Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]#[C:13][C:14]2[CH:34]=[CH:33][C:17]([CH2:18][NH:19][C:20]3[CH:32]=[CH:31][C:23]4[O:24][C:25]([CH3:30])([CH3:29])[O:26][C:27](=[O:28])[C:22]=4[CH:21]=3)=[CH:16][CH:15]=2)=[CH:8][CH:7]=1)[CH2:3][CH2:4][CH3:5].[S:35]1[C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=2[CH:37]=[C:36]1[C:44](Cl)=[O:45]>>[CH2:2]([C:6]1[CH:7]=[CH:8][C:9]([C:12]#[C:13][C:14]2[CH:34]=[CH:33][C:17]([CH2:18][N:19]([C:20]3[CH:32]=[CH:31][C:23]4[O:24][C:25]([CH3:30])([CH3:29])[O:26][C:27](=[O:28])[C:22]=4[CH:21]=3)[C:44]([C:36]3[S:35][C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=4[CH:37]=3)=[O:45])=[CH:16][CH:15]=2)=[CH:10][CH:11]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCCc1ccc(C#Cc2ccc(CNc3ccc4c(c3)C(=O)OC(C)(C)O4)cc2)cc1
Reactant: O=C(Cl)c1cc2ccccc2s1
Agent: Cl
Product: CCCCc1ccc(C#Cc2ccc(CN(C(=O)c3cc4ccccc4s3)c3ccc4c(c3)C(=O)OC(C)(C)O4)cc2)cc1

Procedure:
The titled compound was prepared following the procedure K using 6-({4-[(4-butylphenyl)ethynyl]benzyl}amino)-2,2-dimethyl-4H-1,3-benzodioxin-4-one hydrochloride and 1-benzothiophene-2-carbonyl chloride as a yellow oil (95%). HPLC, Rt: 6.04 min (Purity: 92.1%).
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[C:17]2[NH:19][N:20]=[C:21](I)[C:16]2=[CH:15][N:14]=1.[OH:23][CH2:24][CH:25]([N:27]1[CH2:35][C:34]2[C:29](=[CH:30][CH:31]=[C:32](B3OC(C)(C)C(C)(C)O3)[CH:33]=2)[C:28]1=[O:45])[CH3:26]>>[F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[C:17]2[NH:19][N:20]=[C:21]([C:32]3[CH:33]=[C:34]4[C:29](=[CH:30][CH:31]=3)[C:28](=[O:45])[N:27]([CH:25]([CH3:26])[CH2:24][OH:23])[CH2:35]4)[C:16]2=[CH:15][N:14]=1
Reactant: COc1cc(OC)c(F)c(-c2ncc3c(I)n[nH]c3n2)c1F
Reactant: CC(CO)N1Cc2cc(B3OC(C)(C)C(C)(C)O3)ccc2C1=O
Product: COc1cc(OC)c(F)c(-c2ncc3c(-c4ccc5c(c4)CN(C(C)CO)C5=O)n[nH]c3n2)c1F

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 4, Step 2 starting from 6-(2,6-difluoro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidine and 2-(2-hydroxy-1-methylethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one. LCMS (M+H)+=482.0.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:13])[O:12][CH2:11][CH2:10][O:9]2)=[CH:4][N:3]=1.[Li]CCCC.[CH3:19][N:20]1[CH2:25][CH2:24][C:23](=[O:26])[CH2:22][CH2:21]1>O1CCCC1>[CH3:19][N:20]1[CH2:25][CH2:24][C:23]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3([CH3:13])[O:12][CH2:11][CH2:10][O:9]3)=[CH:4][N:3]=2)([OH:26])[CH2:22][CH2:21]1
Reactant: CC1(c2ccc(Br)nc2)OCCO1
Reactant: CN1CCC(=O)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CN1CCC(O)(c2ccc(C3(C)OCCO3)cn2)CC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 84.8 %

Procedure:
2-bromo-5-(2-methyl-1,3-dioxolan-2-yl)pyridine (500 mg, 2.048 mmol) (described in the literature: Bioorg. Med. Chem., 2005, 13, 6763) was dissolved in anhydrous tetrahydrofuran (10 mL) and cooled to −78° C. under nitrogen. n-BuLi (901.2 μL of 2.5 M, 2.253 mmol) was added dropwise and the reaction mixture was stirred at −78° C. for 30 minutes. 1-Methyl-4-piperidone (602.6 mg, 655.0 μL, 5.325 mmol) was added and the reaction was allowed to stir at −78° C. for 20 minutes then warmed slowly to ambient temperature. The reaction mixture was stirred at room temperature for 18 hours and concentrated in vacuo. The residue was purified on silica gel by flash column chromatography to afford the title compound as a sticky orange solid (483.4 mg, 85% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:12])[CH2:10]Cl)=[C:4]([C:13](=[O:21])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[N:28]1[CH:33]=[CH:32][CH:31]=[N:30][C:29]=1[N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1>CC(C)=O.C(OCC)(=O)C.CCCCCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:12])[CH2:10][N:37]2[CH2:38][CH2:39][N:34]([C:29]3[N:28]=[CH:33][CH:32]=[CH:31][N:30]=3)[CH2:35][CH2:36]2)=[C:4]([C:13](=[O:21])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])[CH:3]=1
Reactant: c1cnc(N2CCNCC2)nc1
Reactant: O=C(CCl)Nc1ccc(Cl)cc1C(=O)c1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CC(C)=O
Product: O=C(CN1CCN(c2ncccn2)CC1)Nc1ccc(Cl)cc1C(=O)c1ccccc1Cl
Yield: 83.7 %

Procedure:
To a compound of N1-[4-chloro-2-(2-chlorobenzoyl)phenyl]-2-chloroacetamide (500 mg, 1.46 mmol) in dry acetone (20 mL) was added anhydrous potassium carbonate (1 g, 7.30 mmol) and 1-(2-pyrimidinyl)piperazine (239 mg, 1.46 mmol). The reaction mixture was refluxed for 24 h and the reaction was monitored by TLC using ethyl acetate-hexane (6:4) as a solvent system. The potassium carbonate was then removed by suction filtration and the solvent was evaporated under vacuum to afford the crude product. This was further purified by column chromatography using ethyl acetate:hexane (6:4) as a solvent system to obtain the pure product 6b (575 mg, 83% yield).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(=O)([O-])[O-].[K+].[K+].[CH:16](Br)([CH3:18])[CH3:17]>CC(C)CC(=O)C>[CH:16]([N:2]([CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:1])([CH3:18])[CH3:17]
Reactant: CNCc1ccccc1
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: CC(C)N(C)Cc1ccccc1

Procedure:
A flask containing N-methylbenzylamine (3.87 ml, 3.63 g, 0.03 moles), potassium carbonate (8.29 g, 0.06 moles) and 4-methyl-2-pentanone (100 ml) was treated with isopropyl bromide (2.69 ml, 0.03 moles) then heated under reflux for 18 hours. The reaction was checked by thin layer chromatography (tlc) to ensure the starting materials had been consumed. The reaction mixture was gravity filtered hot to remove the potassium salts and the filtrate was concentrated to an oil under reduced pressure on the rotovap. The oil was purified by flash chromatography (davisil 633, 20% ethyl acetate/hexane). The appropriate fractions were pooled and concentrated to an oil which was dissolved in anhydrous diethyl ether. The ether solution was treated with gaseous HCl. The ether was removed under reduced pressure. The residue was dissolved in absolute ethanol, treated with activated carbon, filtered, and cooled. The liquid was concentrated with acetone to remove traces of water. The solid was collected by vacuum filtration. m.p. 127.5°-128.5° C. Proton NMR (CDC13 +TMS) 1.36 doublet J= 6.66 Hz 3 H ipr methyl, 1.51 doublet J=6.66 Hz 3 H ipr methyl, 1.88 ppm NH+, 2.62 doublet J=5.04 Hz 3 H N-Methyl, 3.47 septette 1 H tertiary, 4.15 doublet J=6.05 Hz 2 H benzylic CH2 --, 7.28-7.42 5 H aromatic; C-13 (DMSO) ref:39.5, 131.16(11.88), 130.53(8.72), 129.12(5.74), 128.56 (10.92), 55.99(2.06), 55.11(7.14), 39.51(1.48), 34.36(6.93), 1845(3.11), 16.89(6.18), 15 19(5.20). EI Mass spec. M/e-(int) M+163(6.3), 148(40.7), 120(1.2), 92(8.0), 91(100), 90(1.5), 89(3.1), 78(2.2), 77(4.1), 65(18.8), 57(1.6), 56(8.1), 51(3.5), 44(6.0), 43(3.5) 42(11.8), 41(5.2).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([CH3:26])=[N:8][N:9]2[C:14]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:18]=3[F:24])=[CH:13][C:12]([CH3:25])=[CH:11][C:10]=12)=[O:5])C.[OH-].[Na+].CS(C)=O>O1CCOCC1>[F:24][C:18]1[C:19]([F:23])=[CH:20][CH:21]=[CH:22][C:17]=1[CH2:16][O:15][C:14]1[N:9]2[N:8]=[C:7]([CH3:26])[C:6]([C:4]([OH:5])=[O:3])=[C:10]2[CH:11]=[C:12]([CH3:25])[CH:13]=1
Reactant: CCOC(=O)c1c(C)nn2c(OCc3cccc(F)c3F)cc(C)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CS(C)=O
Product: Cc1cc(OCc2cccc(F)c2F)n2nc(C)c(C(=O)O)c2c1
Temperature: 90 °C
Reaction time: 15 h

Procedure:
A solution of 190 mg (0.527 mmol) of 7-[(2,3-difluorobenzyl)oxy]-2,5-dimethylpyrazolo[1,5-a]pyridine-3-carboxylic acid ethyl ester from Example 116A in 5 ml of dioxane was admixed with 2.1 ml of 2 N sodium hydroxide solution. The resulting mixture was stirred at 90° C. for 15 h. Owing to incomplete mixing, 1 ml of dimethyl sulphoxide was added, followed by further 2 N sodium hydroxide solution (1 ml). The resulting mixture was stirred for a further 2 h. After the reaction had ended, the solvent was removed under reduced pressure. The residue was admixed with acetonitrile (5 ml), followed by the dropwise addition of trifluoroacetic acid (2 ml). The resulting precipitate was filtered off and dried under reduced pressure, which gave 130 mg (71% of theory, 93% pure) of the target compound.
Reaction SMILES: CN(C)C=O.[NH2:6][C:7]1[N:12]=[C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([F:25])=[C:20](F)[C:21]=3[Cl:23])[C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14]2)[CH:10]=[CH:9][C:8]=1[F:30].Cl.Cl.[CH3:33][NH:34][CH:35]1[CH2:38][NH:37][CH2:36]1.CN1CCCC1>C(O)C>[NH2:6][C:7]1[N:12]=[C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([F:25])=[C:20]([N:37]4[CH2:38][CH:35]([NH:34][CH3:33])[CH2:36]4)[C:21]=3[Cl:23])[C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14]2)[CH:10]=[CH:9][C:8]=1[F:30]
Reactant: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)ccc1F
Reactant: CNC1CNC1
Agent: CN1CCCC1
Agent: Cl
Solvent: CCO
Solvent: CN(C)C=O
Product: CNC1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(-c4ccc(F)c(N)n4)c3c2Cl)C1
Temperature: 85 °C
Reaction time: 0.5 h
Yield: 68.9 %

Procedure:
To 300 mg of N,N-dimethylformamide were added 101 mg of 1-(6-amino-5-fluoropyridine-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 85 mg of 3-methylaminoazetidine dihydrochloride, and 150 mg of N-methylpyrrolidine, and the mixture was stirred at 85° C. for 30 minutes. After adding 0.3 ml of ethanol, the mixture was allowed to cool, and the precipitate was collected by filtration and washed with ethanol and diisopropylether successively to obtain 82 mg of the title compound as a colorless powder.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:12]=[CH:13][C:14]([N:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]4)=[N:15][CH:16]=3)[CH:9]=2)[N:4]([S:30]([C:33]2[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=2)(=[O:32])=[O:31])[CH:3]=1.[CH3:40][C:41]1[CH:42]=[C:43]([CH:59]=[CH:60][CH:61]=1)[CH2:44][N:45]1[CH:49]=[C:48](B2OC(C)(C)C(C)(C)O2)[CH:47]=[N:46]1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)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>[CH3:40][C:41]1[CH:42]=[C:43]([CH:59]=[CH:60][CH:61]=1)[CH2:44][N:45]1[CH:49]=[C:48]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[C:8]([C:11]4[CH:12]=[CH:13][C:14]([N:17]5[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]5)=[N:15][CH:16]=4)[CH:9]=3)[N:4]([S:30]([C:33]3[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=3)(=[O:32])=[O:31])[CH:3]=2)[CH:47]=[N:46]1
Reactant: Cc1cccc(Cn2cc(B3OC(C)(C)C(C)(C)O3)cn2)c1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)nc4)cnc32)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(C)c4)c3)c3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)nc4)cnc32)cc1
Yield: 93.8 %

Procedure:
Using similar reaction conditions as described in step-i of example-1, tert-butyl 4-(5-(3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-2-yl)piperazine-1-carboxylate (Intermediate 66K) (200 mg, 0.303 mmol) was coupled with 1-(3-methylbenzyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (intermediate 64D) (99 mg, 0.333 mmol) using sodium carbonate (96 mg, 0.909 mmol) and Pd(PPh3)2Cl2 (11 mg, 0.015 mmol) in toluene/ethanol/water (2/2/0.5 ml) to afford 200 mg (94% yield) of titled compound after purification by column (Silica gel 60/120) using 0.5% methanol in DCM as eluent. MS: m/z=704.3 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:29])[C:5]2[CH2:6][CH:7]([CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]3[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][CH:21]=3)[CH2:8][C:9]=2[C:10](=[O:14])[C:11]=1[O:12][CH3:13].[C:30]1(N2CCNCC2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.Cl.C(N=C=NCCCN(C)C)C.O.O[N:56]1[C:60]2C=[CH:62][CH:63]=[CH:64][C:59]=2N=N1>C1COCC1.O.C(N(CC)CC)C>[CH3:1][O:2][C:3]1[C:4](=[O:29])[C:5]2[CH2:6][CH:7]([CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]3[CH:21]=[CH:22][C:23]([C:24]([N:56]4[CH2:62][CH2:63][CH:64]([C:30]5[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=5)[CH2:59][CH2:60]4)=[O:25])=[CH:27][CH:28]=3)[CH2:8][C:9]=2[C:10](=[O:14])[C:11]=1[O:12][CH3:13]
Reactant: COC1=C(OC)C(=O)C2=C(CC(CCCCOc3ccc(C(=O)O)cc3)C2)C1=O
Reactant: On1nnc2ccccc21
Reactant: c1ccc(N2CCNCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: COC1=C(OC)C(=O)C2=C(CC(CCCCOc3ccc(C(=O)N4CCC(c5ccccc5)CC4)cc3)C2)C1=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 58.9 %

Procedure:
A mixture of 4-[4-(5,6-dimethoxy-4,7-dioxoindan-2-yl)butoxy]benzoic acid (500 mg), 1-phenylpiperazine (406 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (479 mg), 1-hydroxybenzotriazole monohydrate (383 mg), triethylamine (0.697 ml) in THF (20 ml) was stirred at room temperature for 6 hr. The reaction mixture was diluted with water and extracted with combined solvent of THF and ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride and dried. The solvent was removed in vacuo. The residue was recrystallized from THF-diisopropylether to yield the entitled compound (400 mg) as crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([F:10])[CH:3]=1.[CH3:11][C:12]1([CH3:20])[O:19][C:17](=[O:18])[CH2:16][C:14](=[O:15])[O:13]1.[CH3:21][S:22][CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]2[C:32]=1[NH:31][CH:30]=[CH:29]2>C(#N)C.N1CCCC1C(O)=O>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]([C:29]2[C:28]3[C:32](=[C:24]([CH2:23][S:22][CH3:21])[CH:25]=[CH:26][CH:27]=3)[NH:31][CH:30]=2)[CH:16]2[C:17](=[O:18])[O:19][C:12]([CH3:20])([CH3:11])[O:13][C:14]2=[O:15])=[C:4]([F:10])[CH:3]=1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: CSCc1cccc2cc[nH]c12
Reactant: O=Cc1ccc(Cl)cc1F
Agent: O=C(O)C1CCCN1
Solvent: CC#N
Product: CSCc1cccc2c(C(c3ccc(Cl)cc3F)C3C(=O)OC(C)(C)OC3=O)c[nH]c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.1 %

Procedure:
1.48 g (9.31 mmol) of 4-chloro-2-fluorobenzaldehyde, 1.34 g (9.31 mmol) of Meldrum's acid and 48.7 mg (0.42 mmol) of D,L-proline were added to a solution of 1.50 g (8.46 mmol) of the compound from Example 8A in 70 ml of acetonitrile. The reaction mixture was stirred at RT overnight. It was concentrated, and the residue was taken up in ethyl acetate, washed with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. 3.60 g of the title compound were obtained and were reacted without further purification.
Reaction SMILES: Br[C:2]1(Br)[C:7]([F:8])=[C:6]([F:9])[C:5]([S:10][C:11]2[C:16]([F:17])=[C:15]([F:18])[C:14](Br)(Br)[CH:13]([F:21])[C:12]=2[F:22])=[C:4]([F:23])[CH:3]1[F:24].[CH3:26][C:27]([OH:31])([C:29]#[CH:30])[CH3:28]>[Pd].C([O-])(=O)C.[Cu+]>[OH:31][C:27]([CH3:28])([CH3:26])[C:29]#[C:30][C:2]1([C:30]#[C:29][C:27]([CH3:28])([OH:31])[CH3:26])[C:7]([F:8])=[C:6]([F:9])[C:5]([S:10][C:11]2[C:16]([F:17])=[C:15]([F:18])[C:14]([C:30]#[C:29][C:27]([CH3:28])([OH:31])[CH3:26])([C:30]#[C:29][C:27]([CH3:28])([OH:31])[CH3:26])[CH:13]([F:21])[C:12]=2[F:22])=[C:4]([F:23])[CH:3]1[F:24]
Reactant: C#CC(C)(C)O
Reactant: FC1=C(F)C(Br)(Br)C(F)C(F)=C1SC1=C(F)C(F)C(Br)(Br)C(F)=C1F
Agent: [Cu+]
Agent: [Pd]
Agent: CC(=O)[O-]
Product: CC(C)(O)C#CC1(C#CC(C)(C)O)C(F)=C(F)C(SC2=C(F)C(F)C(C#CC(C)(C)O)(C#CC(C)(C)O)C(F)=C2F)=C(F)C1F
Temperature: 25 °C

Procedure:
To a solution of bis(4,4'-dibromo tetrafluorophenyl) sulfide (4.86 g, 10 mmol) in dry deoxygenated diisopropylamine was added dichlorobis(triphenylphasphine) palladium (700 mg, 1 mmol) and copper (1) acetate (200 mg, 1 mmol). The solution was cooled by means of an ice bath and to the cooled solution was added 2-methyl 3-butyn 2-ol (2.13 g, 25 mmol). The solution was allowed to warm to room temperature over a period of 1 hour and was then heated at reflux for a period of 24 hours. The solution was cooled and filtered to remove the precipitate of diisopropylammonium bromide. The residue was dissolved in methylene chloride, extracted with water, the organic layer was dried (magnesium sulfate), and the solvent removed. The residue was chromatographed on silica gel using diethyl ether/hexane (3:7 v/v) as the eluent. A white crystalline compound was removed from the column which was identified by mass spectrometry as 1,4-bis-(3-hydroxy 3-methyl-1-butynyl)tetrafluorobenzene. Further elution with diethyl ether/hexane (1:1 v/v) then yielded the desired product as pale yellow crystals. The yield was 2.2 g (44.5%), mp 148-150 C. IR (KBr) 3300, 2980, 2220, 1360, 1190, 1150, 975, 940 cm-1. 1H NMR (80 MHz, d6 -acetone) δ2.8(s, 2H), 1.55(s, 12H); Mass Spectrum (E1)(rel. intensity) 494 (1.0), 479 (0.3), 262 (100). Anal. Calcd. or C22H14F8O2S: C, 53.44; H, 2.83. Found: C, 53.87, H, 2.62.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[C:10]([F:18])[CH:9]=2)[CH:5]=[C:4]([C:19]([F:22])([F:21])[F:20])[N:3]=1.[Br:23][C:24]1[N:25]=[CH:26][NH:27][CH:28]=1>>[Br:23][C:24]1[N:25]=[CH:26][N:27]([C:2]2[N:7]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[C:10]([F:18])[CH:9]=3)[CH:5]=[C:4]([C:19]([F:22])([F:21])[F:20])[N:3]=2)[CH:28]=1
Reactant: Brc1c[nH]cn1
Reactant: Fc1cc(-c2cc(C(F)(F)F)nc(Cl)n2)ccc1C(F)(F)F
Product: Fc1cc(-c2cc(C(F)(F)F)nc(-n3cnc(Br)c3)n2)ccc1C(F)(F)F

Procedure:
The title compound was prepared from 2-chloro-4-(3-fluoro-4-trifluoromethyl-phenyl)-6-trifluoromethyl-pyrimidine (example A.6) (0.50 g, 1.45 mmol) and commercially available 4-bromo-imidazole (0.32 g, 2.18 mmol) according to the general procedure IVa. Obtained as a white solid (0.34 g, 51%). MS (EI) 455.1 [(M)+]; mp 164.5° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([F:12])[C:3]=1[C:4]([NH2:6])=[O:5].[N:13]1[CH:18]=[CH:17][C:16]([CH:19]=O)=[CH:15][CH:14]=1.S([O-])(O)=O.[Na+].C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C>[F:12][C:7]1[CH:8]=[C:9]([F:11])[CH:10]=[C:2]2[C:3]=1[C:4](=[O:5])[NH:6][C:19]([C:16]1[CH:17]=[CH:18][N:13]=[CH:14][CH:15]=1)=[N:1]2
Reactant: NC(=O)c1c(N)cc(F)cc1F
Reactant: O=Cc1ccncc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: O=c1[nH]c(-c2ccncc2)nc2cc(F)cc(F)c12
Temperature: 115 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 2-amino-4,6-difluoro-benzamide (0.50 g, 2.9 mmol) and pyridine-4-carbaldehyde (0.35 g, 3.2 mmol) in N,N-dimethylacetamide (10 mL) were added sodium hydrogen sulfite (0.63 g, 3.5 mmol) and p-toluenesulfonic acid (0.06 g, 0.3 mmol); the reaction mixture was stirred at 115° C. for 16 hours. The solvent was evaporated in vacuo, water was added, and the precipitated solid was filtered off to obtain 5,7-difluoro-2-pyridin-4-yl-3H-quinazolin-4-one as a yellow solid, which was used in the next step without further purification. Yield: 0.4 g (53%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)#[CH:2].[NH:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1>C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:3]1([C:1]#[C:2][C:10]2[CH:4]=[CH:3][CH:1]=[CH:2][C:11]=2[CH2:12][C:13]2[C:8]3[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:1]=[CH:2][N:9]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C1CCNC1
Reactant: C#Cc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Product: C(#Cc1ccccc1Cc1nccc2ccccc12)c1ccccc1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
A solution of tetrakis(triphenylphosphine)palladium (58 mg, 0.05 mmol) and ethynylbenzene (204 mg, 2.0 mmol) in pyrrolidine (1.5 ml) was added to a solution of the compound of Example B25 (345 mg, 1.07 mmol) in pyrrolidine (1.5 ml) under nitrogen atmosphere, and the mixture was stirred at 80° C. for 3 hours. The mixture was cooled to room temperature, diluted with ethyl acetate, washed with a saturated aqueous ammonium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel chromatography to give the title compound (280 mg).
Reaction SMILES: CC([N:5]([C@H:9]([CH3:31])[C:10]([NH:12][C:13]1[CH:14]=[N:15][C:16]([O:19][C:20]2[C:25]3[C:26]([CH3:30])([CH3:29])[CH2:27][O:28][C:24]=3[CH:23]=[CH:22][CH:21]=2)=[CH:17][CH:18]=1)=[O:11])C(=O)[O-])(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH3:30][C:26]1([CH3:29])[C:25]2[C:20]([O:19][C:16]3[N:15]=[CH:14][C:13]([NH:12][C:10](=[O:11])[C@@H:9]([CH3:31])[NH2:5])=[CH:18][CH:17]=3)=[CH:21][CH:22]=[CH:23][C:24]=2[O:28][CH2:27]1
Reactant: C[C@H](C(=O)Nc1ccc(Oc2cccc3c2C(C)(C)CO3)nc1)N(C(=O)[O-])C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H](N)C(=O)Nc1ccc(Oc2cccc3c2C(C)(C)CO3)nc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 119.1 %

Procedure:
To a solution of 1,1-dimethylethyl[(1R)-2-({6-[(3,3-dimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]-3-pyridinyl}amino)-1-methyl-2-oxoethyl]carbamate (Intermediate 60, 35 mg) in dry dichloromethane (3 ml), TFA (0.189 ml, 2.456 mmol) was slowly added at 0° C. and the reaction mixture was stirred for 1.5 hours at room temperature. The solvent and the excess of TFA were evaporated and the residue was purified with an SCX cartridge. The cartridge was washed with 3 CV of methanol, then the compound was adsorbed on the cartridge, washed with 5 CV of methanol and desorbed with 2 CV of methanolic ammonia (1N). This afforded the title compound (32 mg).
Reaction SMILES: [OH:1]/[CH:2]=[C:3](/[CH2:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([CH3:18])[CH:10]=1)\[C:4](OC)=O.[NH2:19][C:20]([NH2:22])=[S:21]>CO>[CH3:18][N:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]([CH2:8][C:3]2[C:2](=[O:1])[NH:19][C:20](=[S:21])[NH:22][CH:4]=2)=[CH:10]1
Reactant: COC(=O)/C(=C\O)Cc1cn(C)c2ccccc12
Reactant: NC(N)=S
Solvent: CO
Product: Cn1cc(Cc2c[nH]c(=S)[nH]c2=O)c2ccccc21
Temperature: 50 °C
Yield: 18.3 %

Procedure:
To the solution of methyl (2Z)-3-hydroxy-2-[(1-methyl-1H-indol-3-yl)methyl]-2-propenoate (0.790 g, 3.22 mmol) in methanol (10 mL) was added thiourea (0.25 g, 3.28 mmol). The mixture was heated at 50° C. for 6 h. After cooling to room temperature, purification via reverse phase flash chromatography then afforded the title compound (200 mg, 0.590 mmol, 18.31% yield). LCMS: rt=2.36 min, [M+H+]=272
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2O)[N:5]=[C:4]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:37]([O:44][CH2:45][C@H:46]([OH:48])[CH3:47])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.O>[CH2:37]([O:44][CH2:45][C@H:46]([CH3:47])[O:48][C:9]1[CH:8]=[C:7]([N:6]2[C:2]([NH2:1])=[CH:3][C:4]([C:14]([CH3:17])([CH3:16])[CH3:15])=[N:5]2)[CH:12]=[CH:11][CH:10]=1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: C[C@@H](O)COCc1ccccc1
Reactant: CC(C)(C)c1cc(N)n(-c2ccccc2O)n1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](COCc1ccccc1)Oc1cccc(-n2nc(C(C)(C)C)cc2N)c1
Temperature: 25 °C
Reaction time: 1.75 h
Yield: 46.7 %

Procedure:
A mixture of Intermediate 95a (0.50 g, 2.2 mmol) in dry THF (17 mL) was treated with triphenylphosphine (1.13 g, 4.32 mmol) and (R)-(−)-1-benzyloxy-2-propanol (0.52 mL, 3.24 mmol) then diisopropylazodicarboxylate (0.85 mL, 4.32 mmol) was added dropwise (the reaction mixture became very warm). After stirring at ambient temperature for 1.75 h the mixture was treated with water (0.2 mL) then concentrated in vacuo to a viscous orange oil. The oil was purified by FCC, using 0-7% EtOAc in DCM. The resulting oil was purified further by FCC, using 0-30% EtOAc in cyclohexane. The product was applied to a pre-conditioned (with MeOH)SCX-2 cartridge and eluted with MeOH then 2N NH3 in MeOH. The product containing fractions were combined and concentrated in vacuo to give the title compound as a viscous golden oil (0.39 g, 48%). LCMS (Method 3): Rt 3.77 min, m/z 380.4 [MH+].