Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([CH3:22])[C@@H:3]([OH:21])[CH2:4][N:5]([CH2:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[CH2:6][C:7]([F:10])([F:9])[F:8].[CH3:23][N:24]1[C:28]([C:29]2[CH:30]=[C:31]([NH:35][C:36](=O)[O:37]C3C=CC=CC=3)[CH:32]=[CH:33][CH:34]=2)=[N:27][N:26]=[N:25]1>C(#N)C>[F:20][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][CH2:12][CH2:11][N:5]([CH2:6][C:7]([F:8])([F:9])[F:10])[CH2:4][C@H:3]([OH:21])[C@H:2]([NH:1][C:36]([NH:35][C:31]2[CH:32]=[CH:33][CH:34]=[C:29]([C:28]3[N:24]([CH3:23])[N:25]=[N:26][N:27]=3)[CH:30]=2)=[O:37])[CH3:22])=[CH:19][CH:18]=1
Reactant: Cn1nnnc1-c1cccc(NC(=O)Oc2ccccc2)c1
Reactant: C[C@@H](N)[C@@H](O)CN(CCCc1ccc(F)cc1)CC(F)(F)F
Solvent: CC#N
Product: C[C@@H](NC(=O)Nc1cccc(-c2nnnn2C)c1)[C@@H](O)CN(CCCc1ccc(F)cc1)CC(F)(F)F
Yield: 6.7 %

Procedure:
The product of Step e (192 mg, 0.60 mmol, 1 eq.), phenyl 3-(1-methyl-1H-tetraazol-5-yl)phenylcarbamate (176 mg, 0.60 mmol, 1 eq.) and acetonitrile (4 mL) were mixed at 25° C. under N2 overnight. Worked up by stripping off the solvents then purifying the residue over silica gel in 9:1 Hexanes/EtOAc to 100% EtOAc. Obtained 21 mg of a viscous oil. NMR (300 MHz, CDCl3) δ 8.35-8.20 (M, 1H); 7.79 (s, 1H); 7.70 (d, 1H, J=7 Hz); 7.45-7.20 (m, 2H); 7.10 (t, 2H, J=7 Hz); 6.93 (t, 2H, J=7 Hz); 6.20-5.80 (m, 1H); 4.05 (s, 3H); 3.93 (m, 1H); 3.80-3.40 (m, 2H); 3.25-3.05 (m, 2H); 2.85-2.40 (m, 4H); 1.85-1.60 (m, 2H); 1.20 (d, 3H, J=7 Hz); 1.00-0.70 (m, 1H).
Reaction SMILES: C(O[C:4]([C:6]1[N:14]([CH3:15])[C:13]2[CH:12]=[CH:11][N:10]=[C:9](CC)[C:8]=2[C:7]=1[NH:18][C:19]1[CH:24]=[CH:23][C:22]([I:25])=[CH:21][C:20]=1[F:26])=[O:5])C.[OH-].[Na+].[CH:29]([O:31][CH2:32][CH2:33][O:34][NH2:35])=[CH2:30].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C1COCC1.CO>[CH:29]([O:31][CH2:32][CH2:33][O:34][NH:35][C:4]([C:6]1[N:14]([CH3:15])[C:13]2[CH:12]=[CH:11][N:10]=[CH:9][C:8]=2[C:7]=1[NH:18][C:19]1[CH:24]=[CH:23][C:22]([I:25])=[CH:21][C:20]=1[F:26])=[O:5])=[CH2:30]
Reactant: C=COCCON
Reactant: CCOC(=O)c1c(Nc2ccc(I)cc2F)c2c(CC)nccc2n1C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: C1CCOC1
Product: C=COCCONC(=O)c1c(Nc2ccc(I)cc2F)c2cnccc2n1C
Temperature: 65 °C
Reaction time: 72 h
Yield: 56.1 %

Procedure:
A mixture of ethyl 3-(2-fluoro-4-iodo-phenylamino)-1-methyl-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid ethyl ester (100 mg, 0.23 mmol), 1N aqueous sodium hydroxide (0.25 ml) and MeOH (3.0 ml) was heated at 65° C. for 1.5 hours. The reaction mixture was concentrated and azeotroped with toluene (2×2 ml) to give a solid residue. The solid residue was dissolved in anhydrous THF (4 ml) and O-(2-vinyloxy-ethyl)-hydroxylamine (47 mg, 0.46 mmol), EDCI (55 mg, 0.29 mmol), HOBt (43 mg, 0.32 mmol) and DIPEA (119 μl, 0.68 mmol) were added. After stirring for 72 hours at ambient temperature, the mixture was evaporated and the residue was partitioned between ethyl acetate (30 ml) and water (20 ml). The organic layer was isolated, dried over sodium sulphate, then filtered and evaporated to give a yellow oil. The oil was purified by flash chromatography (Si-PPC, dichloromethane:methanol, gradient 100:0 to 90:10) to afford the title compound as a yellow solid (64 mg, 57%). LCMS (method B): RT=2.20 min, M+H+=497.
Reaction SMILES: [CH3:1][C:2]([CH3:4])=[CH2:3].B1C2CCCC1CCC2.[CH2:14]([O:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[C:24](OS(C(F)(F)F)(=O)=O)[CH:23]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+]>C1COCC1.CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[CH2:14]([O:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[C:24]([CH2:1][CH:2]([CH3:4])[CH3:3])[CH:23]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: C=C(C)C
Reactant: COC(=O)c1ccc(OCc2ccccc2)cc1OS(=O)(=O)C(F)(F)F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: B1C2CCCC1CCC2
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(OCc2ccccc2)cc1CC(C)C
Temperature: 25 °C
Yield: 31 %

Procedure:
To a condensed liquid 2-methyl-1-propene in THF (10 mL) at −78° C. was added 0.5 M 9-BBN (3 mL, 1.5 mmol), the mixture was allowed to warm up to room temperature with stirring. The mixture was transferred via a syringe to a degassed solution containing the compound of Example 206 (0.5 g, 1.3 mmol), Pd(dppf)Cl2 (82 mg, 0.1 mmol), K2CO3 (0.23 g, 1.7 mmol), water (2 mL) in DMF (21 mL). The resulting mixture was heated at 60° C. overnight. After removal of solvent, the residue was purified by chromatography to afford the title compound (0.11 g, 31% yield). 1HNMR Chloroform-d δ 0.85 (d, 6H), 1.75-1.80 (m, 1H), 2.88 (d, 2H), 3.78 (s, 3H), 5.13 (s, 2H), 6.71-6.80 (m, 2H), 7.30-7.41 (m, 5H), 7.90 (d, 1H). Rf=0.65 ethyl acetate/hexane (1/9).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[S:9][C:10]2[CH2:11][N:12]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C@@H:24]4[O:33][C:28]5=[N:29][CH:30]=[CH:31][CH:32]=[C:27]5[O:26][CH2:25]4)=[CH:20][CH:19]=3)[CH2:13][CH2:14][C:15]=2[N:16]=1)(C)(C)C.Cl.O1CCOCC1>C(Cl)Cl.CO>[O:26]1[C:27]2[C:28](=[N:29][CH:30]=[CH:31][CH:32]=2)[O:33][C@@H:24]([C:21]2[CH:20]=[CH:19][C:18]([CH2:17][N:12]3[CH2:13][CH2:14][C:15]4[N:16]=[C:8]([NH2:7])[S:9][C:10]=4[CH2:11]3)=[CH:23][CH:22]=2)[CH2:25]1
Reactant: CC(C)(C)OC(=O)Nc1nc2c(s1)CN(Cc1ccc([C@H]3COc4cccnc4O3)cc1)CC2
Agent: Cl
Solvent: ClCCl
Solvent: CO
Solvent: C1COCCO1
Product: Nc1nc2c(s1)CN(Cc1ccc([C@H]3COc4cccnc4O3)cc1)CC2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of {5-[(S)-4-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl)-benzyl]-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl}-carbamic acid tert-butyl ester (prepared from Intermediate N according to General Method K) (50 mg, 0.10 mmol) in DCM (2 mL) with several drops MeOH is added 4M HCl in 1,4-dioxane (1.0 mL, 4.0 mmol) and the reaction stirred at rt for 16 h. The reaction is concentrated, suspended in Et2O and filtered to give the title compound 258. (LC/MS method 16: ES+ m/z 381.4 [M+H]+, Rt=0.36 m)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](O)([CH2:11][CH3:12])[CH2:9][CH3:10])=[C:4]([F:14])[CH:3]=1.[Cl-].[In+3].[Cl-].[Cl-].FC(F)(F)C(O)=O.[CH3:26][S:27][CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[C:33]2[C:37]=1[NH:36][CH:35]=[CH:34]2>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:34]2[C:33]3[C:37](=[C:29]([CH2:28][S:27][CH3:26])[CH:30]=[CH:31][CH:32]=3)[NH:36][CH:35]=2)([CH2:11][CH3:12])[CH2:9][CH3:10])=[C:4]([F:14])[CH:3]=1
Reactant: CSCc1cccc2cc[nH]c12
Reactant: CCC(O)(CC)c1ccc(Cl)cc1F
Agent: [Cl-]
Agent: [In+3]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC(CC)(c1ccc(Cl)cc1F)c1c[nH]c2c(CSC)cccc12
Temperature: 80 °C
Reaction time: 1 h

Procedure:
600 mg (2.77 mmol) of the compound from Example 146A, 585 mg (2.64 mmol) of indium(III) chloride and 301 mg (2.64 mmol) of trifluoroacetic acid were added to 446 mg (2.52 mmol) of the compound from Example 8A in 15 ml of dichloromethane. The reaction mixture was stirred at 80° C. for 1 h. After cooling to RT, the reaction solution was mixed with dichloromethane and silica gel, and the solvent was removed in a rotary evaporator. The residue was purified twice by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate gradient) and twice by preparative HPLC (mobile phase: acetonitrile/water gradient). 208 mg (22% of theory) of the title compound were obtained.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[NH:8][C:7]1=[O:17].Cl.[CH2:19]([O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)[CH2:20][CH3:21].[I-].[K+].C(=O)([O-])[O-].[Na+].[Na+]>C(C(C)=O)C(C)C>[CH2:19]([O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[CH2:34][CH2:33][N:32]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:16])[NH:8][C:7]2=[O:17])[CH2:31][CH2:30]1)[CH2:20][CH3:21]
Reactant: CCCOc1ccccc1N1CCNCC1
Reactant: O=c1[nH]c(=O)n(CCCCCl)c2ccccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC(=O)CC(C)C
Product: CCCOc1ccccc1N1CCN(CCCCn2c(=O)[nH]c(=O)c3ccccc32)CC1
Yield: 96.2 %

Procedure:
A mixture of 1-(4-chlorobutyl)-2,4(1H,3H)-quinazolinedione (160 mg), N-(2-propoxyphenyl)piperazine hydrochloride (178 mg), potassium iodide (105 mg), and sodium carbonate (200 mg) in methyl isobutyl ketone (15 ml) was refluxed for 5 hours. After dilution with ethyl acetate, the reaction mixture was washed in turn with water and brine, dried over magnesium sulfate, and evaporated. The residue was chromatographed on silica gel (15 g) eluting with chloroform-methanol (50:1 V/V) to give 1-[4-{4-(2-propoxyphenyl)piperazin-1-yl}butyl]-2,4(1H,3H)-quinazolinedione (266 mg).
Reaction SMILES: [OH-].[Na+].[C:3]([C:6]1[CH:16]=[CH:15][C:9]([O:10][CH2:11][CH:12]2[CH2:14][O:13]2)=[C:8]([CH2:17][CH2:18][CH2:19][CH3:20])[C:7]=1[OH:21])(=[O:5])[CH3:4].[OH:22][C:23]1[CH:40]=[CH:39][C:26]2[C:27](=[O:38])[CH:28]=[C:29]([CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[O:30][C:25]=2[C:24]=1[CH2:41][CH2:42][CH3:43]>C(O)C>[C:3]([C:6]1[CH:16]=[CH:15][C:9]([O:10][CH2:11][CH:12]([OH:13])[CH2:14][O:22][C:23]2[CH:40]=[CH:39][C:26]3[C:27](=[O:38])[CH:28]=[C:29]([CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[O:30][C:25]=3[C:24]=2[CH2:41][CH2:42][CH3:43])=[C:8]([CH2:17][CH2:18][CH2:19][CH3:20])[C:7]=1[OH:21])(=[O:5])[CH3:4]
Reactant: CCCCc1c(OCC2CO2)ccc(C(C)=O)c1O
Reactant: CCCc1c(O)ccc2c(=O)cc(CCC(=O)OCC)oc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCc1c(OCC(O)COc2ccc3c(=O)cc(CCC(=O)OCC)oc3c2CCC)ccc(C(C)=O)c1O

Procedure:
To sodium hydroxide (0.6 g) in ethanol (200 ml) was added (4-acetyl-2-n-butyl-3-hydroxyphenoxy)methyloxiran (6 g) and ethyl 3-(7-hydroxy-4-oxo-8-propyl-4H-1-benzopyran-2-yl)propionate (4.56 g). The mixture was refluxed for 6 hours, evaporated to 1/3 volume and acidified. Extraction with ethyl acetate and subsequent washing with 10% sodium hydroxide solution, and water, and evaporation gave a red oil which was chromatographed on silica with chloroform:ethyl acetate (12:1) mixture to yield a solid. Recrystallisation from ethyl acetate/cyclohexane mixture afforded the title ester as buff micro needles (2.3 g), mp 118°-118.5°.
Reaction SMILES: C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C.[Na:13].[S:14]([C:18]1[CH:23]=[CH:22][C:21]([N:24]2[C:29](=[O:30])[CH2:28][CH:26](O)[C:25]2=[O:31])=[CH:20][CH:19]=1)([OH:17])(=[O:16])=[O:15]>CCO.CC(C)=O>[Na:13].[S:14]([C:18]1[CH:19]=[CH:20][C:21]([N:24]2[C:29](=[O:30])[CH:28]=[CH:26][C:25]2=[O:31])=[CH:22][CH:23]=1)([OH:17])(=[O:15])=[O:16]
Reactant: O=C1CC(O)C(=O)N1c1ccc(S(=O)(=O)O)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CC(C)=O
Solvent: CC(=O)OC(C)=O
Solvent: CCO
Product: O=C1C=CC(=O)N1c1ccc(S(=O)(=O)O)cc1
Temperature: 25 °C

Procedure:
A slurry of 0.8 g. sodium acetate (9.8 mmoles) and 16.0 g. II (54.6 mmoles) in 200 ml. acetic anhydride was refluxed until a color change to a tannish solution was noted. The solution was cooled to room temperature and diluted with 200 ml. EtOH:Acetone 3:2. The solution was filtered and the precipitate was slurried in an additional 200 ml. EtOH:Acetone 3:2 then filtered. The precipitate was dried under high vacuum giving 10.23 g. III (68.1%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=1)[N:6]=[C:5]2[C:24](O)=[O:25].Cl.[OH:28][C:29]1[C:38]([O:39][CH3:40])=[CH:37][CH:36]=[C:35]2[C:30]=1[CH2:31][CH2:32][NH:33][CH2:34]2>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=1)[N:6]=[C:5]2[C:24]([N:33]1[CH2:32][CH2:31][C:30]2[C:35](=[CH:36][CH:37]=[C:38]([O:39][CH3:40])[C:29]=2[OH:28])[CH2:34]1)=[O:25]
Reactant: COc1cc(-c2nc(C(=O)O)c3cc(F)ccc3n2)cc(OC)c1OC
Reactant: COc1ccc2c(c1O)CCNC2
Agent: Cl
Product: COc1ccc2c(c1O)CCN(C(=O)c1nc(-c3cc(OC)c(OC)c(OC)c3)nc3ccc(F)cc13)C2
Yield: 18.6 %

Procedure:
Reaction of 6-fluoro-2-(3,4,5-trimethoxyphenyl)quinazoline-4-carboxylic acid with 5-hydroxy-6-methoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 103 (18.6% yield). 1H NMR (300 MHz, DMSO-d6) δ 2.82 and 2.91 (2t, 2H), 3.56 and 4.02 (2t, 2H), 3.74-3.80 (m, 6H), 3.86 and 3.91 (2s, 6H), 4.45 and 4.90 (2s, 2H), 6.33-6.91 (m, 2H), 7.62-7.86 (m, 3H), 8.00-8.06 (m, 1H), 8.21-8.28 (m, 1H), 8.70 and 8.73 (2s, 1H); MS (ESI) m/z 520 ([M+H]+).
Reaction SMILES: OS(O)(=O)=O.[CH3:6][C:7]1([CH3:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10](=[O:17])[CH2:9][CH2:8]1.[N+:19]([O-])([OH:21])=[O:20]>>[CH3:6][C:7]1([CH3:18])[C:16]2[C:11](=[CH:12][C:13]([N+:19]([O-:21])=[O:20])=[CH:14][CH:15]=2)[C:10](=[O:17])[CH2:9][CH2:8]1
Reactant: O=[N+]([O-])O
Reactant: CC1(C)CCC(=O)c2ccccc21
Agent: O=S(=O)(O)O
Product: CC1(C)CCC(=O)c2cc([N+](=O)[O-])ccc21
Reaction time: 0.33 h

Procedure:
To 1.7 mL (3.0 g, 30.6 mmol, 18M) H2SO4 at −5iC (ice-NaCl bath) was slowly added 783.0 mg (4.49 mmol) of 3,4-dihydro-4,4-dimethyl-naphthalen-1(2H)-one. A solution of HNO3 (426.7 mg 6.88 mmol, 0.43 ml 16M, and 1.31 g (0.013 mol, 0.74 mL, 18 M of H2SO4 were slowly added. After 20 min, ice was added and the resulting mixture was extracted with EtOAc. The combined extracts were concentrated under reduced pressure to give a yellow oil from which the title compound, a pale yellow solid, was isolated by column chromatography (10% EtOAC/hexanes).
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6]([C:8]1[CH:46]=[CH:45][C:11]([CH2:12][CH:13](/[CH:26]=[CH:27]/[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[O:34][CH2:35][CH2:36][CH2:37][N:38]2[CH2:43][CH2:42][O:41][CH2:40][C:39]2=[O:44])[CH2:14][CH2:15][C:16]2[CH:25]=[CH:24][C:19]([C:20]([O:22]C)=[O:21])=[CH:18][CH:17]=2)=[CH:10][CH:9]=1)=[O:7].Cl>C1COCC1.O>[C:6]([C:8]1[CH:9]=[CH:10][C:11]([CH2:12][CH:13](/[CH:26]=[CH:27]/[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[O:34][CH2:35][CH2:36][CH2:37][N:38]2[CH2:43][CH2:42][O:41][CH2:40][C:39]2=[O:44])[CH2:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:20]([OH:22])=[O:21])=[CH:24][CH:25]=2)=[CH:45][CH:46]=1)([OH:7])=[O:5]
Reactant: COC(=O)c1ccc(CCC(/C=C/c2ccccc2OCCCN2CCOCC2=O)Cc2ccc(C(=O)OC)cc2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(CCC(/C=C/c2ccccc2OCCCN2CCOCC2=O)Cc2ccc(C(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
66.6 mg (1.59 mmol) of lithium hydroxide monohydrate are added to a solution of 0.31 g (0.53 mmol) of methyl 4-[(4E)-3-[4-(methoxycarbonyl)benzyl]-5-{2-[3-(3-oxomorpholin-4-yl)propoxy]phenyl}-pent-4-en-1-yl]benzoate (Example 23A) in 2 ml of THF and 2 ml of water, and the mixture is stirred at room temperature for 18 h. The mixture is then adjusted to pH 2 using 1 M hydrochloric acid and extracted twice with ethyl acetate. The combined organic phases are dried over sodium sulfate. After filtration, the solvent is removed to dryness and the crude product is purified by preparative HPLC. This gives 89.5 mg (0.16 mmol, 30.3% of theory) of the title compound as a colorless solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[O:10][N:9]=2)=[CH:4][C:3]=1[CH3:18].[F:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[N:27]=[C:28]=[O:29]>O1CCCC1>[F:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[NH:27][C:28](=[O:29])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[O:10][N:9]=2)=[CH:4][C:3]=1[CH3:18]
Reactant: O=C=Nc1ccc(F)cc1F
Reactant: CCOC(=O)c1cc(-c2ccc(N)c(C)c2)no1
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(-c2ccc(NC(=O)Nc3ccc(F)cc3F)c(C)c2)no1
Yield: 75 %

Procedure:
Ethyl 3-(4-amino-3-methylphenyl)isoxazole-5-carboxylate (1.0 equiv.), 2,4-difluoro phenyl isocyanate (1.2 equiv.) and tetrahydrofuran in a round-bottom flask was stirred at room temperature for 48 hours. The solid precipitate was filtered and washed with a minimum quantity of THF and dried in vacuo to afford the title compound as a white solid (75%); 1H NMR (300 MHz, DMSO-d6) δ: 1.29-1.34 (t, J=7.0 Hz, 3H), 2.29 (s, 3H), 4.32-4.39 (q, 2H), 7.00-7.05 (m, 1H), 7.26-7.33 (m, 1H), 7.72-7.75 (d, J=8.4 Hz, 1H), 7.80 (s, 2H), 8.09-8.16 (m, 2H), 8.45 (s, 1H), 9.09 (s, 1H); IR (KBr) 3297, 3134, 2991, 1727, 1654, 1590, 1558, 1500, 1460, 1424, 1287, 1250, 1139, 1029, 841 cm1.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([NH2:17])[CH:15]=2)[C:10](=[O:18])[NH:9]1)=O)(C)(C)C.[CH:19]1([C:22]2[CH:23]=[C:24]([NH:27][C:28]3[N:33]=[C:32](Cl)[N:31]=[C:30]([Cl:35])[N:29]=3)[NH:25][N:26]=2)[CH2:21][CH2:20]1>C(O)CCC>[Cl:35][C:30]1[N:29]=[C:28]([NH:27][C:24]2[NH:25][N:26]=[C:22]([CH:19]3[CH2:21][CH2:20]3)[CH:23]=2)[N:33]=[C:32]([NH:17][C:14]2[CH:15]=[C:16]3[C:11]([C:10](=[O:18])[NH:9][NH:8]3)=[CH:12][CH:13]=2)[N:31]=1
Reactant: Clc1nc(Cl)nc(Nc2cc(C3CC3)n[nH]2)n1
Reactant: CC(C)(C)OC(=O)n1[nH]c(=O)c2ccc(N)cc21
Solvent: CCCCO
Product: O=c1[nH][nH]c2cc(Nc3nc(Cl)nc(Nc4cc(C5CC5)n[nH]4)n3)ccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 21.2 %

Procedure:
6-Amino-3-oxo-2,3-dihydro-indazole-1-carboxylic acid tert-butyl ester (69 mg, 0.277 mmol) and (5-Cyclopropyl-2H-pyrazol-3-yl)-(4,6-dichloro-[1,3,5]triazin-2-yl)-amine (50 mg, 0.184 mmol) were taken into 1 ml of n-butanol and stirred at room temperature for 2 hours. The solvent was evaporated in vacuo and the resulting white solid residue dissolved in dichloromethane-trifluoro acetic acid (1:1 mixture, 2 ml. After 3 hours, the solvent was evaporated in vacuo and the crude product purified by prep HPLC to afford 15 mg of the desired product as a white solid (16.4% yield). H-NMR (DMSO-d6, 500 mHz) δ 11.11 (m, 1H), 10.41 (s, 1H), 10.29 (s, 1H), 7.11-7.82 (m, 3H), 6.04 (s, 1H), 1.84 (m, 1H), 0.89 (m, 2H), 0.60 (m, 2H). MS (ES+): m/e=384.0 (M+H), 382.0 (M-H); LC/Method A/3.891 min, 98.0% purity by area %.
Reaction SMILES: [CH2:1]([N:3]=[C:4](OC)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[CH2:13]([NH2:15])[CH3:14].[ClH:16]>C(OCC)C>[ClH:16].[CH2:1]([NH:3][C:4](=[N:15][CH2:13][CH3:14])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2]
Reactant: CCN
Reactant: CCN=C(CC(=O)OCC)OC
Agent: Cl
Solvent: CCOCC
Product: CCN=C(CC(=O)OCC)NCC
Temperature: 25 °C

Procedure:
To a solution of 3.46 g. (0.02 mole) of methyl N-ethyl-carbethoxyacetimidate in 30 ml. of diethyl ether is added 900 mg. (0.02 mole) of ethylamine and the reaction mixture allowed to stir several hours at room temperature. Anhydrous hydrogen chloride gas is slowly introduced into the reaction mixture until the formation of the amidine hydrochloride ceases. The product is filtered and dried in vacuo.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][N:9]3[C:12]([C:15]4[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=4)=[CH:13][N:14]=[C:8]3[CH:7]=2)=[CH:2]1.S(C)C.[OH-].[Na+]>C1COCC1>[S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][N:9]3[C:12]([C:15]4[CH:22]=[CH:21][C:18]([CH2:19][NH2:20])=[CH:17][CH:16]=4)=[CH:13][N:14]=[C:8]3[CH:7]=2)=[CH:2]1
Reactant: N#Cc1ccc(-c2cnc3cc(-c4ccsc4)ccn23)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CSC
Solvent: C1CCOC1
Product: NCc1ccc(-c2cnc3cc(-c4ccsc4)ccn23)cc1
Temperature: 50 °C
Reaction time: 0.25 h

Procedure:
Dissolve 4-(7-thien-3-yl-imidazo[1,2-a]pyridin-3-yl)-benzonitrile (0.087 g, 0.29 mmol) in THF (8 mL). To the solution add a BH3.Me2S solution (2 M, 1.0 mL, 2.0 mmol) at room temperature. Stir the solution for 15 minutes and then heat at 50° C. for 3.5 hours. Cool the mixture at 0° C. and acidify to pH=1 slowly and stir for 30 minutes. Make the reaction mixture basic with solid NaOH to pH=12-14, followed by extraction with ethyl acetate. Wash the extracts with saturated aqueous saturated sodium chloride, dry over MgSO4, filter and evaporate to afford 0.070 g. MS(ES), m/z 306 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[CH2:6][NH:7][CH2:8][CH:9](OC)OC.CO/N=[CH:22]/[C:23]1[CH:31]=[CH:30][C:26]2[O:27][CH2:28][O:29][C:25]=2[C:24]=1[CH2:32][N:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1.Cl.[NH4+].[OH-]>O>[CH3:18][O:17][C:16]1[CH:15]=[C:14]2[C:5](=[CH:4][C:3]=1[O:2][CH3:1])[CH:6]=[N:7][C:8]1[C:31]3[CH:30]=[C:26]4[O:27][CH2:28][O:29][C:25]4=[C:24]([CH2:32][N:33]4[CH2:34][CH2:35][CH2:36][CH2:37]4)[C:23]=3[CH2:22][C:9]2=1
Reactant: COc1ccc(CNCC(OC)OC)cc1OC
Reactant: CO/N=C/c1ccc2c(c1CN1CCCC1)OCO2
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: COc1cc2cnc3c(c2cc1OC)Cc1c-3cc2c(c1CN1CCCC1)OCO2
Temperature: 100 °C
Reaction time: 18 h
Yield: 6.1 %

Procedure:
The amine 8 (1.90 g, 7.45 mmol) and oxime ether 13b (0.90 g, 3.44 mmol) were mixed with concentrated hydrochloric acid (15 mL) and the mixture was stirred at 100° C. for 18 h. The reaction mixture was then cooled and washed with ether (3×20 mL). It was then brought to basic pH with NH4OH. The mixture was extracted with chloroform (40 mL×3), and the solution was washed with brine (50 mL), dried (Na2SO4) and concentrated. The residue was dissolved in chloroform (40 mL) and filtered. Hydrochloric acid (2 M HCl in ether, 5 mL) was added to the filtrate. The precipitate that formed was recrystallized from methanol to provide a yellow solid. The solid was dissolved in water, basified with NH4OH and extracted with chloroform. The organic layer was concentrated to dryness. The residue was purified by preparative flash chromatography (SiO2, methanol-chloroform-TEA=3:97:2) to yield the final pure product 14b as a light yellow solid (84.9 mg, 6.1%): mp 210° C. (dec). IR (KBr) 2958, 1449, 1406, 1326, 1246 cm−1; 1H NMR (300 MHz, CDCl3) δ 8.94 (s, 1H), 7.44 (s, 1H), 7.16 (s, 1H), 7.01 (s, 1H), 6.04 (s, 2H), 4.07 (s, 3H), 4.02 (s, 3H), 3.85 (s, 2H), 3.79 (s, 2H), 2.67 (broad s, 4H), 1.82 (broad s, 4H); low resolution ESIMS m/z (rel intensity) 405 (MH+, 15), 334 (100). Anal. (C24H24N2O4.1.75H2O) C, H, N.
Reaction SMILES: O=[CH:2][CH2:3][CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][C:8]([Cl:13])=[CH:9][CH:10]=2)[C:5]1=O.O.[NH2:16][CH2:17][C@@H:18]([OH:20])[CH3:19]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Cl:13][C:8]1[CH:7]=[C:6]2[C:11]([CH2:12][C:4]3[CH:3]=[CH:2][N:16]([CH2:17][C@@H:18]([OH:20])[CH3:19])[C:5]=32)=[CH:10][CH:9]=1
Reactant: C[C@H](O)CN
Reactant: O=CCC1Cc2ccc(Cl)cc2C1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: C[C@H](O)Cn1ccc2c1-c1cc(Cl)ccc1C2
Reaction time: 0.5 h
Yield: 52.6 %

Procedure:
A solution of 2.5 g of (RS)-2-(2-oxoethyl)-6-chloro-1-indanone and 100 mg of p-toluenesulfonic acid in 120 ml in anhydrous toluene was heated on a water separator. A solution of 3.6 g of (S)-1-amino-2-propanol in 20 ml of anhydrous toluene was added dropwise to the boiling solution over a period of 5 minutes. Subsequently, the mixture was boiled for 30 minutes, during which the solvent was reduced to a volume of 20 ml. The cooled reaction mixture was purified by column chromatography on silica gel (ethyl acetate/toluene 1:1). 1.56 g (53%) of (S)-1-(7-chloro-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-propan-2-ol were obtained as a brown oil which was used directly in the next reaction.
Reaction SMILES: C([O:5][C:6](=[O:20])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)[CH:8]=1)(C)(C)C.C(Cl)Cl>C(O)(C(F)(F)F)=O.C1(C)C=CC=CC=1>[CH3:19][N:16]1[CH2:15][CH2:14][N:13]([C:9]2[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=2)[C:6]([OH:20])=[O:5])[CH2:18][CH2:17]1
Reactant: CN1CCN(c2cccc(C(=O)OC(C)(C)C)c2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CN1CCN(c2cccc(C(=O)O)c2)CC1

Procedure:
3-(4-Methylpiperazinyl)-benzoic acid tert-butyl ester (4.1 g, 14.9 mmol) was dissolved in TFA: CH2Cl2 (70 ml, 1:1) and the reaction was stirred for 2 h at RT. The reaction mixture was diluted with toluene (100 ml), then was concentrated in vacuo and was used in the next reaction without further purification: MS (ES+) 221.3 (M+H+).