Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[C:12]([O:16][C:17](=[O:42])[NH:18][C:19]1[C:20]([NH:31][C:32](=[O:41])[C:33]2[CH:38]=[CH:37][C:36]([CH2:39][NH2:40])=[CH:35][CH:34]=2)=[N:21][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:23][CH:24]=1)([CH3:15])([CH3:14])[CH3:13].CCN(C(C)C)C(C)C.O>C1COCC1>[CH2:5]([O:4][C:2](=[O:3])[NH:40][CH2:39][C:36]1[CH:37]=[CH:38][C:33]([C:32]([NH:31][C:20]2[C:19]([NH:18][C:17]([O:16][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:42])=[CH:24][CH:23]=[C:22]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:21]=2)=[O:41])=[CH:34][CH:35]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2)nc1NC(=O)c1ccc(CN)cc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2)nc1NC(=O)c1ccc(CNC(=O)OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Benzyl chloroformate (0.06 ml, 0.420 mmol) was added to a flask containing tert-butyl(2-{[4-(aminomethyl)benzoyl]amino}-6-phenylpyridin-3-yl)carbamate (158 mg, 0.378 mmol) and DIPEA (0.15 ml, 0.859 mmol) in THF (5 mL) at 0° C. The mixture was stirred at 0° C. for 1 hour. Water was added and the products were extracted into EtOAc (2×). The combined organic extracts were washed with brine, dried over sodium sulfate and concentrated. The organic product was purified by column chromatography on silica gel Biotage 25S, eluting with EtOAc/hexanes (0%-100%) to give a pale slightly yellow transparent gel. MS: cal'd 553 (MH+), exp 553 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([NH2:23])[CH:18]=2)([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:6][CH:7]=1.[C:24](OC(=O)C)(=[O:26])[CH3:25].[C:31](O)(=[O:33])[CH3:32]>>[C:24]([NH:23][C:19]1[CH:18]=[C:17]([C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][C:31](=[O:33])[CH3:32])[CH:3]=2)([C:9]([F:10])([F:11])[F:12])[C:13]([F:14])([F:15])[F:16])[CH:22]=[CH:21][CH:20]=1)(=[O:26])[CH3:25]
Reactant: CC(=O)O
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cccc(C(c2cccc(N)c2)(C(F)(F)F)C(F)(F)F)c1
Product: CC(=O)Nc1cccc(C(c2cccc(NC(C)=O)c2)(C(F)(F)F)C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
66.8 g (0.2 mol) of 2,2-bis-(3-aminophenyl)hexafluoropropane are dissolved in 250 ml of glacial acetic acid and 130 ml of ice water are added. 48.1 g (1.3 mol) of acetic anhydride are added at 5° C. and the mixture is stirred for 30 minutes. The deposited precipitate is filtered off with suction, washed intensively with 500 ml of water and dried at 80° C. Yield 83 g (0.198 mol); white solid; m.p. 309°-311° C.
Reaction SMILES: [H-].[Na+].F[C:4]1[C:9]([F:10])=[C:8]([F:11])[CH:7]=[CH:6][C:5]=1[C:12]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:13]=1[C:14]([OH:16])=[O:15].C(OCC)(=O)C.Cl>CN(C)C=O.O>[F:11][C:8]1[C:9]([F:10])=[C:4]2[C:5]([C:12]3[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:13]=3[C:14](=[O:16])[O:15]2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1-c1ccc(F)c(F)c1F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: O=c1oc2c(F)c(F)ccc2c2ccc([N+](=O)[O-])cc12
Temperature: 80 °C
Reaction time: 24 h
Yield: 59.1 %

Procedure:
60% Sodium hydride (2.82 g, 70.5 mmol) was suspended in anhydrous N,N-dimethylformamide (60 mL), then under ice cooling, an anhydrous N,N-dimethylformamide solution (40 mL) of 2-(2,3,4-trifluorophenyl)-5-nitrobenzoic acid (Reference Compound No. 1-2-(2), 6.97 g, 23.5 mmol) was added dropwise thereto, and then the reaction mixture was stirred under nitrogen atmosphere at 80° C. for 24 hours. After cooling down, ethyl acetate (400 mL), water (400 mL) and 1N aqueous HCl solution (80 mL) were added, and then separated. The organic layer was washed with saturated brine (200 mL), dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. Chloroform was added to the obtained solid, and then filtered to give the titled reference compound (3.85 g) as a brown solid. (Yield 59%)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[NH:10][C:9](=O)[CH:8]=2)[CH:2]=1.P(Cl)(Cl)([Cl:22])=O.P(Cl)(Cl)(Cl)(Cl)Cl.C([O-])(O)=O.[Na+]>>[Cl:22][C:9]1[CH:8]=[C:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[N:10]=1
Reactant: O=c1cc(-c2cccnc2)nc(-c2ccccn2)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Clc1cc(-c2cccnc2)nc(-c2ccccn2)n1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To 6-pyridin-3-yl-2-pyridin-2-yl-3H-pyrimidin-4-one (1 eq, 0.26 mmol, 0.035 g) under inert atmosphere, is added dropwise phosphorus oxychloride (15 eq, 3.9 mmol, 0.36 ml) followed by cautious addition of phosphorus pentachloride (1 eq, 0.26 mmol, 0.054 g). After 4 hours at 100° C., the reaction mixture is added slowly to ice/water. The pH is adjusted to pH 7 using NaHCO3 and the aqueous portion is extracted with EtOAc. The combined organic extracts are separated, washed with brine, dried (MgSO4) and concentrated in vacuo. The crude product is purified by flash chromatography eluting with 0-100% MeOH in DCM to afford 4-chloro-6-pyridin-3-yl-2-pyridin-2-yl-pyrimidine as a white solid [M+H]+=269/271.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[CH:15]=[C:16]([C:32]([NH:34][CH2:35][CH2:36][CH2:37][N:38]([CH3:40])[CH3:39])=[O:33])[C:17](=[O:31])[N:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=4)[C:19]=3[CH3:20])=[CH:12][CH:11]=[N:10]2)=[CH:5][CH:4]=1)#[N:2].[C:41]1([S:47]([O:50]C)(=[O:49])=[O:48])[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>CC(C)=O>[C:41]1([S:47]([O-:50])(=[O:49])=[O:48])[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[CH:15]=[C:16]([C:32]([NH:34][CH2:35][CH2:36][CH2:37][N+:38]([CH3:41])([CH3:40])[CH3:39])=[O:33])[C:17](=[O:31])[N:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:29])([F:28])[F:30])[CH:22]=4)[C:19]=3[CH3:20])=[CH:12][CH:11]=[N:10]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cc(C(=O)NCCCN(C)C)c(=O)n1-c1cccc(C(F)(F)F)c1
Reactant: COS(=O)(=O)c1ccccc1
Solvent: CC(C)=O
Product: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cc(C(=O)NCCC[N+](C)(C)C)c(=O)n1-c1cccc(C(F)(F)F)c1
Product: O=S(=O)([O-])c1ccccc1
Temperature: 80 °C
Yield: 162.8 %

Procedure:
A solution of 5-(1-(4-cyanophenyl)-1H-pyrazol-5-yl)-N-(3-(dimethylamino)propyl)-6-methyl-2-oxo-1-(3-(trifluoromethyl)phenyl)-1,2-dihydropyridine-3-carboxamide (synthesised according to Example 7, step 1) (14.40 g, 26.25 mmol) and methyl benzenesulfonate (3.82 ml, 28.88 mmol) in acetone (127 ml) was heated at 55° C. for 18 h. The solvents were removed by rotary evaporation and the foam-like residue was suspended in a mixture of 2-propanol:ethanol (5:1) (100 mL) and heated to 80° C. and was then stirred at room temperature over night. The precipitate was filtered off, washed twice with a mixture of 2-propanol:ethanol (5:1) (2×20 mL), washed once with heptane (50 mL) and air dried to afford 16.94 g of a white powder. The solid was further dried at 55° C. in vacuum overnight to afford of the title compound (16.75 g, 88%) as an off-white solid; 1H NMR (400 MHz, dmso) δ 1.81 (3H, s), 1.90 (2H, m), 3.01 (9H, s), 3.27 (4H, m), 6.72 (1H, d), 7.30 (3H, m), 7.59 (2H, m), 7.67 (2H, d), 7.71 (1H, d), 7.85 (2H, m), 7.94 (4H, m), 8.04 (1H, s), 9.41 (1H, t); APCI-MS m/z: 563 [M+].
Reaction SMILES: [C:1]([N:9]=[C:10]=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:12][C:13]1[C:14]([O:21][C:22]2[C:27]([F:28])=[CH:26][CH:25]=[CH:24][C:23]=2[F:29])=[C:15]([Cl:20])[C:16]([NH2:19])=[N:17][CH:18]=1>ClCCl>[Br:12][C:13]1[C:14]([O:21][C:22]2[C:27]([F:28])=[CH:26][CH:25]=[CH:24][C:23]=2[F:29])=[C:15]([Cl:20])[C:16]([NH:19][C:10]([NH:9][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[S:11])=[N:17][CH:18]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: Nc1ncc(Br)c(Oc2c(F)cccc2F)c1Cl
Solvent: ClCCl
Product: O=C(NC(=S)Nc1ncc(Br)c(Oc2c(F)cccc2F)c1Cl)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Benzoyl isothiocyanate (163 mg, 1.0 mmol) is added to a solution of 5-bromo-3-chloro-4-(2,6-difluorophenoxy)pyridin-2-amine (336 mg, 1.0 mmol) in dichloromethane (20 mL) at 0° C. The reaction mixture is warmed to room temperature and stirred for one hour. The reaction mixture is diluted with hexanes and filtered to afford N-(5-bromo-3-chloro-4-(2,6-difluorophenoxy)pyridin-2-ylcarbamothioyl)benzamide.
Reaction SMILES: [CH:1]1[N:2]=[C:3]2[CH2:10][CH:9]=[N:8][C:4]2=[C:5]([NH2:7])[N:6]=1.[CH3:11][C:12]1([CH3:24])[O:16][C@H:15]([C@@H:17]([CH2:21][S:22][CH3:23])[CH2:18][NH:19][CH3:20])[CH2:14][O:13]1.[CH2:25]=O.N>CO.O.O1CCOCC1>[CH3:11][C:12]1([CH3:24])[O:16][C@H:15]([C@@H:17]([CH2:21][S:22][CH3:23])[CH2:18][N:19]([CH2:25][C:10]2[C:3]3[N:2]=[CH:1][N:6]=[C:5]([NH2:7])[C:4]=3[NH:8][CH:9]=2)[CH3:20])[CH2:14][O:13]1
Reactant: CNC[C@H](CSC)[C@@H]1COC(C)(C)O1
Reactant: Nc1ncnc2c1N=CC2
Reactant: C=O
Agent: N
Solvent: O
Solvent: CO
Solvent: C1COCCO1
Product: CSC[C@@H](CN(C)Cc1c[nH]c2c(N)ncnc12)[C@@H]1COC(C)(C)O1
Reaction time: 1 h
Yield: 82.5 %

Procedure:
9-Deazaadenine (73 mg, 547 μmol) was added to a solution of (S)-2-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-N-methyl-3-(methylthio)propan-1-amine (80 mg, 365 μmol) and formaldehyde (0.044 ml, 37% aq, 547 μmol) in a 1,4-dioxane (2 ml) and water (0.5 ml) mixture and the resulting suspension heated to 90 C (bath temp). After 1 h the reaction was cooled to ambient and 7N NH3 in MeOH (2.5 ml) was added and the resulting reaction left to stir for a further 1 h. The reaction was then concentrated in vacuo and the residue purified by flash chromatography on silica gel eluting with 10% 7N NH3 in MeOH/DCM=>20% 7N NH3 in MeOH/DCM to afford the title compound (110 mg, 83%) as a syrup. 1H NMR (CD3OD) δ 8.16 (s, 1H), 7.46 (s, 1H), 3.91 (m, 2H), 3.57 (m, 2H), 2.71 (dd, J=13.2, 4.1 Hz, 1H), 2.49 (m, 2H), 2.32 (m, 1H), 2.26 (s, 3H), 2.04 (s, 3H), 1.94 (m, 1H), 1.31 (s, 3H), 1.25 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[NH:6][N:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>COCCOC>[CH2:15]([N:6]1[C:5](=[O:8])[CH:4]=[CH:3][C:2]([Cl:1])=[N:7]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=c1ccc(Cl)n[nH]1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Product: O=c1ccc(Cl)nn1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
6-chloro-2H-pyridazine-3-one (3.50 g) was dissolved in DME (130 mL). To this solution, cesium carbonate (17.5 g) was added and the mixture was stirred at room temperature for 15 min in an argon atmosphere. Subsequently, benzyl bromide (4.00 mL) was added and the mixture was stirred at room temperature for 3.5 hours. The insoluble inorganic residue was removed by filtration and the filtrate was concentrated. Water was then added to the residue and the mixture was extracted with ethyl acetate, washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated and the resulting crystals were recrystallized from ethyl acetate/petroleum ether to afford the title compound as a pale yellow powder (4.94 g).
Reaction SMILES: Cl.Cl.[CH3:3][O:4][C:5](=[O:53])[C@@H:6]([NH:22][C:23]([C@@H:25]1[CH2:34][C:33]2[CH:32]=[C:31]3[O:35][CH2:36][C@H:37]([C:39]4[CH:44]=[CH:43][C:42]([O:45][CH2:46][CH:47]5[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]5)=[CH:41][CH:40]=4)[O:38][C:30]3=[CH:29][C:28]=2[CH2:27][NH:26]1)=[O:24])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([CH3:20])[C:15]=2[CH3:21])=[CH:10][CH:9]=1.[CH3:54][C:55]1[O:56][C:57]([CH3:63])=[C:58]([C:60](Cl)=[O:61])[N:59]=1>>[CH3:3][O:4][C:5](=[O:53])[C@@H:6]([NH:22][C:23]([C@@H:25]1[CH2:34][C:33]2[CH:32]=[C:31]3[O:35][CH2:36][C@H:37]([C:39]4[CH:44]=[CH:43][C:42]([O:45][CH2:46][CH:47]5[CH2:48][CH2:49][CH2:50][CH2:51][CH2:52]5)=[CH:41][CH:40]=4)[O:38][C:30]3=[CH:29][C:28]=2[CH2:27][N:26]1[C:60]([C:58]1[N:59]=[C:55]([CH3:54])[O:56][C:57]=1[CH3:63])=[O:61])=[O:24])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([CH3:20])[C:15]=2[CH3:21])=[CH:10][CH:9]=1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1)O[C@@H](c1ccc(OCC2CCCCC2)cc1)CO3
Reactant: Cc1nc(C(=O)Cl)c(C)o1
Agent: Cl
Product: COC(=O)[C@H](Cc1ccc(-c2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1C(=O)c1nc(C)oc1C)O[C@@H](c1ccc(OCC2CCCCC2)cc1)CO3

Procedure:
(S)-2-{[(3S,8S)-3-(4-Cyclohexylmethoxy-phenyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid methyl ester dihydrochloride (25 mg) was reacted with 2,5-dimethyl-oxazole-4-carbonyl chloride according to General Procedure F to give (S)-2-{[(3S,8S)-3-(4-Cyclohexylmethoxy-phenyl)-7-(2,5-dimethyl-oxazole-4-carbonyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid methyl ester (20 mg). This ester was hydrolyzed according to General Procedure B to give the title compound. LCMS (m/z): 800.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:13]=[CH:12][CH:11]=[N:10]2)=[CH:5][CH:4]=1.[Br:14]N1C(=O)CCC1=O>O1CCCC1>[Br:14][C:12]1[CH:11]=[N:10][N:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[CH:13]=1
Reactant: COc1ccc(-n2cccn2)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Product: COc1ccc(-n2cc(Br)cn2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.7 %

Procedure:
To a solution of 1-(4-methoxyphenyl)-1H-pyrazole (7.2 g, 0.042 mol) in tetrahydrofuran (100 mL) was added N-bromosuccinimide (7.3 g, 0.042 mol). The reaction was stirred at room temperature for 3 hours. The reaction was concentrated and purification by column chromatography gave 4-bromo-1-(4-methoxyphenyl)-1H-pyrazole (8.9 g, 84%) as a white solid. 1H NMR (400 MHz, CDCl3, δ): 7.83 (s, 1H), 7.63 (s, 1H), 7.52 (d, J=8.8 Hz, 2H), 6.97 (d, J=8.8 Hz, 2H), 3.84 (s, 3H).
Reaction SMILES: ClCCCl.[N:5]([C:8]1[C:17]([C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)=[N:16][C:15]([Br:27])=[CH:14][C:9]=1[C:10]([O:12][CH3:13])=[O:11])=[N+]=[N-]>C1COCC1.CCCCCCCC(O)=O.CCCCCCCC(O)=O.CCCCCCCC(O)=O.CCCCCCCC(O)=O.[Rh].[Rh]>[Br:27][C:15]1[CH:14]=[C:9]([C:10]([O:12][CH3:13])=[O:11])[C:8]2[NH:5][C:19]3[CH:20]=[C:21]([N+:24]([O-:26])=[O:25])[CH:22]=[CH:23][C:18]=3[C:17]=2[N:16]=1
Reactant: COC(=O)c1cc(Br)nc(-c2ccc([N+](=O)[O-])cc2)c1N=[N+]=[N-]
Agent: [Rh]
Solvent: ClCCCl
Solvent: CCCCCCCC(=O)O
Solvent: C1CCOC1
Product: COC(=O)c1cc(Br)nc2c1[nH]c1cc([N+](=O)[O-])ccc12
Temperature: 80 °C
Yield: 670 %

Procedure:
1,2-Dichloroethane (30 mL) was added to a mixture of methyl 3-azido-6-bromo-2-(4-nitrophenyl)isonicotinate (6.5 g, 17 2 mmol), rhodium octanoate dimer (0.669 g, 0.859 mmol) and crushed 4A° molecular sieves (6.5 g). The reaction heated at 80° C. for 14 hr. The crude mixture was diluted with THF and filtered. The collected solid were then extracted with additional hot THF. The solvents were removed from the combined filtrates and the residue was suspended in methanol, filtered and air dried to leave methyl 2-bromo-7-nitro-5H-pyrido[3,2-b]indole-4-carboxylate (5.0 g, 13.4 mmol, 78% yield). MS (ESI) m/z 351.91 (M+H). 1H NMR (500 MHz, DMSO-d6) δ ppm 12.31 (1H, br. s.), 8.63 (1H, d, J=2.14 Hz), 8.45 (1H, d, J=8.55 Hz), 8.17 (1H, dd, J=8.55, 2.14 Hz), 8.08 (1H, s), 4.07 (3H, s).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:11]=O)[CH:9]=2)[NH:4][N:3]=1.[NH2:13][C:14]([CH:18]([F:20])[F:19])=[CH:15][C:16]#[N:17]>C(O)(=O)C.CO.ClCCl>[F:19][CH:18]([F:20])[C:14]1[NH:13][C:14]([CH:18]([F:20])[F:19])=[C:15]([C:16]#[N:17])[CH:11]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[NH:4][N:3]=[C:2]3[CH3:1])[C:15]=1[C:16]#[N:17]
Reactant: N#CC=C(N)C(F)F
Reactant: Cc1n[nH]c2ccc(C=O)cc12
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CO
Product: Cc1n[nH]c2ccc(C3C(C#N)=C(C(F)F)NC(C(F)F)=C3C#N)cc12

Procedure:
A solution of 80 mg (0.50 mmol) 3-methyl-1H-indazole-5-carbaldehyde (Example 1A) and 130 mg (1.10 mmol) 3-amino-4,4-difluorobut-2-enenitrile [obtainable by Thorpe reaction of acetonitrile with 2,2-difluoroacetonitrile, cf. Org. React. 15, 1 (1967), ibid. 31, 1 (1984)] in acetic acid (0.5 ml) containing powdered 4 Å molecular sieve was heated to reflux temperature for 3.5 h. After cooling, the reaction mixture was diluted with methanol/dichloromethane and filtered. The filtrate was evaporated, and the residue was purified by preparative RP-HPLC (acetonitrile/water+0.1% TFA gradient) yielding 61 mg (34% of th.) of the title compound.
Reaction SMILES: I[C:2]1[C:3]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[S:17][C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[N:20]=3)=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.CN(C1CCCCC1)C1CCCCC1.[O:39]1[CH2:43][CH:42]=[CH:41][CH2:40]1>O1CCOCC1.CO.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[O:39]1[CH:40]=[CH:41][CH2:42][CH:43]1[C:2]1[C:3]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[S:17][C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[N:20]=3)=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Ic1cccnc1Oc1ccc(Nc2nc3ccccc3s2)cc1
Reactant: C1=CCOC1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: CN(C1CCCCC1)C1CCCCC1
Solvent: CO
Solvent: C1COCCO1
Product: C1=COC(c2cccnc2Oc2ccc(Nc3nc4ccccc4s3)cc2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of N-(4-(3-iodopyridin-2-yloxy)phenyl)benzo[d]thiazol-2-amine (0.403 g, 0.905 mmol), N-methyldicyclohexylamine (0.400 mL, 1.886 mmol, Aldrich), bis(tri-tert-butylphosphine)palladium (0) (0.045 g, 0.088 mmol, Strem) and 2,5-dihydrofuran (0.500 mL, 6.78 mmol, Aldrich) in 5 mL of dioxane was capped under an atmosphere of argon and stirred at rt for 3 h and then heated at 45° C. overnight. The reaction mixture was diluted with MeOH, evaporated onto silica gel and purified by flash chromatography (Isco, (40 gram)) eluting with 2M NH3 in MeOH:CH2Cl2 (0:1→3:97) to give a white amorphous solid. MS (ESI, pos. ion) m/z: 386.0 (M+1).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[C:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH:16][C:17](=O)[CH2:18][N:19]1[C:27](=[O:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]1=[O:29])(=O)[CH3:8].Cl.O=P(Cl)(Cl)[Cl:34]>CN(C=O)C.C1(C)C=CC=CC=1>[Cl:34][C:17]1[C:18]([N:19]2[C:27](=[O:28])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]2=[O:29])=[C:7]([CH3:8])[C:10]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:16]=1
Reactant: CC(=O)c1ccccc1NC(=O)CN1C(=O)c2ccccc2C1=O
Reactant: O=P(Cl)(Cl)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: Cc1c(N2C(=O)c3ccccc3C2=O)c(Cl)nc2ccccc12
Temperature: 60 °C
Reaction time: 16 h
Yield: 79.7 %

Procedure:
1.4 g (10.4 mmol) of K2CO3 were added to a solution of 2.7 g (6.9 mmol) of N-(2-acetylphenyl)-2-(1,3-dioxoisoindolin-2-yl)-acetamide in DMF (27 ml), and the mixture was heated for 16 h at 60° C. After cooling to RT, the pH was adjusted to 2-3 with 2N hydrochloric acid. The resulting precipitate was filtered off with suction and dried in vacuo at 70° C. 9 ml (97 mmol) of POCl3 were added to the residue. This solution was heated for 2 h at 100° C. and then stirred for 16 h at RT. Toluene was then added and concentration was carried out in vacuo. This procedure was repeated, there being obtained as residue 2.13 g (5.5 mmol, 79%) of 2-(2-chloro-4-methylquinolin-3-yl)isoindoline-1,3-dione, which was reacted further without additional purification.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]([NH2:13])=O)=[CH:3]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:23])=CC=1>C1(C)C=CC=CC=1>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11](=[S:23])[NH2:13])=[CH:3]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: Cn1cc(C(N)=O)c2ccccc21
Solvent: Cc1ccccc1
Product: Cn1cc(C(N)=S)c2ccccc21

Procedure:
1-Methylindole-3-carboxamide (0.6 g) was suspended in toluene (20 ml): Lawesson's Reagent (0.7 g) was added and the mixture was heated at reflux under nitrogen for 30 min until dissolution occurred. The solution was cooled and toluene was removed under reduced pressure. The orange residue was purified by column chromatography on alumina using CH2Cl2 as eluant. This afforded an orange crystalline material, (0.5 g). δH (360 MHz, DMSO-d6) 3.82 (3 H, s, NCH3), 7.18 and 7.23 (2 H, 2×dt, J=7.1, 1.1 Hz, H-5 and H-6), 7.49 (1 H. d, J=7.5 Hz, H-7), 8.08 (1 H, s, H-2), 8.59 (1 H, d, J=7.5 Hz, H-4), 8.76 (2 H, brs, NH2); m/z 190 (M+, 100%), 174 (20), 157 (80).
Reaction SMILES: C([N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:10]1)(=O)C1C=CC=CC=1.[OH-].[Na+]>O.C(O)C>[C:18]1([CH:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:9][CH2:10]2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C(c1ccccc1)N1CC(c2ccccc2)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: c1ccc(C2CNc3ccccc32)cc1
Temperature: 0 °C
Yield: 97.2 %

Procedure:
The amount, 5.50 g, of the 1-benzoyl-3-phenylindoline obtained in Example 6 and a solution of 4.0 g of sodium hydroxide in 40 ml of water and 84 ml of ethanol added thereto were refluxed together for six hours. The reaction solution was poured into ice water and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous potassium carbonate solution, then dried over anhydrous magnesium sulfate, and distilled to expel the ethyl acetate and obtain 3.49 g of 3-phenylindoline (97.2%) in the form of an oily semi-solid substance.
Reaction SMILES: [H-].[Na+].[OH:3]CCNC(=O)C.F[C:11]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:12]=1[C:13]([NH:21][C:22]1[CH:23]=[C:24]3[C:28](=[CH:29][CH:30]=1)[N:27]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1)[N:26]=[CH:25]3)=[N:14][CH:15]=[N:16]2>CC(N(C)C)=O>[N:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=1[CH2:31][N:27]1[C:28]2[C:24](=[CH:23][C:22]([NH:21][C:13]3[C:12]4[C:11]([OH:3])=[CH:20][CH:19]=[CH:18][C:17]=4[N:16]=[CH:15][N:14]=3)=[CH:30][CH:29]=2)[CH:25]=[N:26]1
Reactant: CC(=O)NCCO
Reactant: Fc1cccc2ncnc(Nc3ccc4c(cnn4Cc4ccccn4)c3)c12
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4ccccn4)c3)c12
Temperature: 120 °C
Yield: 36 %

Procedure:
To a stirred suspension of sodium hydride (60% in mineral oil, 1.68 g, 42 mmol) in DMA (25 ml) was slowly added N-(2-hydroxyethyl)acetamide (1.80 g, 17.5 mmol). When the effervescence had subsided, 5-fluoro-N-[1-(pyridin-2-ylmethyl)-1H-indazol-5-yl]quinazolin-4-amine (2.60 g, 7.0 mmol) was added and the mixture was heated at 120° C. for 18 hours. The reaction was quenched by addition of saturated aqueous NH4Cl (5 ml) and evaporated (high vacuum). The residue was stirred with water (100 ml) giving a gelatinous precipitate, which was filtered off and washed with water. The product was purified by chromatography (silica, dry loaded, 5 to 10% methanol/DCM) and crystallized by trituration with ether to give 4-{[1-(pyridin-2-ylmethyl)-1H-indazol-5-yl]amino}quinazolin-5-ol (928 mg, 32%); NMR spectrum (373 K) 5.72 (s, 2H), 6.77 (m, 3H), 7.03 (d, 1H), 7.23 (dd, 1H), 7.44 (t, 1H), 7.50 (d, 1H), 7.59 (d, 1H), 7.70 (t, 1H), 8.07 (s, 1H), 8.13 (s, 1H), 8.27 (s, 1H), 8.52 (d, 1H), 11.87 (br s, 1H); Mass spectrum MH+ 369.