Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][N:7]3[C:13]([C:14]4[C:15]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)=[N:16][O:17][C:18]=4[CH3:19])=[N:12][N:11]=[C:8]32)=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:31]1[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=1)CCC>CN(C=O)C>[CH3:19][C:18]1[O:17][N:16]=[C:15]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:14]=1[C:13]1[N:7]2[CH2:6][C:5]3[C:9]([C:8]2=[N:11][N:12]=1)=[CH:10][C:2]([C:31]1[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=1)=[CH:3][CH:4]=3
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccnc1
Reactant: Cc1onc(-c2ccccc2)c1-c1nnc2n1Cc1ccc(Br)cc1-2
Solvent: CN(C)C=O
Product: Cc1onc(-c2ccccc2)c1-c1nnc2n1Cc1ccc(-c3cccnc3)cc1-2
Temperature: 100 °C
Yield: 75.3 %

Procedure:
A mixture of 8-bromo-3-(5-methyl-3-phenylisoxazol-4-yl)-5H-[1,2,4]triazolo[3,4-a]isoindole (100 mg) (as prepared in Example 4), 3-(tri-n-butylstannyl)pyridine (442 mg) and DMF (5 ml) was degassed with a stream of N2 for 0.5 h. Bis(triphenylphosphine)palladium(II) chloride (5 mg) was added and the reaction heated to 100° C. for 2 h. The mixture was concentrated under reduced pressure and the residue purified by column chromatography on silica, eluting with 2.5% MeOH/CH2Cl2 to give the title compound (75 mg, 64%). 1H NMR (400 MHz, CDCl3) δ 8.66 (1H, t, J=3.3 Hz), 8.23 (1H, d, J=1.4 Hz), 7.95–7.92 (1H, m), 7.63 (1H, dd, J=8.0, 1.7 Hz), 7.57–7.54 (2H, m), 7.49–7.38 (5H, m), 4.07 (2H, s), 3.97 (2H, s), 2.73 (3H, s), m/z (ES+) 392 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[CH:34]=[CH:33][C:10]3[N:11]=[C:12]([CH2:14][C:15]4[O:19][C:18]([CH2:20][NH:21][S:22]([NH:25]C(=O)OC(C)(C)C)(=[O:24])=[O:23])=[N:17][N:16]=4)[S:13][C:9]=3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]1([C:7]2[CH:34]=[CH:33][C:10]3[N:11]=[C:12]([CH2:14][C:15]4[O:19][C:18]([CH2:20][NH:21][S:22](=[O:23])(=[O:24])[NH2:25])=[N:17][N:16]=4)[S:13][C:9]=3[CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)NS(=O)(=O)NCc1nnc(Cc2nc3ccc(-c4ccccc4)cc3s2)o1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NS(=O)(=O)NCc1nnc(Cc2nc3ccc(-c4ccccc4)cc3s2)o1
Reaction time: 0.5 h
Yield: 7.4 %

Procedure:
To a solution of Compound 46a (1.16 g, 2.3 mmol) in DCM (10 mL) was added TFA (5 mL) and the reaction mixture stirred for 0.5 h. The reaction mixture was concentrated under reduced pressure then evaporated under reduced pressure from toluene (2×). The residue was diluted with 1.5 M K3PO4 then extracted with DCM (3×). The combined extracts were washed with brine, dried (Na2SO4), filtered and evaporated under reduced pressure. The residue was purified by silica gel chromatography eluting with 1 to 15% MeOH/DCM to give Compound 46b (68 mg, 74% yield) as a pale brown solid. LCMS=1.71 min using analytical method (B), 402.0 (M+H). 1H NMR (400 MHz, CD3OD) δ 8.24 (d, J=1.5 Hz, 1H), 8.01 (d, J=8.8 Hz, 1H), 7.79 (dd, J=8.5, 1.8 Hz, 1H), 7.73-7.65 (m, 2H), 7.47 (t, J=7.7 Hz, 2H), 7.41-7.32 (m, 1H), 4.47 (s, 2H).
Reaction SMILES: [CH2:1]([C:4]1[S:8][C:7]([C:9]([OH:11])=O)=[CH:6][CH:5]=1)[CH2:2][CH3:3].[CH2:12]([C:14]1[CH:15]=[C:16]([CH:21]=[C:22]([CH3:25])[C:23]=1[OH:24])[C:17]([NH:19]O)=[NH:18])[CH3:13]>>[CH2:12]([C:14]1[CH:15]=[C:16]([C:17]2[N:19]=[C:9]([C:7]3[S:8][C:4]([CH2:1][CH2:2][CH3:3])=[CH:5][CH:6]=3)[O:11][N:18]=2)[CH:21]=[C:22]([CH3:25])[C:23]=1[OH:24])[CH3:13]
Reactant: CCCc1ccc(C(=O)O)s1
Reactant: CCc1cc(C(=N)NO)cc(C)c1O
Product: CCCc1ccc(-c2nc(-c3cc(C)c(O)c(CC)c3)no2)s1

Procedure:
2-Ethyl-6-methyl-4-[5-(5-propyl-thiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-phenol is prepared in analogy to Example 1 starting from 5-propyl-thiophene-2-carboxylic acid and 3-ethyl-4,N-dihydroxy-5-methyl-benzamidine; LC-MS: tR=1.12 min, [M+1]+=329.14.
Reaction SMILES: Br[CH2:2][C:3](=[O:8])[CH2:4][CH:5]([CH3:7])[CH3:6].[C:9]1(=[O:19])[NH:13][C:12](=[O:14])[C:11]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:10]12.[K]>C1(C)C=CC=CC=1>[CH3:6][CH:5]([CH3:7])[CH2:4][C:3](=[O:8])[CH2:2][N:13]1[C:9](=[O:19])[C:10]2[C:11](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:12]1=[O:14]
Reactant: CC(C)CC(=O)CBr
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: Cc1ccccc1
Product: CC(C)CC(=O)CN1C(=O)c2ccccc2C1=O
Temperature: 100 °C
Reaction time: 16 h
Yield: 23.9 %

Procedure:
Dissolve 1-bromo-4-methyl-2-pentanone (11.0 g, 61.4 mmol) and potassium phthalimide (11.9 g, 64.5 mmol) in toluene (60 mL) at room temperature under a nitrogen atmosphere. Heat the mixture to 100° C. and stir for 16 h. Cool the resulting slurry to room temperature, filter off solids, and concentrate the filtrate in vacuo to a solid. Purify the residue by chromatography on silica gel (40 g) eluting with hexane/EtOAc (1:1) to obtain the desired intermediate (3.6 g, 24%). MS (ES+) m/z: 246.3 (M+H)+.
Reaction SMILES: I[CH2:2][C:3]1[N:4]([CH3:16])[C:5](=[O:15])[CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][N:10]=2)[N:8]=1.[C:17]1(=[O:27])[NH:21][C:20](=[O:22])[C:19]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:18]12.[K].O>CN(C)C=O>[CH3:16][N:4]1[C:5](=[O:15])[CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][N:10]=2)[N:8]=[C:3]1[CH2:2][N:21]1[C:17](=[O:27])[C:18]2[C:19](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:20]1=[O:22]
Reactant: Cn1c(CI)nc(-c2ccncn2)cc1=O
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(CN2C(=O)c3ccccc3C2=O)nc(-c2ccncn2)cc1=O
Temperature: 130 °C
Reaction time: 3 h
Yield: 33.8 %

Procedure:
To a solution of 14.80 g (45.11 mmol) of 2-iodomethyl-1-methyl-1H-[4,4′]bipyrimidinyl-6-one in 30 ml of anhydrous dimethylformamide was added 16.71 g (90.21 mmol) of potassium phthalimide. The resulting mixture was stirred at 130° C. for 3 h. After cooling, water was added and the resulting mixture was stirred for 12 h at 0° C. The precipitate was filtered, heated in ethyl acetate and the precipitate was filtered. The product was dried to give 5.3 g (30%) of pure compound as a brown solid.
Reaction SMILES: CO[C:3]([CH3:5])=[CH2:4].[C:6]([O:10][C:11]([NH:13][C@H:14]([CH2:21][OH:22])[CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])=[O:12])([CH3:9])([CH3:8])[CH3:7].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl>[C:6]([O:10][C:11]([N:13]1[C@@H:14]([CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH2:21][O:22][C:3]1([CH3:5])[CH3:4])=[O:12])([CH3:7])([CH3:9])[CH3:8]
Reactant: COC(=O)CC[C@@H](CO)NC(=O)OC(C)(C)C
Reactant: C=C(C)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Product: COC(=O)CC[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 3 h

Procedure:
120 ml of isopropenyl methyl ether are added to a solution of 159.5 g of methyl 4(S)-tert-butoxycarbonylamino-5-hydroxyvalerate and 3 g of p-toluenesulfonic acid hydrate in 500 ml of methylene chloride at 0° C. The reaction mixture is stirred at 0° C. for 2 h and at room temperature for 3 h. The reaction solution is washed with 100 ml of saturated sodium bicarbonate solution and evaporated. The title compound is obtained by FC (800 g of silica gel, mobile phase E): [α]D =+20.5 (c=0.8 in CHCl3); Rf (D)=0.24; MS: (M)+ =287.
Reaction SMILES: O[CH2:2][CH2:3][O:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[NH:13][C:14](=[O:26])[C:15]3[C:21]([O:22][CH3:23])=[CH:20][C:19]([O:24][CH3:25])=[N:18][C:16]=3[N:17]=2)=[CH:7][C:6]=1[CH3:27].C(Br)(Br)(Br)[Br:29].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C>[Br:29][CH2:2][CH2:3][O:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[NH:13][C:14](=[O:26])[C:15]3[C:21]([O:22][CH3:23])=[CH:20][C:19]([O:24][CH3:25])=[N:18][C:16]=3[N:17]=2)=[CH:7][C:6]=1[CH3:27]
Reactant: BrC(Br)(Br)Br
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(OCCO)c(C)c3)nc2n1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(OCCBr)c(C)c3)nc2n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-[4-(2-hydroxy-ethoxy)-3,5-dimethyl-phenyl]-5,7-dimethoxy-3H-pyrido[2,3-d]pyrimidin-4-one (0.50 g, 1.34 mmol) in anhydrous DMF (6 mL) was added carbon tetrabromide (0.53 g, 1.61 mmol) and triphenylphosphine (0.42 g, 1.61 mmol). The reaction mixture was stirred at 25° C. for 16 hours. DMF was removed under vacuum and dichloromethane (200 mL) was added. The organic phase was washed with water (100 mL), then brine (100 mL), and dried over anhydrous sodium sulfate. Solvent was removed and the residue was washed with ether (100 mL) to give 2-[4-(2-bromo-ethoxy)-3,5-dimethyl-phenyl]-5,7-dimethoxy-3H-pyrido[2,3-d]pyrimidin-4-one as a white solid. Yield: 0.23 g (40%).
Reaction SMILES: [O:1]([C:8]1[N:13]=[C:12]([N:14]2[CH2:19][CH2:18][N:17](C=O)[CH2:16][CH2:15]2)[CH:11]=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.Cl>[O:1]([C:8]1[N:13]=[C:12]([N:14]2[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]2)[CH:11]=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=CN1CCN(c2ccnc(Oc3ccccc3)n2)CC1
Agent: Cl
Solvent: CO
Product: c1ccc(Oc2nccc(N3CCNCC3)n2)cc1
Yield: 64 %

Procedure:
2-Phenoxy-4-(4-formylpiperazino)pyrimidine (2.6 g) in methanol (27 ml) and 2 N hydrochloric acid (6.9 ml) was left at room temperature for 24 hours and then heated on a steam bath for 30 minutes. The solvent was evaporated in vacuo and the residue re-crystallized twice from isopropanol to give 2-phenoxy-4-piperazinopyrimidine (1.5 g) characterized spectroscopically, and used directly.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[CH2:7]/[N:8]=[CH:9]/[CH2:10][C:11]([CH:14]1[CH2:16][CH2:15]1)([CH3:13])[CH3:12])(C)(C)C.[Cl:18][C:19]1[C:20]([F:37])=[C:21](/[CH:25]=[C:26](/[C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:30]=2[F:36])\[C:27]#[N:28])[CH:22]=[CH:23][CH:24]=1.C(N(CC)CC)C>ClCCl>[CH3:1][O:5][C:6]([CH:7]1[CH:25]([C:21]2[CH:22]=[CH:23][CH:24]=[C:19]([Cl:18])[C:20]=2[F:37])[C:26]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:30]=2[F:36])([C:27]#[N:28])[CH:9]([CH2:10][C:11]([CH:14]2[CH2:16][CH2:15]2)([CH3:13])[CH3:12])[NH:8]1)=[O:17]
Reactant: CC(C)(C)OC(=O)C/N=C/CC(C)(C)C1CC1
Reactant: N#C/C(=C\c1cccc(Cl)c1F)c1ccc(Cl)cc1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C1NC(CC(C)(C)C2CC2)C(C#N)(c2ccc(Cl)cc2F)C1c1cccc(Cl)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.8 %

Procedure:
To a solution of [3-cyclopropyl-3-methyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 99a (0.9 g, 3.76 mmol) and (Z)-3-(3-chloro-2-fluoro-phenyl)-2-(4-chloro-2-fluoro-phenyl)-acrylonitrile (1.16 g, 3.76 mmol) prepared in Example 52a in dichloromethane (100 mL) were added triethylamine (0.76 g, 7.5 mmol) and AgF (0.47 g, 3.76 mmol), in one portion. The mixture was stirred at room temperature for overnight. The mixture was then quenched with sat. NH4Cl and extracted with CH2Cl2. The organic phase was separated, filtered through celite and dried over Na2SO4, and concentrated. The residue was dissolved into methanol (40 mL), and DBU (3 mL) was added. The mixture was heated at 100° C. for 5 h, then cooled to room temperature, and concentrated. The residue was partitioned between ethyl acetate and water. The organic layer were separated, dried over MgSO4, and concentrated. The residue was purified by chromatography (EtOAc:hexanes=1:5, 1:3) to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2-cyclopropyl-2-methyl-propyl)-pyrrolidine-2-carboxylic acid methyl ester as a white foam (0.95 g, 50%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C@@H:2]1[C:7]([NH:9][C:10]1([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH2:12][CH2:11]1)=[O:8].[F:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27]Br.C([O-])([O-])=O.[Na+].[Na+]>>[F:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27][N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C@@H:2]1[C:7]([NH:9][C:10]1([C:13]2[CH:14]=[CH:15][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:21][CH:22]=2)[CH2:12][CH2:11]1)=[O:8]
Reactant: Fc1cccc(CBr)c1
Reactant: COC(=O)c1ccc(C2(NC(=O)[C@H]3CCCCN3)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COC(=O)c1ccc(C2(NC(=O)[C@H]3CCCCN3Cc3cccc(F)c3)CC2)cc1
Yield: 94.4 %

Procedure:
The title compound (D28) (62 mg) was prepared according to the general procedure for substituted benzyl amines preparation starting from (R)-methyl 4-(1-(piperidine-2-carboxamido)cyclopropyl)benzoate (D13) (50 mg, 0.16 mmol) and 3-fluoro benzyl bromide (0.03 ml, 0.25 mmol). (Na2CO3: 2.5 eq; reaction time: 6 hrs; 60° C.)
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].Br[C:27]1[CH:35]=[CH:34][C:30]([CH:31]([OH:33])[CH3:32])=[CH:29][CH:28]=1>>[F:15][C:12]([F:14])([F:13])[C:11]1[N:6]2[N:5]=[CH:4][C:3]([C:1]#[C:2][C:27]3[CH:35]=[CH:34][C:30]([CH:31]([OH:33])[CH3:32])=[CH:29][CH:28]=3)=[C:7]2[N:8]=[C:9]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH:10]=1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: CC(O)c1ccc(Br)cc1
Product: CC(O)c1ccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)cc1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (355 mg, 1.0 mmol) and commercially available 4-bromo-methylbenzylalcohol (181 mg, 1.0 mmol, [CAS 5391-88-8]) according to general procedure II. Obtained as an orange solid (115 mg, 24%). MS (ISP) 476.2[(M+H)+]; mp 175–178° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1.[SH:13][C:14]1[CH:15]=[C:16]([B:20]([OH:22])[OH:21])[CH:17]=[CH:18][CH:19]=1>>[C:10]([CH2:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:2][S:13][C:14]2[CH:15]=[C:16]([B:20]([OH:22])[OH:21])[CH:17]=[CH:18][CH:19]=2)=[CH:4][CH:5]=1)([OH:12])=[O:11]
Reactant: O=C(O)Cc1ccc(CBr)cc1
Reactant: OB(O)c1cccc(S)c1
Product: O=C(O)Cc1ccc(CSc2cccc(B(O)O)c2)cc1

Procedure:
3-(4-Carboxymethyl-benzylsulfanyl)phenylboronic acid was prepared from 4-(bromomethyl)phenyl acetic acid and 3-mecaptophenylboronic acid according to the procedure of Example 41.
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[C:13]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:12]=[CH:11][C:3]=1[C:4]([O:6]C(C)(C)C)=[O:5].FC(F)(F)C(O)=O>ClCCl>[CH3:1][C:2]1[CH:14]=[C:13]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:12]=[CH:11][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Cc1cc(Oc2ccccc2)ccc1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(Oc2ccccc2)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.7 %

Procedure:
To a solution of tert-butyl 2-methyl-4-phenoxybenzoate (150 mg, 0.53 mmol) in dichloromethane (10 mL) was added 2,2,2-trifluoroacetic acid (2 mL). The mixture was stirred at room temperature for 0.5 hour, and then concentrated to give 2-methyl-4-phenoxybenzoic acid (100 mg, 84% yield) as a white solid.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[C:13](OCC)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]1=[O:23])(=O)C.[NH:24]1[CH:28]=[C:27]([C:29]2[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=2)[N:26]=[CH:25]1.[OH-].[Na+]>CN(C=O)C.CO>[NH:24]1[CH:28]=[C:27]([C:29]2[CH:35]=[CH:34][C:32]([NH:33]/[C:13](=[C:6]3\[C:5](=[O:23])[NH:4][C:12]4[C:7]\3=[CH:8][CH:9]=[CH:10][CH:11]=4)/[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:31][CH:30]=2)[N:26]=[CH:25]1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccccc21)c1ccccc1
Reactant: Nc1ccc(-c2c[nH]cn2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Product: O=C1Nc2ccccc2/C1=C(/Nc1ccc(-c2c[nH]cn2)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylidene}-2-indolinone and 1.5 equivalents of 4-(1H-imidazol-4-yl)-aniline in DMF followed by treatment with 1N sodium hydroxide solution in MeOH.
Reaction SMILES: [Si:1]([C:5]#[CH:6])([CH3:4])([CH3:3])[CH3:2].Br[C:8]1[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][CH:9]=1.CCN(CC)CC>CC#N.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>[CH3:2][Si:1]([C:5]#[C:6][C:8]1[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][CH:9]=1)([CH3:4])[CH3:3]
Reactant: CCOC(=O)c1ccc(Br)cc1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)c1ccc(C#C[Si](C)(C)C)cc1

Procedure:
TMS-acetylene (Aldrich) (5.0 mL, 35.5 mmol), ethyl 4-bromobenzoate (58 mL, 35.5 mmol) and Et3N (20 mL, 144 mmol) were combined in 50 mL CH3CN in a glass pressure tube. (Ph3P)2PdCl2 (198 mg, 0.28 mmol) and CuI (100 mg, 0.53 mmol) were added, and the reaction was sealed and heated at 100° for 18 h. Dilution with EtOAc, washing twice with water, then brine, drying and concentration provided 29-1 as a brown liquid.
Reaction SMILES: [CH2:1]([OH:7])/[CH:2]=[CH:3]\[CH2:4][CH2:5][CH3:6].[H-].[Na+].Cl[C:11]1[C:15]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[N:14][S:13][N:12]=1.O>O1CCCC1>[CH2:1]([O:7][C:11]1[C:15]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[N:14][S:13][N:12]=1)/[CH:2]=[CH:3]\[CH2:4][CH2:5][CH3:6]
Reactant: Clc1nsnc1-c1cccnc1
Reactant: CCC/C=C\CO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCC/C=C\COc1nsnc1-c1cccnc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of cis-2-hexen-1-ol (900 mg, 9 mmol) and sodium hydride (310 mg, 9 mmol) in dry tetrahydrofuran was added a solution of 3-(3-chloro-1,2,5-thiadiazol-4-yl) pyridine (590 mg, 3 mmol) in dry tetrahydrofuran. The reaction mixture was stirred at room temperature for 1 h. Water was added and the mixture was extracted with ether. The ether phase was dried and evaporated to give the title compound.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][N:15]=[CH:14][C:13]=3[OH:18])[O:9][C:6]2=[N:7][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C.[F:32][CH:33]([F:43])[CH2:34]OS(C(F)(F)F)(=O)=O>O>[F:32][CH:33]([F:43])[CH2:34][O:18][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][C:12]=1[C:10]1[O:9][C:6]2[C:5]([N:11]=1)=[CH:4][C:3]([C:2]([F:19])([F:1])[F:20])=[CH:8][N:7]=2
Reactant: O=S(=O)(OCC(F)F)C(F)(F)F
Reactant: Oc1cnccc1-c1nc2cc(C(F)(F)F)cnc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)COc1cnccc1-c1nc2cc(C(F)(F)F)cnc2o1
Temperature: 60 °C
Yield: 26.3 %

Procedure:
To a mixture of 0.31 g of 4-(6-trifluoromethyl-oxazolo[5,4-b]pyridin-2-yl)pyridin-3-ol, 0.23 g of potassium carbonate and 3 ml of DMF, a mixture of 0.50 g of trifluoromethanesulfonate (2,2-difluoroethyl) ester and 7 ml of DMF was added at room temperature, and then stirred while heating at 60° C. for six hours. The reaction mixture was cooled to room temperature, and then water was added to the reaction mixture, followed by extraction with ethyl acetate twice. The combined organic layers were washed with water and a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.10 g of 2-[3-(2,2-difluoroethoxy)pyridin-4-yl]-6-trifluoromethyl-oxazolo[5,4-b]pyridine (hereinafter, referred to as “active compound 162”).
Reaction SMILES: Cl.[C@H:2]12[CH2:8][C@H:5]([NH:6][CH2:7]1)[CH2:4][N:3]2[C:9](=[O:11])[CH3:10].C([O-])([O-])=O.[K+].[K+].Cl[CH2:19][C:20]1[C:24]2[CH:25]=[CH:26][C:27]([O:29]C(=O)C)=[CH:28][C:23]=2[O:22][CH:21]=1>CC#N>[OH:29][C:27]1[CH:26]=[CH:25][C:24]2[C:20]([CH2:19][N:6]3[CH2:7][C@@H:2]4[CH2:8][C@H:5]3[CH2:4][N:3]4[C:9](=[O:11])[CH3:10])=[CH:21][O:22][C:23]=2[CH:28]=1
Reactant: CC(=O)Oc1ccc2c(CCl)coc2c1
Reactant: CC(=O)N1C[C@@H]2C[C@H]1CN2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)N1C[C@@H]2C[C@H]1CN2Cc1coc2cc(O)ccc12
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 94.3 %

Procedure:
To a solution of (1S,4S)-1-(2,5-diaza-bicyclo[2.2.1]hept-2-yl)-ethanone hydrochloride (330 mg, 2.35 mmol) and K2CO3 (0.831 g, 6.01 mmol) in MeCN (20 mL) was added acetic acid 3-chloromethyl-benzofuran-6-yl ester (450 mg, 2.00 mmol) and the reaction mixture was heated (50° C., 20 h). The solvent was removed in vacuo and the remaining residue was dissolved in water (10 mL) and 2-3 mL of 4 M KOH was slowly added to reach pH 13-14. The dark green solution was stirred (10 min) and treated with concentrated acetic acid until the solution reached pH 10. The aqueous mixture was extracted with 20% IPA/DCM (4×30 mL). The organic layer was dried, filtered and concentrated in vacuo to provide the title compound as a gummy yellow solid (540 mg, 94%). MS (ESI): mass calcd. for C16H18N2O3, 286.1; m/z found, 287.1 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.54-7.51 (m, 1H), 7.48 (dd, J=8.4, 2.5, 1H), 6.84 (t, J=1.8, 1H), 6.75 (ddd, J=8.4, 2.9, 2.2, 1H), 4.66 (s, 0.5H), 4.44 (s, 0.5H), 3.89-3.75 (m, 2H), 3.69-3.58 (m, 2H), 3.40 (dd, J=9.8, 2.3, 0.5H), 3.23 (dd, J=11.4, 2.0, 0.5H), 2.96 (dd, J=10.0, 2.2, 0.5H), 2.88 (dd, J=9.9, 2.2, 0.5H), 2.73 (dd, J=9.4, 7.0, 1H), 2.09 (s, 1.5H), 2.03-1.92 (m, 2.5H), 1.80 (d, J=10.1, 0.5H), 1.71 (d, J=10.1, 0.5H).
Reaction SMILES: C([O:8][C:9]1[CH:17]=[CH:16][C:15]2[N:14]3[C@@H:18]([CH3:23])[CH2:19][NH:20][C:21](=[O:22])[C:13]3=[CH:12][C:11]=2[CH:10]=1)C1C=CC=CC=1>[Pd].CO>[OH:8][C:9]1[CH:17]=[CH:16][C:15]2[N:14]3[C@@H:18]([CH3:23])[CH2:19][NH:20][C:21](=[O:22])[C:13]3=[CH:12][C:11]=2[CH:10]=1
Reactant: C[C@H]1CNC(=O)c2cc3cc(OCc4ccccc4)ccc3n21
Agent: [Pd]
Solvent: CO
Product: C[C@H]1CNC(=O)c2cc3cc(O)ccc3n21
Yield: 100 %

Procedure:
The suspension consistent of 3.50 g (11.4 mmol) (S)-8-benzyloxy-4-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one and 0.35 g palladium on activated charcoal (10% Pd; commercially available) in 40 mL methanol was hydrogenated at room temperature at 1.5 bar for 3 hours. The reaction mixture was filtered over dicalite speed plush (Aldrich) and the volatile components were evaporated at a rotary evaporator to give the desired compound as a light yellow foam (100%) which was used in the next step without further purification.
Reaction SMILES: [H-].[Na+].CN(C)C=O.[NH:8]1[CH:12]=[CH:11][N:10]=[CH:9]1.[Cl:13][C:14]1[N:23]=[C:22](Cl)[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=1>O1CCCC1>[Cl:13][C:14]1[N:23]=[C:22]([N:8]2[CH:12]=[CH:11][N:10]=[CH:9]2)[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=1
Reactant: Clc1nc(Cl)c2ccccc2n1
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Clc1nc(-n2ccnc2)c2ccccc2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.5 %

Procedure:
To a suspension of 60% sodium hydride (426 mg) in tetrahydrofuran (4 mL)-N,N-dimethylformamide (24 mL) was added imidazole (725 mg), and the mixture was stirred at room temperature for 30 minutes. To the mixture was added dropwise a tetrahydrofuran solution (35 mL) of 2,4-dichloroquinazoline (2.12 g) synthesized according to the method of H. C. Scarborough et al. (Journal of Organic Chemistry, 1962, pp. 957-961), in ice-acetone bath, and the mixture was stirred for 30 minutes. The reaction mixture was poured into ice-cold water, and precipitated powder was collected by filtration, washed with water and dried. The obtained powder was purified by silica gel column chromatography, (ethyl acetate), to give 1.88 g of 2-chloro-4-(1-imidazolyl)-quinazoline as colorless crystals (yield 77%).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:3]=1[C:4]([C:6]1[C:15]([OH:16])=[CH:14][C:9]2C(C#N)=[CH:11][C:8]=2[CH:7]=1)=[O:5].[C:22]([OH:25])(=[O:24])[CH3:23]>Cl>[Cl:1][C:2]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:3]=1[C:4]([C:6]1[C:15]([OH:16])=[CH:14][C:9]2[C:23]([C:22]([OH:25])=[O:24])=[CH:11][C:8]=2[CH:7]=1)=[O:5]
Reactant: N#CC1=Cc2cc(C(=O)c3c(Cl)cccc3Cl)c(O)cc21
Reactant: CC(=O)O
Agent: Cl
Product: O=C(O)C1=Cc2cc(C(=O)c3c(Cl)cccc3Cl)c(O)cc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
10.65 g of 4-(2,6-dichlorobenzoyl)-5-hydroxybenzocyclobutene-1-carbonitrile are suspended in a mixture of 100 ml of concentrated hydrochloric acid and 100 ml of acetic acid and stirring is carried out for 4 hours at 100°. The whole is left to cool to room temperature, filtered with suction, washed thoroughly with water, left to dry in the air and recrystallised from trichloromethane/hexane with the addition of a small amount of methanol. 4-(2,6-dichlorobenzoyl)-5-hydroxybenzocyclobutene-1-carboxylic acid is obtained having a melting point of 202°-203°.