Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:12])[C@H:6]([CH2:8][CH:9]([CH3:11])[CH3:10])[NH2:7])[CH3:3].C(N(CC)CC)C.[Br:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26](Cl)=[O:27]>C1COCC1.[Cl-].[NH4+].C(OCC)(=O)C>[CH2:2]([O:4][C:5](=[O:12])[C@H:6]([CH2:8][CH:9]([CH3:11])[CH3:10])[NH:7][C:26](=[O:27])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][Br:20])[CH3:3]
Reactant: CCOC(=O)[C@@H](N)CC(C)C
Reactant: O=C(Cl)CCCCCBr
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@H](CC(C)C)NC(=O)CCCCCBr
Temperature: 25 °C
Reaction time: 4 h
Yield: 80 %

Procedure:
A stirred suspension of L-leucine ethyl ester hydrochloride (8.38 g, 45 mmol) in dry THF (80 ml) at room temperature was treated with triethylamine (6.3 ml, 45 mmol). The reaction mixture was treated with 6-bromohexanoyl chloride (6.91 ml, 45 mmol). The reaction mixture was stirred for 4 h at room temperature and then diluted with a mixture of saturated aqueous ammonium chloride and ethyl acetate. The organic layer was separated, washed with saturated aqueous ammonium chloride, dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure to give N-6-bromohexanoyl-L-leucine ethyl ester (12.1 g, 80%) as an oil which was used for the next step without further purification.
Reaction SMILES: [OH:1][C@H:2]1[C@H:11]([N:12]2[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]2=[O:21])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:22]3[C:23](=[O:31])[C:24](=[O:30])[C:25]=3OC(C)C)[CH:9]=2)[O:4][C:3]1([CH3:33])[CH3:32].[CH2:34]([CH2:36][NH2:37])[OH:35]>CC#N.O>[OH:1][C@H:2]1[C@H:11]([N:12]2[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]2=[O:21])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:22]3[C:23](=[O:31])[C:24](=[O:30])[C:25]=3[NH:37][CH2:36][CH2:34][OH:35])[CH:9]=2)[O:4][C:3]1([CH3:32])[CH3:33]
Reactant: CC(C)Oc1c(-c2ccc3c(c2)[C@@H](N2Cc4ccccc4C2=O)[C@H](O)C(C)(C)O3)c(=O)c1=O
Reactant: NCCO
Solvent: CC#N
Solvent: O
Product: CC1(C)Oc2ccc(-c3c(NCCO)c(=O)c3=O)cc2[C@@H](N2Cc3ccccc3C2=O)[C@@H]1O
Temperature: 50 °C
Yield: 23.4 %

Procedure:
A solution of 529 mg(1.18 mmol) of 3-[trans-3-hydroxy-2,2-dimethyl-4-(1-oxo-1,3-dihydroisoindol-2-yl)-chroman-6-yl]-4-isopropoxy-cyclobut-3-ene- 1,2-dione as prepared in Example 3 in CH3CN (20 mL) and ethanolamine (716 μL; 11.8 mmol) was stirred at room temperature for 4 days. The reaction mixture was heated at 50° C. for 1 h, cooled to room temperature, diluted with H2O, and extracted into 20% THF/CH2Cl2. The organic extracts were dried over MgSO4 and purified by flash chromatography (CH2Cl2 : MeOH :NH4OH (93.25; 4.5; 2.25)) followed by trituration from MeOH/ether to give 124 mg of the title compound as a tan solid, mp 205°-215° C.: 1H-NMR (DMSO-d6 ; 400 MHz) δ8.93 (t, 1 H), 7.79 (dd, 1 H), 7.74 (s, 1 H), 7.69 (dd, 1 H), 7.5-7.64 (m, 3 H), 7.00 (d, 1 H), 5.75 (d, 1 H), 5.2-5.5 (br, 1 H), 4.86 (t, 1 H), 4.4-4.5 (br d, 1 H), 3.67 (m, 2 H), 3.53 (q, 3 H), and 1.27 ppm (s, 3 H); IR (KBr) 1780, 1710, 1660, and 1600 cm-1 ; mass spectrum (+FAB), m/e 449 (M +H), and 471 (M+Na). Anal. Calcd. for C25H24N2O6. 1 H2O C, 64.37; H, 5.62; N, 6.01 Found: C, 64.32; H, 5.83; N, 6.18.
Reaction SMILES: [N:1]([C:4]1[CH:11]=[C:10]([CH3:12])[C:7]([C:8]#[N:9])=[C:6]([CH3:13])[N:5]=1)=[C:2]=S.C(N(CC)CC)C.Cl.Cl.[NH2:23][CH2:24][C:25]1([OH:33])[CH:30]2[CH2:31][CH2:32][N:27]([CH2:28][CH2:29]2)[CH2:26]1.C(N=C=NC(C)C)(C)C>CN(C)C=O>[N:27]12[CH2:32][CH2:31][CH:30]([CH2:29][CH2:28]1)[C@@:25]1([O:33][C:2]([NH:1][C:4]3[CH:11]=[C:10]([CH3:12])[C:7]([C:8]#[N:9])=[C:6]([CH3:13])[N:5]=3)=[N:23][CH2:24]1)[CH2:26]2
Reactant: Cc1cc(N=C=S)nc(C)c1C#N
Reactant: NCC1(O)CN2CCC1CC2
Agent: CC(C)N=C=NC(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(NC2=NC[C@@]3(CN4CCC3CC4)O2)nc(C)c1C#N
Temperature: 70 °C
Reaction time: 2 h
Yield: 66.7 %

Procedure:
To 6-isothiocyanato-2,4-dimethylnicotinonitrile (0.09 g, 0.48 mmol) in N,N-dimethylformamide (20 mL) was added triethylamine (0.17 mL, 1.19 mmol) and 3-(aminomethyl)quinuclidin-3-ol dihydrochloride (0.11 g, 0.49 mmol) at room temperature. The reaction was stirred at 70° C. for 2 hours. The reaction was cooled to room temperature and concentrated in vacuo. The crude urea was purified by chromatography (Biotage: 85% CHCl3, 14% MeOH, 1% NH4OH). The product was then treated with N,N-dimethylformamide (20 mL) and N,N′-diisopropylcarbodiimide (0.22 mL, 1.43 mmol). The reaction was heated to 70° C. for 2 hours. The reaction was cooled to room temperature and concentrated in vacuo to yield the crude product. The crude product was purified by chromatography (Biotage: 85% CHCl3, 14% MeOH, 1% NH4OH) to yield (R)-6-(4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octane]-2-ylamino)-2,4-dimethylnicotinonitrile (0.10 g, 0.32 mmol, 66% yield) as a white powder. 1H NMR (500 MHz, DMSO-D6) δ ppm 9.08 (s, 1 H), 6.60 (s, 1 H), 3.88 (d, J=10.38 Hz, 1 H), 3.61 (d, J=10.38 Hz, 1 H), 2.98 (s, 2 H), 2.70-2.79 (m, 2 H), 2.63-2.69 (m, 2 H), 2.55-2.60 (m, 4 H), 2.31-2.39 (m, 4 H), 1.99 (s, 1 H), 1.89 (s, 1 H), 1.54-1.62 (m, 2 H), 1.41-1.49 (m, 1 H). MS (LC/MS) R.T.=0.78; [M+H]+=312.1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:10]([CH3:19])[C:11](=[O:18])[CH:12]=[CH:13][C:14]=2[C:15]([OH:17])=O)=[C:4]([F:20])[CH:3]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[CH:42]1([CH2:45][O:46][NH2:47])[CH2:44][CH2:43]1.CCN(CC)CC>CC(N(C)C)=O.CCOC(C)=O>[CH:42]1([CH2:45][O:46][NH:47][C:15]([C:14]2[CH:13]=[CH:12][C:11](=[O:18])[N:10]([CH3:19])[C:9]=2[NH:8][C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=2[F:20])=[O:17])[CH2:44][CH2:43]1
Reactant: NOCC1CC1
Reactant: Cn1c(Nc2ccc(Br)cc2F)c(C(=O)O)ccc1=O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: Cn1c(Nc2ccc(Br)cc2F)c(C(=O)NOCC2CC2)ccc1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.1 %

Procedure:
A mixture of 2-(4-bromo-2-fluorophenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid (0.022 g, 0.064 mmol), EDCI (0.019 g, 0.097 mmol), and HOBt (0.019 g, 0.097 mmol) in DMA (1 mL) was stirred for 30 minutes at room temperature under N2. O-Cyclopropylmethyl-hydroxylamine (0.017 g, 0.19 mmol) was added followed by Et3N (0.022 mL, 0.016 g, 0.16 mmol). After the reaction mixture was stirred for 16 hours at room temperature, it was diluted with EtOAc and washed with saturated NH4Cl solution, saturated NaHCO3 solution and saturated NaCl. The organic layer was dried (Na2SO4) and concentrated under reduced pressure. Purification by flash column chromatography (methylene chloride/methanol, 20:1) gave 0.015 g (57%) pure desired product as a yellow solid. MS APCI (−) m/z 410, 411 (M−, Br pattern) detected; 1H NMR (400 MHz, DMSO-d6) δ 11.4 (s, 1H), 9.81 (s, 1H), 7.58 (m, 2H), 7.28 (d, 1H), 6.82 (t, 1H), 6.17 (d, 1H), 3.46 (d, 2H), 3.22 (s, 3H), 0.99 (m, 1H), 0.48 (m, 2H), 0.18 (m, 2H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[C:5]([N+:13]([O-:15])=[O:14])[CH:4]=1)#[N:2].[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:2][C:1]2[CH:3]=[CH:4][CH:5]=[C:20]3[C:21]=2[N:16]=[CH:17][CH:18]=[CH:19]3)(=[O:11])=[O:10])=[C:5]([N+:13]([O-:15])=[O:14])[CH:4]=1)#[N:2]
Reactant: c1ccncc1
Reactant: N#Cc1ccc(S(=O)(=O)Cl)c([N+](=O)[O-])c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: N#Cc1ccc(S(=O)(=O)Nc2cccc3cccnc23)c([N+](=O)[O-])c1
Yield: 46 %

Procedure:
In a similar fashion using route 14 general procedure 27, 8-aminoqunoline (0.60 g, 4.16 mmol), 4-cyano-2-nitro-benzenesulfonyl chloride (Intermediate 217) (1.33 g, 5.41 mmol), DMAP (cat), pyridine (5 ml) and DCM (3 ml) gave the title compound (0.65 g, 46%) after purification by column chromatography with n-hexane/EtOAc (90:10) as the eluent.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C:6]1[N:7]([S:18]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]([OH:17])=[O:16])=[CH:10][CH:9]=2)=[O:5]>C(OC(OC(C)(C)C)N(C)C)(C)(C)C.C(OCC)(=O)C.O>[CH3:1][CH2:2][O:3][C:4]([C:6]1[N:7]([S:18]([C:21]2[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=2)(=[O:20])=[O:19])[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]([O:17][C:11]([CH3:15])([CH3:12])[CH3:10])=[O:16])=[CH:10][CH:9]=2)=[O:5]
Reactant: CCOC(=O)c1cc2cc(C(=O)O)ccc2n1S(=O)(=O)c1ccc(C)cc1
Agent: CN(C)C(OC(C)(C)C)OC(C)(C)C
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc2cc(C(=O)OC(C)(C)C)ccc2n1S(=O)(=O)c1ccc(C)cc1
Temperature: 80 °C
Yield: 134.3 %

Procedure:
1-(Toluene-4-sulfonyl)-1H-indole-2,5-dicarboxylic acid 2-ethyl ester (690 mg, 1.85 mmol) was dissolved in N,N-dimethylformamide di-tert-butyl acetal (3.0 ml), and stirred at 80° C. for two and half hours. N,N-dimethylformamide di-tert-butyl acetal (2.0 ml) was further added thereto and stirred at 80° C. for three hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (150 ml) and water (75 ml). The organic layer was isolated, washed with water and a saturated aqueous solution of sodium chloride, and then dried over anhydrous sodium sulfate. The desiccant was removed by filtration. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=25/1 to 5/1) to give 1-(toluene-4-sulfonyl)-1H-indole-2,5-dicarboxylic acid 5-tert-butyl ester 2-ethyl ester (551 mg, 69%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7](OC2C=C3C(=CC=2)OC(C2C=CC=CC=2)CC3)=[N:8][CH:9]=1)([O-:3])=[O:2].[OH:27][C:28]1[CH:37]=[C:36]2[C:31]([C:32](=[O:44])[CH2:33][CH:34]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[O:35]2)=[CH:30][CH:29]=1>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:27][C:28]2[CH:37]=[C:36]3[C:31]([C:32](=[O:44])[CH2:33][CH:34]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[O:35]3)=[CH:30][CH:29]=2)=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=C1CC(c2ccccc2)Oc2cc(O)ccc21
Reactant: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Product: O=C1CC(c2ccccc2)Oc2cc(Oc3ccc([N+](=O)[O-])cn3)ccc21

Procedure:
7-(5-Nitropyridin-2-yloxy)-2-phenylchroman-4-one was prepared as described for 5-Nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example 1(b) using 150 mg of 7-hydroxyflavanone. 1H NMR (400 MHz, d6-DMSO) δ: 9.07 (d, 1H, J 2.8 Hz), 8.67 (dd, 1H, J 9.0, 2.8 Hz), 7.89 (d, 1H, 8.6 Hz), 7.60-7.35 (m, 6H), 7.04 (d, 1H, 2.1 Hz), 6.97 (dd, 1 H, 8.6, 2.1 HZ), 5.75 (dd, 1H, J 13.0, 2.7 Hz), 3.32 (dd, 1H, 16.9, 13.0 Hz), 2.85 (d, −16.9, 2.7 Hz).
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[O:9])=[C:6]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])[N:5]=[C:4]([S:18][CH3:19])[N:3]=1.[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1B(O)O>>[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:2]1[C:7]([CH:8]=[O:9])=[C:6]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])[N:5]=[C:4]([S:18][CH3:19])[N:3]=1
Reactant: CSc1nc(Cl)c(C=O)c(Nc2ccccc2F)n1
Reactant: OB(O)c1ccccc1F
Product: CSc1nc(Nc2ccccc2F)c(C=O)c(-c2ccccc2F)n1

Procedure:
Prepared as described above in Example 11 starting from 4-chloro-6-(2-fluoro-phenylamino)-2-methylsulfanyl-pyrimidine-5-carbaldehyde and 2-fluorophenylboronic acid to give the title compound 4-(2-fluoro-phenyl)-6-(2-fluoro-phenylamino)-2-methylsulfanyl-pyrimidine-5-carbaldehyde. 1H-NMR: δ0.61 (s, 3H), 7.11-7.23 (m, 4H), 7.26 (m, 1H), 7.45-7.62 (m, 2H), 8.38 (m, 1H), 9.80 (s, 1H), 11.33 (br s, 1H). LC MS (m/e)=358 (MH+).
Reaction SMILES: [C:1]1(=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][C:3](=[O:8])[CH2:2]1.O.[C:11]1(C)C=CC(S(O)(=O)=O)=C[CH:12]=1.C(O)C>C1(C)C=CC=CC=1>[CH2:11]([O:8][C:3]1[CH2:4][CH2:5][CH2:6][CH2:7][C:1](=[O:9])[CH:2]=1)[CH3:12]
Reactant: O=C1CCCCC(=O)C1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC1=CC(=O)CCCC1
Yield: 93 %

Procedure:
A solution of 22.3 g. (0.177 mole) of cycloheptan-1,3-dione and 600 mg. (3.16 mmoles) of p-toluenesulfonic acid monohydrate in 86 ml. of ethanol and 250 ml. of toluene was heated at reflux for 18 hours. A soxhlet extractor filled with molecular sieves (3 Å) was used to remove water from the reaction. The reaction was cooled, added to 800 ml. saturated sodium chloride and extracted with four 800 ml. portions of ether. The combined organic extract was dried over magnesium sulfate and evaporated to an oil. Distillation of the crude oil gave 25.3 g. (93%) of the title compound as an oil.
Reaction SMILES: Br[C:2]1[CH:7]=[N:6][C:5]([Br:8])=[CH:4][N:3]=1.Cl.[F:10][C:11]1([F:17])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CS(C)=O>[Br:8][C:5]1[CH:4]=[N:3][C:2]([N:14]2[CH2:15][CH2:16][C:11]([F:17])([F:10])[CH2:12][CH2:13]2)=[CH:7][N:6]=1
Reactant: FC1(F)CCNCC1
Reactant: Brc1cnc(Br)cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: FC1(F)CCN(c2cnc(Br)cn2)CC1
Yield: 38.2 %

Procedure:
A solution of 2,5-dibromopyrazine (200 mg), 4,4-difluoropiperidine hydrochloride (132 mg) and cesium carbonate (603 mg) in dimethyl sulfoxide (5 mL) was stirred overnight at 90° C. under nitrogen atmosphere. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (89 mg).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:11]2=[N:12][CH:13]=[N:14][C:15]([O:16][C:17]3[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=3)=[C:10]2[CH:9]=[N:8]1.[F:24][C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:32]([C:34]2([C:37](O)=[O:38])[CH2:36][CH2:35]2)=[O:33])=[CH:27][CH:26]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>C(OCC)(=O)C.CN(C=O)C>[F:24][C:25]1[CH:26]=[CH:27][C:28]([NH:31][C:32]([C:34]2([C:37]([NH:23][C:20]3[CH:21]=[CH:22][C:17]([O:16][C:15]4[N:14]=[CH:13][N:12]=[C:11]5[N:7]([CH:2]6[CH2:3][CH2:4][CH2:5][CH2:6][O:1]6)[N:8]=[CH:9][C:10]=45)=[CH:18][CH:19]=3)=[O:38])[CH2:36][CH2:35]2)=[O:33])=[CH:29][CH:30]=1
Reactant: O=C(O)C1(C(=O)Nc2ccc(F)cc2)CC1
Reactant: Nc1ccc(Oc2ncnc3c2cnn3C2CCCCO2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(F)cc1)C1(C(=O)Nc2ccc(Oc3ncnc4c3cnn4C3CCCCO3)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.9 %

Procedure:
To a round bottom flask equipped with a magnetic stir bar was added 4-[1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-phenylamine (0.199 g, 0.63 mmol, 1.0 eq.), 1-(4-fluoro-phenylcarbamoyl)-cyclopropanecarboxylic acid (0.213 g, 0.95 mmol, 1.5 eq), HATU (0.607 g, 1.6 mmol, 2.5 eq), triethylamine (0.26 ml, 1.9 mmol, 3 eq), and anhydrous DMF (5 ml). The mixture was stirred at room temperature for 1 hour. The mixture was diluted with ethyl acetate, washed with (2×) H2O (50 ml), sat'd NaHCO3 (2×), 5% LiCl (3×), sat'd NaCl (1×), dried (Na2SO4), and concentrated in vacuo to give N-(4-fluorophenyl)-N′-(4-{[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]oxy}phenyl)cyclopropane-1,1-dicarboxamide as a white solid (0.312 g, 95% yield). 1H NMR (400 MHz, CDCl3): 9.21 (s, 1H), 8.82 (bs, 1H), 8.56 (s, 1H), 7.96 (s, 2H), 7.65 (dd, 2H), 7.48 (m, 2H), 7.21 (m, 2H), 7.05 (t, 2H), 6.05 (dd, 1H), 3.78 (m, 1H), 2.61 (m, 1H), 2.16 (m, 1H), 2.14 (s,1H), 1.99 (m, 1H), 1.81 (m, 2H), 1.69 (m, 4H), 1.60 (s, 1H); MS (ESI) for C27H25FN7O4: 517 (MH+).
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[C:8]([C:10]1[CH:11]=[C:12]([CH:14]=[CH:15][CH:16]=1)[NH2:13])#[CH:9].O>CN(C)C1C=CN=CC=1.O1CCCC1>[C:5]([NH:13][C:12]1[CH:11]=[C:10]([C:8]#[CH:9])[CH:16]=[CH:15][CH:14]=1)(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: C#Cc1cccc(N)c1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: C1CCOC1
Product: C#Cc1cccc(NC(C)=O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.8 %

Procedure:
Acetic anhydride (13.8 mL, 144 mmol) was added dropwise to a solution of 3-ethynylaniline (14.0 g, 120 mmol) and 4-(Dimethylamino-)pyridine (DMAP) (1.5 g, 12 mmol) in tetrahydrofuran (300 mL). The mixture was stirred at room temperature for 2 hours, water (100 mL) was added to the mixture and the whole was extracted with dichloromethane (2×250 mL). The combined organics was washed with 10% citric acid (100 mL) followed by saturated sodium bicarbonate solution (100 mL), dried over MgSO4, filtered and concentrated in vacuo to afford 3-(acetylamino)phenylacetylene as a yellow solid (18.3 g, 96%).
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:17])[N:4]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)[CH:5]=[CH:6][C:7]=1[OH:8].C([O-])([O-])=O.[K+].[K+].[F:24][C:25]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:26]=1[CH2:27]Br>CC(C)=O>[Br:1][C:2]1[C:3](=[O:17])[N:4]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:27][C:26]1[CH:29]=[CH:30][C:31]([F:33])=[CH:32][C:25]=1[F:24]
Reactant: O=c1c(Br)c(O)ccn1Cc1cccc(F)c1
Reactant: Fc1ccc(CBr)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=c1c(Br)c(OCc2ccc(F)cc2F)ccn1Cc1cccc(F)c1
Temperature: 25 °C

Procedure:
To a solution of 3-bromo-1-(3-fluorobenzyl)-4-hydroxy-1H-pyridin-2-one (0.20 g, 0.67) and K2CO3 (0.27 g, 1.34 mmol) in acetone (10 mL) was added 2,4-difluorobenzyl bromide (0.16 g, 0.8 mmol), and the reaction mixture was heated at reflux for 1 h. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was dissolved in EtOAc. The organic solution was washed with water and then brine, dried (Na2SO4), filtered and concentrated under reduced pressure. 1H NMR (300 MHz, CDCl3) δ 7.65-7.55 (m, 1H), 7.40-7.25 (m, 2H), 7.15-6.80 (m, 5H), 6.14 (d, J=8 Hz, 1H), 5.22 (s, 2H), 5.16 (s, 2H). ESHRMS m/z 424.0159 (M+H C19H14BrF3NO2 requires 424.0155).
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([CH2:10][CH2:11][C:12]([NH2:14])=[O:13])[CH:2]=1.[ClH:15].C(O[CH:20]([CH3:22])[CH3:21])(C)C.[CH:23](O)([CH3:25])[CH3:24]>>[ClH:15].[Cl:15][C:23]1[CH:25]=[CH:8][C:7]([C:2]2[N:3]([CH2:10][CH2:11][C:12]([NH:14][C:21]3[CH:20]=[CH:22][C:10]([N:3]([CH3:4])[CH3:2])=[CH:11][CH:12]=3)=[O:13])[C:4]3=[N:5][CH:6]=[CH:7][CH:8]=[C:9]3[N:1]=2)=[CH:6][CH:24]=1
Reactant: CC(C)OC(C)C
Reactant: CC(C)O
Reactant: NC(=O)CCn1cnc2cccnc21
Agent: Cl
Product: CN(C)c1ccc(NC(=O)CCn2c(-c3ccc(Cl)cc3)nc3cccnc32)cc1

Procedure:
A solution of 0.9 g of 2-(4-chlorophenyl)-N-[4-dimethylamino)-phenyl]-3H-imidazo [4,5-b]pyridine-3-propanamide (obtained in Example 245), in hot isopropyl alcohol was acidified with ethereal hydrogen chloride. Isopropyl ether was added and a pink solid formed. The solid was collected by filtration, rinsed with isopropyl ether and then recrystallized from isopropyl alcohol-isopropyl ether to give 0.81 g of a lavender solid. After drying at high vacuum, mp 215.5°-217° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]([CH3:14])[C:10]([O:12][CH3:13])=[O:11])#[CH:2].C(N(CC)CC)C.Cl[C:23]1[C:28]([C:29]([F:32])([F:31])[F:30])=[CH:27][N:26]=[C:25]([NH:33][C:34]2[CH:39]=[CH:38][C:37]([CH:40]3[CH2:45][CH2:44][N:43]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:42][CH2:41]3)=[CH:36][CH:35]=2)[N:24]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C)C=O.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:13][O:12][C:10](=[O:11])[CH:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:1]#[C:2][C:27]1[C:28]([C:29]([F:30])([F:31])[F:32])=[CH:23][N:24]=[C:25]([NH:33][C:34]2[CH:39]=[CH:38][C:37]([CH:40]3[CH2:41][CH2:42][N:43]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:44][CH2:45]3)=[CH:36][CH:35]=2)[N:26]=1)[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(Cl)n3)cc2)CC1
Reactant: C#Cc1ccccc1C(C)C(=O)OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)C(C)c1ccccc1C#Cc1nc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2)ncc1C(F)(F)F
Temperature: 120 °C
Yield: 54.1 %

Procedure:
A solution of methyl 2-(2-ethynylphenyl)propanoate (I51) (0.074 g, 0.39 mmol) in dimethylformamide (2 mL) and triethylamine (0.183 mL, 1.31 mmol) was added to a mixture of tert-butyl 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (I45) (0.150 g, 0.328 mmol), Pd(PPh3)2Cl2 (0.023 g, 0.033 mmol), CuI (0.0090 g, 0.049 mmol) and triphenylphosphine (0.013 g, 0.049 mmol) in dimethylformamide (2 mL). The reaction mixture was heated under microwave irradiation at 120° C. for 15 minutes. The reaction was cooled and the mixture diluted with EtOAc and passed through a plug of Celite washing with ethyl acetate (50 mL). Water (50 mL) was added and the layers separated. The aqueous layer was extracted with EtOAc (2×50 mL). The combined organic extracts were washed with water (50 mL) and brine (50 mL) and dried over Na2SO4. After filtration the solvent was removed under reduced pressure to give a dark brown residue. The residue was purified by column chromatography on silica gel (0-20% EtOAc in cyclohexane) to yield the title compound (I52) (0.108 g, 54%) as a brown viscous oil.
Reaction SMILES: [OH-].[CH2:2]([N+:9](C)(C)C)[C:3]1C=CC=C[CH:4]=1.[CH:13]1[C:26]2[NH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[S:18][C:17]=2[CH:16]=[CH:15][CH:14]=1.C(#N)C=C.CC(C1C(O)=C(C(C)(C)C)C=C(CCC(OCC(COC(CCC2C=C(C(C)(C)C)C(O)=C(C(C)(C)C)C=2)=O)(COC(CCC2C=C(C(C)(C)C)C(O)=C(C(C)(C)C)C=2)=O)COC(CCC2C=C(C(C)(C)C)C(O)=C(C(C)(C)C)C=2)=O)=O)C=1)(C)C>CC(C)=O.C(#N)C>[C:2]([CH2:3][CH2:4][N:25]1[C:26]2[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=2[S:18][C:19]2[C:24]1=[CH:23][CH:22]=[CH:21][CH:20]=2)#[N:9]
Reactant: c1ccc2c(c1)Nc1ccccc1S2
Reactant: C[N+](C)(C)Cc1ccccc1
Agent: CC(C)(C)c1cc(CCC(=O)OCC(COC(=O)CCc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)(COC(=O)CCc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)COC(=O)CCc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cc(C(C)(C)C)c1O
Agent: [OH-]
Solvent: CC#N
Solvent: CC(C)=O
Solvent: C=CC#N
Product: N#CCCN1c2ccccc2Sc2ccccc21
Reaction time: 2 h

Procedure:
4 ml of Triton B (40%) (benzyltrimethylammonium hydroxide) was dropwise added to an acetonitrile solution (200 ml) containing 199 g of phenothiazine, 106 g of acrylonitrile, and a small quantity of Irganox 1010 (made by Ciba Geigy Co.). Irganox 1010 has the formula ##STR4## After refluxing for 3 hours while heating, 53 g of acrylonitrile was added thereto, followed by relfuxing for a further 2 hours while heating. After being allowed to cool, acetone was added to the reaction solution to crystallize the reaction product. Crystals thus formed were collected by filtration, and recrystallized from 900 ml of acetone to obtain 135 g of the desired compound.
Reaction SMILES: Cl[CH:2]([CH:28]([CH3:30])[CH3:29])[C:3]([NH:5][C:6]1[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][CH:9]=[CH:8][C:7]=1[C:16](=[O:27])[CH2:17][C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1)=[O:19])=O>CN(C)C1C=CN=CC=1.O1CCCC1.O.CC(C)=O>[CH3:30][CH:28]([CH:2]1[C:3]2=[N:5][C:6]3[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][CH:9]=[CH:8][C:7]=3[C:16]([OH:27])=[C:17]2[C:18](=[N:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[O:19]1)[CH3:29]
Reactant: CC(C)C(Cl)C(=O)Nc1c(C(=O)CC(=O)Nc2ccccn2)cccc1C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: O
Solvent: CC(C)=O
Product: CC(C)C1OC(=Nc2ccccn2)c2c1nc1c(C(F)(F)F)cccc1c2O
Yield: 84.7 %

Procedure:
10.5 g of the product of Step A and 2.9 g of 4-dimethylamino-pyridine in 100 ml of tetrahydrofuran were refluxed for 7 hours 30 minutes and after cooling, the solvent was eliminated under reduced pressure. The residue was taken up in 100 ml of water and 10 ml of acetone. After separating, washing with water and drying at 70° C. under reduced pressure, 7.8 g of 1,3-dihydro-3-(1-methylethyl)-1-[(2-pyridinyl)-imino]-5-trifluoromethyl furo-[3,4-b]-quinolin-9-ol melting at 178°-180° C. were obtained.