetonitrile (2.8 g, 47%)
Reaction SMILES: [OH:1][N:2]1[C:10](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:12].[C:13]1(B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.N1C=CC=CC=1>ClCCCl.C(Cl)Cl.[Cu]Cl>[O:1]([N:2]1[C:10](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:12])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: OB(O)c1ccccc1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: Cl[Cu]
Solvent: ClCCCl
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C1c2ccccc2C(=O)N1Oc1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a 50 mL single neck RB flask wash charged with 2-hydroxy-1H-isoindole-1,3(2H)-dione (1 g, 6.13 mmol), 4 A° molecular sieves (1 g) and copper (I) chloride (0.61 g, 0.06 mmol) in DCE under open atmosphere. To the stirred reaction mixture, was added phenyl boronic acid (1.5 g, 12.2 mmol) followed by pyridine (0.53 g, 6.7 mmol) drop wise. Resulting mixture was stirred at RT for 12 h. The Reaction mixture was diluted with DCM and then filtered through celite pad. The organic layer was washed with saturated brine solution (50 mL) and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure to afford off white solid. 1H NMR (300 MHz, CDCl3): δ 7.83-7.86 (q, 2H), 7.73-7.77 (m, 2H), 7.28-7.30 (m, 2H), 7.07-7.11 (m, 3H).
Reaction SMILES: C([O:3][C:4](=[O:32])/[C:5](/[O:29][CH2:30][CH3:31])=[CH:6]/[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:19][C:20]=2[CH3:21])=[CH:9][C:8]=1[CH3:28])C>C1COCC1.CO.O>[CH2:30]([O:29]/[C:5](=[CH:6]\[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[O:19][C:20]=2[CH3:21])=[CH:9][C:8]=1[CH3:28])/[C:4]([OH:32])=[O:3])[CH3:31]
Reactant: CCOC(=O)/C(=C/c1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1C)OCC
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CCO/C(=C\c1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1C)C(=O)O
Reaction time: 48 h
Yield: 90.9 %

Procedure:
To a solution of 0.40 g of 2Z-ethoxy-3-{2-methyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-acrylic acid ethyl ester in 10 ml of THF, 5 ml of MeOH and 5 ml of water was added at 22° C. 0.116 g of LiOHxH2O and stirring was continued for 2 d. The yellow solution was evaporated, the residue dissolved in 20 ml of water and the pH was adjusted to 5 using ca. 2.6 ml of 1 N aqueous HCl. The suspension was filtered, the residue washed with water and dried to give 0.34 g (91%) of the title compound as a white solid.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[N:26]1[C:35]2[C:30](=[CH:31][C:32]([C:36](O)=[O:37])=[CH:33][CH:34]=2)[CH:29]=[CH:28][CH:27]=1>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:36]([C:32]4[CH:31]=[C:30]5[C:35](=[CH:34][CH:33]=4)[N:26]=[CH:27][CH:28]=[CH:29]5)=[O:37])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: O=C(O)c1ccc2ncccc2c1
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4ccc5ncccc5c4)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP2-WU2 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one (compound B1) and quinoline-6-carboxylic acid as starting compounds. The crude product is purified by chromatography (amino phase silica gel and DCM) and by crystallization from DCM and diethyl ether to yield the title compound.
Reaction SMILES: C([O:3][CH:4](OCC)[C:5]1[O:9][CH:8]=[C:7]([C:10]2[CH:22]=[CH:21][C:13]3[NH:14][C:15](=[O:20])[O:16][C:17]([CH3:19])([CH3:18])[C:12]=3[CH:11]=2)[CH:6]=1)C.Cl>C1COCC1>[CH3:18][C:17]1([CH3:19])[O:16][C:15](=[O:20])[NH:14][C:13]2[CH:21]=[CH:22][C:10]([C:7]3[CH:6]=[C:5]([CH:4]=[O:3])[O:9][CH:8]=3)=[CH:11][C:12]1=2
Reactant: CCOC(OCC)c1cc(-c2ccc3c(c2)C(C)(C)OC(=O)N3)co1
Agent: Cl
Solvent: C1CCOC1
Product: CC1(C)OC(=O)Nc2ccc(-c3coc(C=O)c3)cc21

Procedure:
A solution of 6-(5-diethoxymethyl-furan-3-yl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one (1.1 g, 3 mmol) was stirred in THF (20 mL) and 2N HCl (2 mL) for 1 hour. The crystalline product was filtered and dried (0.52 g, 69%): mp 262-263° C.; 1H NMR (DMSO-d6) δ10.3 (s, 1H), 9.65 (s, 1H), 8.59 (s, 1H), 8.04 (s, 1H), 7.65-7.64 (d, 1H, J=1.5 Hz), 7.61-7.60 (d, 1H, J=1.8 Hz), 7.59-7.58 (d, 1H, J=1.8 Hz), 6.94-6.91 (d, 1H, J=8.2 Hz), 1.65 (s, 6H). MS (ESI) m/z 270 [M−H]−.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:20][CH3:21])[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[C:15]([F:17])[C:14]([F:18])=[C:13]([F:19])[CH:12]=3)[C:6]=2[N:7]=1.[Cl:22][C:23]1[N:24]=[CH:25][N:26]([C:28]2[N:33]=[CH:32][C:31]([NH2:34])=[CH:30][C:29]=2[O:35][CH3:36])[CH:27]=1>C(O)(=O)C.C1COCC1>[Cl:22][C:23]1[N:24]=[CH:25][N:26]([C:28]2[N:33]=[CH:32][C:31]([NH:34][C:2]3[N:3]=[C:4]([NH:20][CH3:21])[C:5]4[CH2:10][CH2:9][CH:8]([C:11]5[CH:16]=[C:15]([F:17])[C:14]([F:18])=[C:13]([F:19])[CH:12]=5)[C:6]=4[N:7]=3)=[CH:30][C:29]=2[O:35][CH3:36])[CH:27]=1
Reactant: CNc1nc(Cl)nc2c1CCC2c1cc(F)c(F)c(F)c1
Reactant: COc1cc(N)cnc1-n1cnc(Cl)c1
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CNc1nc(Nc2cnc(-n3cnc(Cl)c3)c(OC)c2)nc2c1CCC2c1cc(F)c(F)c(F)c1
Temperature: 80 °C

Procedure:
2-Chloro-N-methyl-7-(3,4,5-trifluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine (100 mg, 0.319 mmol) was added to a solution of 6-(4-chloro-1H-imidazol-1-yl)-5-methoxypyridin-3-amine (107 mg, 0.478 mmol) in acetic acid (2 mL) and THF (2.000 mL). The reaction mixture was heated at 80° C. overnight. Partial formation of the desired product was observed. The reaction mixture was heated at 130° C. for 6 h. The crude reaction mixture was purified by preparative HPLC. The appropriate fractions were evaporated to afford N2-(6-(4-chloro-1H-imidazol-1-yl)-5-methoxypyridin-3-yl)-N4-methyl-7-(3,4,5-trifluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine, TFA salt (12.9 mg, 0.021 mmol, 6.50% yield). LC-MS (M+H)+=502.2. 1H NMR (500 MHz, CDCl3) δ ppm 12.33 (1H, s), 8.75 (1H, s), 8.56 (1H, s), 7.61-7.89 (2H, m), 6.85-7.00 (2H, m), 5.62-5.79 (1H, m), 4.36-4.49 (1H, m), 4.02 (3H, s), 3.29 (3H, d, J=4.9 Hz), 2.88-2.98 (1H, m), 2.76-2.85 (2H, m), 2.21-2.38 (1H, m).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:5]2=[O:20].N1C=CC=CC=1.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>C1COCC1>[CH3:27][S:28]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([CH2:12][C:13]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:14])[C:5]2=[O:20])(=[O:30])=[O:29]
Reactant: CC(C)(C)OC(=O)CN1C(=O)c2ccc(N)cc2C1=O
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CN1C(=O)c2ccc(NS(C)(=O)=O)cc2C1=O
Yield: 14.5 %

Procedure:
To a solution of tert-butyl 2-(5-amino-1,3-dioxoisoindolin-2-yl)acetate (14 g, 50.7 mmol) in THF (100 ml), pyridine (8.20 ml, 101 mmol) was added followed by methanesulfonyl chloride (7.74 ml, 101 mmol), and the resulting mixture was heated to reflux for 5 hours. The volatiles were removed under vacuum, the residue was dissolved in DCM (200 ml) and washed with 0.2M HCl (3×50 ml) and brine; the organic phase was dried over Na2SO4 and evaporated to dryness. The resulting solid was triturated with ethyl acetate, and the title compound was recovered by filtration (12.5 g). The mother liquors were evaporated in vacuo and purified by silica gel chromatography (DCM:AcOEt 10:1), affording additional 2.6 g of the title compound. These two batches were dissolved in DCM, combined, and the solvent was evaporated in vacuo to afford tert-butyl 2-(5-(methylsulfonamido)-1,3-dioxoisoindolin-2-yl)acetate (15.1 g, 42.6 mmol, 84% yield, MS/ESI+ 354.9 [MH]+).
Reaction SMILES: CS(O[CH2:6][C@H:7]1[CH2:11][CH2:10][N:9]([C:12]2[C:21]3[C:16](=[N:17][CH:18]=[CH:19][N:20]=3)[CH:15]=[C:14]([C:22]3[CH:27]=[CH:26][C:25]([N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)=[CH:24][CH:23]=3)[N:13]=2)[CH2:8]1)(=O)=O.[CH3:34][NH2:35]>>[CH3:34][NH:35][CH2:6][C@H:7]1[CH2:11][CH2:10][N:9]([C:12]2[C:21]3[C:16](=[N:17][CH:18]=[CH:19][N:20]=3)[CH:15]=[C:14]([C:22]3[CH:23]=[CH:24][C:25]([N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)=[CH:26][CH:27]=3)[N:13]=2)[CH2:8]1
Reactant: CN
Reactant: CS(=O)(=O)OC[C@H]1CCN(c2nc(-c3ccc(N4CCOCC4)cc3)cc3nccnc23)C1
Product: CNC[C@H]1CCN(c2nc(-c3ccc(N4CCOCC4)cc3)cc3nccnc23)C1

Procedure:
The mixture of (S)-(1-(7-(4-morpholinophenyl)pyrido[4,3-b]pyrazin-5-yl)pyrrolidin-3-yl)methyl methanesulfonate (100 mg, 0.21 mmol) and MeNH2 solution (33% in water, 5 mL) was refluxed overnight, concentrated, and purified by chromatography to give the title compound. MS (m/z): 405 (M+H)+
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[C:10]([C:15]([OH:17])=[O:16])[CH:9]=[CH:8]2)(=O)C>O>[OH:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[C:10]([C:15]([OH:17])=[O:16])[CH:9]=[CH:8]2
Reactant: CC(=O)Oc1ccc2cc(C(=O)O)ccc2c1
Solvent: O
Product: O=C(O)c1ccc2cc(O)ccc2c1
Reaction time: 4 h

Procedure:
100 parts of a moist 6-acetoxy-2-naphthoic acid containing 60 parts of water, such as obtainable, for example, according to the above Example 6 before this product has been dried, are stirred in 300 parts of an about 70% aqueous sulfuric acid solution at a temperature between 90° and 100° C. for 4 hours. The 6-hydroxy-2-naphthoic acid which is formed and which precipitates, is filtered off after the reaction batch has been cooled to 70° to 80° C., washed with hot water and dried. 31 parts of a pure 6-hydroxy-2-naphthoic acid is obtained, having a melting point of 245° C. (according to Example 1 of U.S. Pat. No. 1,593,816, recrystallized 6-hydroxy-2-naphthoic acid has a melting point of 245° C.).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)=[CH:4][C:3]=1[CH:15]([OH:17])[CH3:16].Cl[C:19](Cl)([O:21]C(=O)OC(Cl)(Cl)Cl)Cl.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>C1COCC1>[F:14][C:10]1[CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]3[NH:1][C:19](=[O:21])[O:17][CH:15]([CH3:16])[C:3]=3[CH:4]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(O)c1cc(-c2cccc(F)c2)ccc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC1OC(=O)Nc2ccc(-c3cccc(F)c3)cc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 81 %

Procedure:
A mixture of the above alcohol (0.2 g, 0.87 mmol) and triphosgene in anhydrous THF (20 mL) was stirred at room temperature under nitrogen. After 15 minutes, the mixture was treated with a saturated aqueous sodium bicarbonate solution (30 mL) and ethyl acetate (40 mL). The organic layer was separated, dried (MgSO4), and evaporated to give 6-(3-fluorophenyl)-4-methyl-1,4-dihydro-2H-3,1-benzoxazin-2-one as a white solid (0.18 g, 81%): mp 160-161° C.; 1H-NMR (DMSO-d6) δ 10.31 (s, 1H), 7.62 (dd, 1H, J=8.2, 1.9 Hz), 7.57 (s, 1H), 7.44-7.53 (m, 3H), 7.13-7.20 (m 1H), 6.97 (d, 1H, J=8.2 Hz), 5.57 (q, 1H, J=6.6 Hz), 1.63 (d, 3H, J=6.6 Hz). MS (ESI) m/z 256 [M−H]−.
Reaction SMILES: CS(Cl)(=O)=O.[O:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH:7]1[O:12][CH2:13][CH2:14][CH2:15][CH2:16]C#CCO.Cl.[Br:22]CC#CCCCCOC1CCCCO1>N1C=CC=CC=1>[O:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH:7]1[O:12][CH2:13][CH2:14][CH2:15][CH2:16][Br:22]
Reactant: OCC#CCCCCOC1CCCCO1
Reactant: BrCC#CCCCCOC1CCCCO1
Agent: CS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: BrCCCCOC1CCCCO1
Temperature: -20 °C
Reaction time: 1 h

Procedure:
Methanesulfonyl chloride (20.3 ml.) is added slowly with stirring to a solution of 7-tetrahydropyranyloxyhept-2-yne-1-ol (52.5 g.) in 400 ml. of pyridine at -20° C. The mixture is stirred one hour at -20° C., and then is poured into a stirred mixture of 3-normal hydrochloric acid (1727 ml.) and 2,540 ml. of ice water. This mixture is extracted with diethyl ether. The extract is washed with cold one normal hydrochloric acid and then with saturated aqueous sodium chloride solution, dried, and evaporated at reduced pressure. The residue is dissolved in 500 ml. of dry acetone. Lithium bromide (26 g.) is added to the acetone solution, and the mixture is stirred and heated at reflux 1 hour, and then kept at 25° C. for 15 hours. The acetone is evaporated under reduced pressure, and the residue is extracted with diethyl ether. The diethyl ether extract is washed with water and then 3 times with saturated aqueous sodium chloride solution, dried, and evaporated. The residue is chromatographed on 3.5 kg. of silica gel, eluting with 24 l. of 10% ethyl acetate in Skellysolve B, collecting 1.5 l. fractions. Fractions 5-10 are combined and evaporated to give 25 g. of 1-bromo-7-tetrahydropyranyloxyhept-2-yne.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C@@H:5]([C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)[OH:6].C(OCC)(=O)C.[C:18]12([CH2:28][S:29](O)(=[O:31])=[O:30])[C:25]([CH3:27])([CH3:26])[CH:22]([CH2:23][CH2:24]1)[CH2:21][C:19]2=[O:20]>C(O)C>[CH3:26][C:25]1([CH3:27])[CH:22]2[CH2:23][CH2:24][C@@:18]1([CH2:28][S:29]([O:6][C@H:5]([C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)[CH2:4][CH2:3][NH:2][CH3:1])(=[O:31])=[O:30])[C:19](=[O:20])[CH2:21]2
Reactant: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Reactant: CNCC[C@H](O)c1cccs1
Solvent: CCO
Solvent: CCOC(C)=O
Product: CNCC[C@H](OS(=O)(=O)C[C@]12CCC(CC1=O)C2(C)C)c1cccs1
Temperature: 30 °C
Reaction time: 0.25 h
Yield: 92.7 %

Procedure:
A mixture of (S)-3-methylamino-1-thiophen-2-yl-propan-1-ol (34.2 g, 200 mmol) and ethyl acetate (400 mL) is heated to 30° C., then a mixture of (+)-camphor-10-sulfonic acid (46.4 g, 200 mmol), ethyl acetate (100 mL) and ethanol (100 mL) is added dropwise at 30° C. in 40 minutes. At the end of the addition, the resulting solution is heated to 50° C., stirred for 15 minutes at that temperature, then cooled to 25° C. Once cold, the reaction mixture is concentrated to dryness and ethyl acetate (500 mL) is added to the residue. The resulting mixture is then heated to reflux, kept at that temperature for 15 minutes, then cooled to 25° C. in 30 minutes while seeding the reaction mixture when the temperature reaches about 40° C. Once cold, the resulting suspension is stirred for 30 additional minutes. Afterwards, the precipitate is filtrated, washed with ethyl acetate (2×50 mL) and dried at 40° C. under vacuum (20 mbar) for 15 h affording a white solid (71.5 g, 89%); 1H-NMR (CDCl3, 400 MHz): 7.2 (1H, dm), 7.0 (1H, m), 6.9 (1H, m), 5.21 (1H, t), 3.3 (3H, m), 2.82 (1H, d), 2.75 (3H, s), 2.50 (1H, m, symm.), 2.3 (3H, m), 2.1 (1H, m), 2.0 (1H, m), 1.85 (1H, d), 1.74 (1H, m, symm.), 1.4 (1H, m), 1.04 (3H, s), 0.82 (3H, s).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[C:5]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[C:6]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8][C:7]=2[N:13]=1.[CH3:25][O:26][C:27](=[O:36])[C:28]1[CH:33]=[C:32]([Cl:34])[C:31](Cl)=[N:30][CH:29]=1.CCN(CC)CC>CN(C=O)C.O>[Cl:34][C:32]1[CH:33]=[C:28]([C:27]([O:26][CH3:25])=[O:36])[CH:29]=[N:30][C:31]=1[N:10]1[CH2:11][CH2:12][C:6]2[C:5]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:24])[F:23])=[CH:17][CH:16]=3)=[N:4][C:3]([S:2][CH3:1])=[N:13][C:7]=2[CH2:8][CH2:9]1
Reactant: COC(=O)c1cnc(Cl)c(Cl)c1
Reactant: CSc1nc2c(c(Nc3ccc(C(F)(F)F)cc3)n1)CCNCC2
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)c1cnc(N2CCc3nc(SC)nc(Nc4ccc(C(F)(F)F)cc4)c3CC2)c(Cl)c1
Temperature: 25 °C
Yield: 73.1 %

Procedure:
A solution of (2-methylsulfanyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl)-(4-trifluoromethyl-phenyl)-amine (187 mg, 0.53 mmol), 5,6-dichloro-nicotinic acid methyl ester (129 mg, 0.58 mmol), and Et3N (0.2 mL, 1.58 mmol) in DMF (1.2 mL) was heated at 120° C. for 2 h. The mixture was cooled to rt, diluted with water, and extracted with EtOAc. The combined organic layers were dried and concentrated. The residue was purified (FCC) to give the title compound (203 mg, 74%). MS (ESI): mass calcd. for C23H21ClF3N5O2S, 523.11; m/z found, 524.1 [M+H]+. 1H NMR (CDCl3): 8.57 (d, J=2.0 Hz, 1H), 8.00 (d, J=2.0 Hz, 1H), 7.59 (d, J=8.6 Hz, 2H), 7.48 (d, J=8.6 Hz, 2H), 6.73-6.59 (m, 1H), 3.89-3.65 (m, 7H), 3.19-3.07 (m, 2H), 2.95-2.87 (m, 2H), 2.40 (s, 3H).
Reaction SMILES: [C:1]([N:4]([CH3:32])[CH2:5][CH2:6][N:7]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH:15]=2)[C:10]([OH:25])=[C:9]([C:26](OCC)=[O:27])[C:8]1=[O:31])(=[O:3])[CH3:2].[CH2:33]([CH2:35][NH2:36])[OH:34]>>[C:1]([N:4]([CH3:32])[CH2:5][CH2:6][N:7]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([CH2:17][C:18]3[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=3)[CH:15]=2)[C:10]([OH:25])=[C:9]([C:26]([NH:36][CH2:35][CH2:33][OH:34])=[O:27])[C:8]1=[O:31])(=[O:3])[CH3:2]
Reactant: NCCO
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN(C)C(C)=O)c1=O
Product: CC(=O)N(C)CCn1c(=O)c(C(=O)NCCO)c(O)c2ncc(Cc3ccc(F)cc3)cc21

Procedure:
This compound was prepared from ethyl 1-{2-[acetyl(methyl)amino]ethyl}-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and ethanolamine using methods similar to Example 574: step 2 to provide an off-white solid: 1H NMR (400 MHz, DMSO-d690° C.) δ ppm 1.85 (s, 3 H), 2.95 (s, 2 H), 3.49 (q, J=5.58 Hz, 3 H), 3.53 (d, J=13.58 Hz, 2 H), 3.58-3.66 (m, 2 H), 4.18 (s, 2 H), 4.36 (d, J=6.04 Hz, 2 H), 4.62-4.65 (m, 1 H), 7.12 (t, J=8.92 Hz, 2 H), 7.37-7.43 (m, 2 H), 8.07 (s, 1 H), 8.55 (s, 1 H), 10.32 (s, 1 H), 17.08 (s, 1 H); ES+ MS: 457 (M+H+).
Reaction SMILES: [C:1]([NH:4][N:5]1[CH:9]=[N:8][N:7]=[C:6]1[N:10]([C:21](=[O:23])[CH3:22])[N:11]=[CH:12][C:13]1[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:20])(=[O:3])[CH3:2].[C:24](=O)([O-])[O-].[Na+].[Na+].S(OC)(OC)(=O)=O>O>[CH3:24][N:4]([N:5]1[CH:9]=[N:8][N:7]=[C:6]1[N:10]([C:21](=[O:23])[CH3:22])[N:11]=[CH:12][C:13]1[C:14]([Cl:20])=[CH:15][CH:16]=[CH:17][C:18]=1[Cl:19])[C:1](=[O:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CC(=O)Nn1cnnc1N(N=Cc1c(Cl)cccc1Cl)C(C)=O
Agent: [Na+]
Solvent: O
Solvent: COS(=O)(=O)OC
Product: CC(=O)N(N=Cc1c(Cl)cccc1Cl)c1nncn1N(C)C(C)=O
Reaction time: 8 h

Procedure:
To a solution of 31.5 g of 4-acetamido-3[1-acetyl-2-(2,6-dichlorobenzylidene)hydrazino] -1,2,4-triazole and 53.0 g of sodium carbonate in 400 ml of water is added dropwise, while stirring and cooling in an ice bath, 40 ml of dimethyl sulphate (2 h). After the addition the mixture was stirred for 2,5 h while cooling in ice and left overnight at room temperature. The obtained precipitate is collected and recrystallized twice from dioxane-isopropyl ether. Yield: 7.3 g, m.p. 167°-169° .
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:10]2[N:11]=[C:12]([S:15][CH2:16][C:17]([OH:19])=O)[CH:13]=[CH:14][C:9]2=[N:8][N:7]=1.CN(C(ON1N=N[C:30]2[CH:31]=[CH:32][CH:33]=[N:34][C:29]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.N1CCCCC1.CCN(C(C)C)C(C)C>CN(C=O)C>[N:34]1([C:17](=[O:19])[CH2:16][S:15][C:12]2[CH:13]=[CH:14][C:9]3[N:10]([C:6]([C:2]4[S:1][CH:5]=[CH:4][CH:3]=4)=[N:7][N:8]=3)[N:11]=2)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]1
Reactant: O=C(O)CSc1ccc2nnc(-c3cccs3)n2n1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCNCC1
Product: O=C(CSc1ccc2nnc(-c3cccs3)n2n1)N1CCCCC1
Reaction time: 0.25 h

Procedure:
To 2-((3-(thiophen-2-yl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)thio)acetic acid (100 mg, 0.34 mmol) dissolved in DMF (3 mL) was added HATU (150 mg), and after 15 minutes stirring, piperidine (40 mg) was added followed by DIPEA (200 μL). The mixture was stirred for room temperature overnight and then evaporated to dryness. 1-(Piperidin-1-yl)-2-((3-(thiophen-2-yl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)thio)ethanone was then isolated by preparative TLC (silica gel plates, 9:1 CHCl3/MeOH).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1>C(O)C.C(OCC)(=O)C.[Pt](=O)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[C:11]1[CH:12]=[CH:13][N:14]=[CH:15][CH:16]=1
Reactant: O=[N+]([O-])c1ccc(F)c(-c2ccncc2)c1
Agent: O=[Pt]=O
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1ccc(F)c(-c2ccncc2)c1
Reaction time: 0.58 h
Yield: 82.1 %

Procedure:
To a solution of 4-(2-fluoro-5-nitrophenyl)pyridine (1.0 g, 5.58 mmol) in ethanol (30 ml) and ethyl acetate (10 ml) was added platinum(IV) oxide (52 mg) and the mixture stirred for 35 min under hydrogen (40 psi). The reaction was filtered through glass microfibre filter paper and the filtrate evaporated to dryness to give 4-fluoro-3-(pyridin-4-yl)phenylamine (862 mg, 100%) as a white solid: δH (360 MHz, CDCl3) 3.49 (2H, s), 6.66-6.70 (1H, m), 6.71-6.76 (1H, m), 6.99 (1H, t, J 9), 7.44-7.46 (2H, m), 8.66 (2H, d, J 5).