Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([OH:13])=[C:4]([C:10](=[O:12])[CH3:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].[Cu](C#N)[C:15]#[N:16]>CN1CCCC1=O.CCOC(C)=O.Cl>[C:10]([C:4]1[C:3]([OH:13])=[C:2]([C:7]([CH3:8])=[C:6]([Cl:9])[CH:5]=1)[C:15]#[N:16])(=[O:12])[CH3:11]
Reactant: CC(=O)c1cc(Cl)c(C)c(Br)c1O
Reactant: N#C[Cu]C#N
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CC(=O)c1cc(Cl)c(C)c(C#N)c1O
Temperature: 200 °C

Procedure:
A mixture of 1-(3-bromo-5-chloro-2-hydroxy-4-methylphenyl)ethanone (4.85 g, 18.4 mmol) and copper cyanide (2.47 g, 27.6 mmol) in N-methylpyrrolidinone (15 mL) was heated at 200° C. for 1 h. After cooled to rt, the mixture was diluted with EtOAc and 1 N HCl. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with water, then brine and dried over magnesium sulfate, then concentrated to dry under reduced pressure. The residue was used directly in next step (3.7 g, 96%). LCMS calculated for C10H9ClNO2 (M+H)+: m/z=210.0; Found: 210.1.
Reaction SMILES: [CH3:1]/[C:2](/[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:3]\[C:4](OCC)=[O:5].CC(C[AlH]CC(C)C)C>C1(C)C=CC=CC=1>[CH3:1]/[C:2](/[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:3]\[CH2:4][OH:5]
Reactant: CCCCCCCCCC/C(C)=C/C(=O)OCC
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Product: CCCCCCCCCC/C(C)=C/CO
Temperature: -78 °C

Procedure:
Compound E (0.19 mmol) was dissolved in anhydrous toluene (3 mL) and chilled to −78° C. DIBAL-H (0.585 mmol, 2.0 M in toluene) was added dropwise. The solution reacted for 45 minutes and was warmed slightly. The reaction was quenched with 10% aqueous sodium potassium tartrate. The layers were separated and the aqueous layer was extracted (3×20 mL) with ethyl acetate. The organic layers were combined, washed with brine (10 mL), dried, filtered and concentrated. Purification by flash chromatography (9:1 hexane/ethyl acetate) gave F in yields of 85-90%. 1H NMR (300 MHz, CDCl3): δ 0.8 (t, 3H), 1.25 (narrow m, 20H), 1.5 (s, 3H), 1.8 (narrow m, 2H), 4.0 (d, 2H), and 5.4 (t, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.C([Li])CCC.Br[CH2:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1COCC1>[CH3:9][O:8][C:5]1[CH:4]=[CH:3][C:2]([CH2:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:7][N:6]=1
Reactant: BrCCCc1ccccc1
Reactant: COc1ccc(Br)cn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(CCCc2ccccc2)cn1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 17 %

Procedure:
According to Scheme 22 Method A: To a solution of 5-bromo-2-methoxypyridine (1 eq, 2.70 mmol, 0.50 g) in THF (4.4 mL) at −78° C. under nitrogen was added dropwise n-butyl lithium (1 eq, 2.5M in hexanes, 2.70 mmol, 1.10 mL). The reaction mixture was stirred at −78° C. for 30 min. and 1-(3-bromopropyl)benzene (1 eq, 2.70 mmol, 0.40 mL) in solution in THF (1 mL) was added dropwise. The reaction mixture was stirred at −78° C. for 30 min. and then allowed to warm to room temperature for 1 hour. The reaction was quenched at 0° C. with water and extracted with Et2O. The organic phase was dried over Na2SO4, filtered and solvent was removed under reduced pressure leaving an orange oil. This residue was purified by flash chromatography over silicagel (AIT Flashsmart prepacked column SiO2, cyclohexane/AcOEt 97.5/2.5), yielding the title compound (0.46 mmol, 0.10 g, 17%) as a colorless semi-solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][CH2:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:5]=[C:4]([CH3:16])[C:3]=1[C:17]1[CH:25]=[CH:24][C:23]([F:26])=[C:22]2[C:18]=1[CH2:19][CH2:20][C@H:21]2[O:27][C:28]1[CH:41]=[CH:40][C:31]2[C@H:32]([CH2:35][C:36]([O:38]C)=[O:37])[CH2:33][O:34][C:30]=2[CH:29]=1.[OH-].[Na+]>C(O)C>[CH3:16][C:4]1[CH:5]=[C:6]([O:8][CH2:9][CH2:10][CH2:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:7]=[C:2]([CH3:1])[C:3]=1[C:17]1[CH:25]=[CH:24][C:23]([F:26])=[C:22]2[C:18]=1[CH2:19][CH2:20][C@H:21]2[O:27][C:28]1[CH:41]=[CH:40][C:31]2[C@H:32]([CH2:35][C:36]([OH:38])=[O:37])[CH2:33][O:34][C:30]=2[CH:29]=1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(OCCCS(C)(=O)=O)cc5C)ccc(F)c43)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(OCCCS(C)(=O)=O)cc(C)c1-c1ccc(F)c2c1CC[C@H]2Oc1ccc2c(c1)OC[C@H]2CC(=O)O
Reaction time: 1 h
Yield: 96.8 %

Procedure:
Methyl 2-((S)-6-((R)-4-(2,6-dimethyl-4-(3-(methylsulfonyl)propoxy)phenyl)-7-fluoro-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate (Intermediate 29; 9 mg) is suspended in ethanol (1 mL) and aqueous NaOH (1 M; 0.2 mL) is added. The mixture is stirred for 1 hour then concentrated under vacuum, acidified with aqueous HCl (1 M) and extracted twice with dichloromethane. The combined organic extracts are dried and the solvent is removed to give the title compound (8.5 mg). LC (method 20): tR=6.37 min; Mass spectrum (ESI−): m/z=567 [M−H]−.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7](/[C:12](/[C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=3)=[CH:13]/[C@@H:14]3[NH:18][C:17](=[O:19])[CH2:16][CH2:15]3)=[N:8][C:9]=2[O:10][CH3:11])[CH2:3][CH2:2]1.[H][H]>CO.[Br-].[Zn+2].[Br-].[Pd]>[CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([CH:12]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=3)[CH2:13][C@@H:14]3[NH:18][C:17](=[O:19])[CH2:16][CH2:15]3)=[N:8][C:9]=2[O:10][CH3:11])[CH2:3][CH2:2]1
Reactant: [H][H]
Reactant: COc1nc(/C(=C/[C@H]2CCC(=O)N2)c2ccc(Cl)c(Cl)c2)ccc1C1CC1
Agent: [Pd]
Agent: [Br-]
Agent: [Zn+2]
Solvent: CO
Product: COc1nc(C(C[C@H]2CCC(=O)N2)c2ccc(Cl)c(Cl)c2)ccc1C1CC1

Procedure:
Zinc bromide (20 mg) and 10% palladium-activated carbon (40 mg) were added to a solution of (5R)-5-[(E)-2-(5-cyclopropyl-6-methoxypyridin-2-yl)-2-(3,4-dichlorophenyl)ethenyl]pyrrolidin-2-one (100 mg) in methanol (3 mL), and the mixture was stirred at room temperature for 18 hours in a hydrogen atmosphere. The reaction solution was filtered through celite, after which the filtrate was concentrated under reduced pressure to give a crude product of (5R)-5-[2-(5-cyclopropyl-6-methoxypyridin-2-yl)-2-(3,4-dichlorophenyl)ethyl]pyrrolidin-2-one as an amorphous (120 mg).
Reaction SMILES: Br[CH2:2][C@@:3]([OH:17])([CH3:16])[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[C:9]([CH3:15])[CH:8]=1)=[O:5].[OH-].[Na+]>C1(C)C=CC=CC=1>[C:13]([C:10]1[CH:11]=[CH:12][C:7]([NH:6][C:4]([C@@:3]2([CH3:16])[CH2:2][O:17]2)=[O:5])=[CH:8][C:9]=1[CH3:15])#[N:14]
Reactant: Cc1cc(NC(=O)[C@@](C)(O)CBr)ccc1C#N
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: Cc1cc(NC(=O)[C@@]2(C)CO2)ccc1C#N
Yield: 80.5 %

Procedure:
(2R)-3-Bromo-2-hydroxy-2-methyl-N-(4-cyano-3-methylphenyl)propion-amide (1.54 g, 5.2 mmol) was dissolved in 50 ml of toluene and stirred for 5 minutes with 15 ml of 1 M NaOH at room temperature. Organic layer was separated and washed with 2×25 ml of water. Toluene was filtered and evaporated to give 0.905 g of the product.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[C:27](=[O:28])[N:26]2[CH:22]([CH2:23][CH:24]([O:29][C:30]3[C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[CH:33]=[CH:32][N:31]=3)[CH2:25]2)[C:21](=[O:40])[NH:20][C:19]2([C:41]([OH:43])=O)[CH:17]([CH2:18]2)[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:44]([C:47]1([S:50]([NH2:53])(=[O:52])=[O:51])[CH2:49][CH2:48]1)[CH2:45][CH3:46]>>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]1[C:27](=[O:28])[N:26]2[CH:22]([CH2:23][CH:24]([O:29][C:30]3[C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[CH:33]=[CH:32][N:31]=3)[CH2:25]2)[C:21](=[O:40])[NH:20][C:19]2([C:41]([NH:53][S:50]([C:47]3([CH2:44][CH2:45][CH3:46])[CH2:49][CH2:48]3)(=[O:52])=[O:51])=[O:43])[CH:17]([CH2:18]2)[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC1CCCCCC=CC2CC2(C(=O)O)NC(=O)C2CC(Oc3nccc4ccccc34)CN2C1=O
Reactant: CCCC1(S(N)(=O)=O)CC1
Product: CCCC1(S(=O)(=O)NC(=O)C23CC2C=CCCCCCC(NC(=O)OC(C)(C)C)C(=O)N2CC(Oc4nccc5ccccc45)CC2C(=O)N3)CC1

Procedure:
Prepared from 14-tert-butoxycarbonylamino-18-(isoquinolin-1-yloxy)-2,15-dioxo-3,16-diaza-tricyclo[14.3.0.04,6]-nonadec-7-ene-4-carboxylic acid (50 mg, 0.075 mmol) and 1-propyl-cyclopropanesulfonic acid amide (16 mg, 0.098 mmol, prepared as described above) to give [18-(isoquinolin-1-yloxy)-2,15-dioxo-4-(1-propyl-cyclopropanesulfonylaminocarbonyl)-3,16-diaza-tricyclo[14.3.0.04,6]nonadec-7-en-14-yl]-carbamic acid tert-butyl ester as a white powder: 1H NMR (300 MHz, CD3Cl3) δ 0.82–0.93 (m, 5H), 1.23 (s, 9H), 1.30–1.94 (m, 17H), 2.28 (m, 1H), 2.54(m, 1H), 2.68 (dd, J=8.1 Hz, 3.2 Hz, 2H), 4.05 (m, 1H), 4.30 (m, 1H), 4.63–4.66 (m, 2H), 4.96–5.09 (m, 2H), 5.70 (m, 1H), 5.92 (s, 1H), 6.69 (s, 1H), 7.23 (m, 1H), 7.46 (t, J=8.1 Hz, 1H), 7.63 (t, J=8.1 Hz, 1H), 7.72 (d, J=8.1 Hz, 1H), 7.97(d, J=5.9 Hz, 1H), 8.17 (d, J=8.4 Hz, 1H), 10.12 (s, 1H). LC-MS (Method A, retention time: 3.77 min), MS m/z 738 (M++1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13](/[CH:14]=[CH:15]/[C:16]([O:18]C)=[O:17])=[C:12]([CH:20]([CH3:22])[CH3:21])[N:11]=[C:10]([N:23]([CH3:28])[S:24]([CH3:27])(=[O:26])=[O:25])[N:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13](/[CH:14]=[CH:15]/[C:16]([OH:18])=[O:17])=[C:12]([CH:20]([CH3:21])[CH3:22])[N:11]=[C:10]([N:23]([CH3:28])[S:24]([CH3:27])(=[O:26])=[O:25])[N:9]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)/C=C/c1c(-c2ccc(F)cc2)nc(N(C)S(C)(=O)=O)nc1C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)c1nc(N(C)S(C)(=O)=O)nc(-c2ccc(F)cc2)c1/C=C/C(=O)O
Yield: 97.4 %

Procedure:
A suspension of methyl 3-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)pyrimidin-5-yl](2E)-propenoate (10 g) in ethanol (200 ml) was treated with aqueous sodium hydroxide solution (0.1N, 246 ml) at 0-5° C. The reaction mixture was stirred at 25-30° C. for 12 h for completion of hydrolysis and ethanol was evaporated under reduced pressure. The resulting mass was acidified and extracted with methylene chloride (2×100 ml). The organic layer was washed with water, dried and concentrated to give the title product (Yield 9.4 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[N:13]([CH2:18][CH2:19][N:20]([CH3:22])[CH3:21])[C:12]3[CH:23]=[CH:24][CH:25]=[C:26]([F:27])[C:11]=3[S:10]2)=[CH:5][CH:4]=1.[ClH:28].[C:29](OC(=O)C)(=[O:31])[CH3:30]>>[ClH:28].[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([O:16][C:29](=[O:31])[CH3:30])[C:14](=[O:17])[N:13]([CH2:18][CH2:19][N:20]([CH3:22])[CH3:21])[C:12]3[CH:23]=[CH:24][CH:25]=[C:26]([F:27])[C:11]=3[S:10]2)=[CH:5][CH:4]=1
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc([C@@H]2Sc3c(F)cccc3N(CCN(C)C)C(=O)[C@@H]2O)cc1
Agent: Cl
Product: COc1ccc([C@@H]2Sc3c(F)cccc3N(CCN(C)C)C(=O)[C@@H]2OC(C)=O)cc1

Procedure:
A mixture of 1 g of (±)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(dimethylamino)ethyl]-9-fluoro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one and 10 ml of acetic anhydride is treated in the same manner as described in Example 54. The crude product is converted to its hydrochloride and recrystallized from a mixture of isopropanol and ether. 0.729 g of (±)-cis-2-(4-methoxyphenyl)-3-acetoxy-5-[2-(dimethylamino)ethyl]-9-fluoro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one hydrochloride is obtained.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14]3[CH:15]=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=3)[CH:9]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:3]=1.[CH2:34]([CH2:36][NH2:37])[OH:35]>C1COCC1.CCOC(C)=O>[OH:35][CH2:34][CH2:36][NH:37][S:20]([C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([C:10]2[CH:9]=[C:8]([C:6]3[CH:5]=[C:4]([C:24]4[CH:25]=[CH:26][C:27]([C:30]([F:32])([F:33])[F:31])=[CH:28][CH:29]=4)[CH:3]=[C:2]([CH3:1])[N:7]=3)[CH:13]=[CH:12][N:11]=2)[CH:15]=1)(=[O:21])=[O:22]
Reactant: NCCO
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccnc(-c3cccc(S(=O)(=O)Cl)c3)c2)n1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccnc(-c3cccc(S(=O)(=O)NCCO)c3)c2)n1
Temperature: 25 °C
Yield: 21 %

Procedure:
The title compound was prepared from the solution of 3-[6-methyl-4-(4-trifluoromethylphenyl)-[2,4′]bipyridinyl-2′-yl]-benzenesulfonyl chloride (example 346 step 2) (ca. 0.2 g, 0.41 mmol) by treatment with excess ethanolamine in THF (5 mL) at 50° C. for 16 h. Cooled to rt, diluted with EtOAc, washed with 1 N HCl, dried organic layer over Na2SO4. Removal of the solvent in vacuum left a crude product, which was purified by silica gel column chromatography with n-heptane/EtOAc followed by trituration with n-heptane/diethyl ether to give the title compound (0.045 g, 21%) as a white solid. MS (ISP) 514.0 [(M+H)+]; mp 103° C. (dec.).
Reaction SMILES: Cl.Br[C:3]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[CH:10][CH:9]=1)([CH3:7])[CH2:4][CH2:5][NH2:6].CC(C)=[O:23]>O.S(=O)(=O)(O)O>[F:20][C:17]1[CH:18]=[CH:19][C:14]([C:11]2[CH:12]=[CH:13][C:8]([C:3]([OH:23])([CH3:7])[CH2:4][CH2:5][NH2:6])=[CH:9][CH:10]=2)=[CH:15][CH:16]=1
Reactant: CC(Br)(CCN)c1ccc(-c2ccc(F)cc2)cc1
Reactant: CC(C)=O
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(O)(CCN)c1ccc(-c2ccc(F)cc2)cc1

Procedure:
3.59 g of 3-bromo-3-(4'-fluoro-4-biphenylyl)butylamine hydrochloride [obtainable by reacting 3-hydroxy-3-(4'-fluoro-4-biphenylyl)-butyramide with PBr3 to give 3-bromo-3-(4'-fluoro-4-biphenylyl)-butyramide and reduction with LiAlH4 ] are dissolved in a mixture of 15 ml of acetone and 15 ml of water, 1 drop of sulfuric acid is added, and the mixture is warmed to 45° for 4 hours and worked up in the customary manner to give 3-(4'-fluoro-4-biphenylyl)-3-hydroxybutylamine, m.p. 144° - 146°. A little 3-(4'-fluoro-4-biphenylyl)-2-butenylamine, which can be removed by chromatography (over SiO2), is formed as a by-product.
Reaction SMILES: [I:1]I.[CH3:3][N:4]1[C:8]([C:9]([F:12])([F:11])[F:10])=[CH:7][C:6]([CH3:13])=[N:5]1>S(=O)(=O)(O)O>[I:1][C:7]1[C:6]([CH3:13])=[N:5][N:4]([CH3:3])[C:8]=1[C:9]([F:10])([F:11])[F:12]
Reactant: Cc1cc(C(F)(F)F)n(C)n1
Reactant: II
Agent: O=S(=O)(O)O
Product: Cc1nn(C)c(C(F)(F)F)c1I
Temperature: 0 °C
Reaction time: 2 h
Yield: 86.2 %

Procedure:
Iodine (30 g) was dissolved in 60% sulfuric acid (fuming, 80 g), and 1,3-dimethyl-5-trifluoromethylpyrazole (13.12 g, 80 mmol) was slowly added under ice-cooling. The mixture was stirred at 0° C. for 2 hr. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with aqueous sodium thiosulfate and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained crude crystals were washed with hexane to give the desired compound (20 g) as crystals.
Reaction SMILES: [C:1]1([C:7]2[S:8][C:9]([C:18]([O:20]C)=O)=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:22][OH:23].[OH-].[K+]>CO.C1COCC1>[OH:23][NH:22][C:18]([C:9]1[S:8][C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[N:11][C:10]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:20]
Reactant: NO
Reactant: COC(=O)c1sc(-c2ccccc2)nc1-c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(NO)c1sc(-c2ccccc2)nc1-c1ccccc1
Temperature: 0 °C
Reaction time: 18 h
Yield: 71.9 %

Procedure:
A 100 mL round-bottomed flask was charged with methyl 2,4-diphenylthiazole-5-carboxylate 73 (420 mg, 1.422 mmol) in MeOH (2.844 ml) and THF (2.84 ml) and the solution was cooled down to 0° C. Then a 50% aqueous solution of hydroxylamine (4697 mg, 71.1 mmol) and 4M potassium hydroxide solution (0.427 ml, 1.706 mmol) were added and the reaction mixture was allowed to warm up to rt while stirring for 18 h. The reaction mixture was partitioned between EtOAc and water. The aqueous layer was extracted with fresh EtOAc and the combined organic layers were washed with 1M HCl, sat NaHCO3, and brine, dried over MgSO4, filtered and concentrated. The resulting solid was triturated (Et2O) to afford the title compound 74 (0.303 g, 72% yield). 1H NMR: (DMSO-d6) d(ppm) 1H, 11.29 (s, 1H), 9.44 (s, 1H), 8.03 (dd, J=6.3, 2.7 Hz, 2H), 7.84 (d, J=7.0 Hz, 2H), 7.56-7.55 (m, 3H), 7.50-7.43 (m, 3H). LRMS (ESI): (calc.) 296.34 (found) 297.1 (MH)+
Reaction SMILES: [C:1]([CH:6]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:3]CC)=[O:2].[F:26][C:27]([F:43])([F:42])[C:28]([NH:30][C:31]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=1[O:38][CH2:39][CH2:40][CH3:41])=O>C1(C)C=CC=CC=1>[F:26][C:27]([F:43])([F:42])[C:28]([NH:30][C:31]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=1[O:38][CH2:39][CH2:40][CH3:41])=[CH:6][C:1]([OH:3])=[O:2]
Reactant: CCCOc1ccc(F)cc1NC(=O)C(F)(F)F
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: CCCOc1ccc(F)cc1NC(=CC(=O)O)C(F)(F)F
Temperature: 25 °C
Yield: 99 %

Procedure:
Carboethoxymethylene triphenylphosphorane (41.52 g, 119.2 mmol) was added to a toluene solution (100 ml) of 2,2,2-trifluoro-N-(5-fluoro-2-propoxyphenyl)acetamide (15.83 g, 59.1 mmol). The mixture was stirred under a nitrogen atmosphere while heating under reflux for 4 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was then purified by silica gel column chromatography (n-hexane:ethyl acetate=10:1). The purified product was concentrated under reduced pressure to thereby obtain 19.7 g of oily yellow ethyl ester of 4,4,4-trifluoro-3-(5-fluoro-2-propoxyphenylamino)buta-2-enoic acid (yield: 99%).
Reaction SMILES: C([N:8]1[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([F:20])[CH:14]=2)[C@@H:10]([C@@H:21]([O:23][C:24]2[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][N:25]=2)[CH3:22])[CH2:9]1)C1C=CC=CC=1.ClC(OC(Cl)C)=O.CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([C@H:11]2[CH2:12][NH:8][CH2:9][C@@H:10]2[C@@H:21]([O:23][C:24]2[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][N:25]=2)[CH3:22])=[CH:14][C:15]=1[F:20]
Reactant: C[C@H](Oc1ccc(C#N)cn1)[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(Cl)c(F)c1
Agent: CC(Cl)OC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: C[C@H](Oc1ccc(C#N)cn1)[C@H]1CNC[C@@H]1c1ccc(Cl)c(F)c1
Temperature: 100 °C
Yield: 75.4 %

Procedure:
To a solution of 6-{(S)-1-[(3R,4S)-1-benzyl-4-(4-chloro-3-fluoro-phenyl)-pyrrolidin-3-yl]-ethoxy}-nicotinonitrile—100 mg (0.23 mmol) dissolved in toluene (2 mL) were added 98 mg (0.69 mmol) of 1-chloroethyl chloroformate and 89 mg (0.69 mmol) of Hunig's base. The reaction mixture was heated at 100° C. for one hour. After cooling down to RT, volatiles were removed under vacuo and the crude was dissolved in MeOH (10 mL). The reaction mixture was heated at 85° C. for 30 minutes and after cooling down to RT, volatiles were removed under vacuo and the residue was directly purified on column chromatography (SiO2, CH2Cl2/MeOH 9:1) yielded 60 mg (76%) of the title compound as a light yellow oil. ES-MS m/e: 346.1 (M+H+).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([N+:15]([O-])=O)[CH:14]=1)[C:8]([O:10][CH3:11])=[O:9])=[O:4].C([O-])=O.[NH4+]>C(O)C.[Pd]>[NH2:15][C:13]1[CH:12]=[C:7]([CH:6]=[C:5]([C:3]([NH:2][CH3:1])=[O:4])[CH:14]=1)[C:8]([O:10][CH3:11])=[O:9]
Reactant: CNC(=O)c1cc(C(=O)OC)cc([N+](=O)[O-])c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CNC(=O)c1cc(N)cc(C(=O)OC)c1
Temperature: 40 °C
Yield: 48.1 %

Procedure:
To a solution of methyl 3-[(methylamino)carbonyl]-5-nitrobenzoate (Intermediate 29) (1.33 g, 5.59 mmol), in ethanol (30 mL) were added ammonium formiate (3.52 g, leg.) and Pd/C (catalytic quantity). The reaction was stirred at 40° C. for one night. After filtration on celite, the solvent was evaporated in vacuo. The residue was dissolved in DCM, washed with water, dried over sodium sulfate and concentrated to give the title compound as a white solid (0.56 g, 48.3%). LC/MS: m/z 209 (M+H)+, Rt: 1.50 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([NH2:12])=[N:8][NH:9]2)=[CH:5][CH:4]=1.Br[CH2:14][C:15]([C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)=O>>[F:23][C:20]1[CH:21]=[CH:22][C:17]([C:15]2[N:12]=[C:7]3[C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:11][C:10]=4[NH:9][N:8]3[CH:14]=2)=[CH:18][CH:19]=1
Reactant: COc1ccc2c(N)n[nH]c2c1
Reactant: O=C(CBr)c1ccc(F)cc1
Product: COc1ccc2c(c1)[nH]n1cc(-c3ccc(F)cc3)nc21

Procedure:
Compound 2-(4-fluorophenyl)-7-methoxy-5H-imidazo[1,2-b]indazole (W289) was prepared using the general procedure for cyclization between 6-methoxy-1H-indazol-3-amine (80 mg, 0.5 mmol) and 2-bromo-1-(4-fluorophenyl)ethanone (119 mg, 0.55 mmol), as an off-white solid (30 mg, 16%). 1H NMR (400 MHz, DMSO-d6) δ 8.64 (s, 1 H), 7.94-7.91 (m, 2 H), 7.83 (d, J=8.8 Hz, 1 H), 7.44 (m, 2 H), 7.11 (d, J=2.4 Hz, 1 H), 6.96 (dd, J=9.2, 2.0 Hz, 1 H), 3.89 (s, 3 H); MS (ESI) m/z 282 (M+H+).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])[CH3:11])=[CH:6][CH:5]=1.[Br:13][CH2:14][CH2:15]Br.O>CN(C=O)C>[Br:13][CH2:14][CH2:15][NH:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])[CH3:11])=[CH:6][CH:5]=1
Reactant: CC(=O)c1ccc(N)cc1
Reactant: BrCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(NCCBr)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 14.2 %

Procedure:
To a suspension of 60% NaH (5.93 g, 247.08 mmol) in DMF (80 mL) taken in a one liter 2 neck round bottom flask fitted with a pressure equalizing addition funnel and a septum was added a solution of p-aminoacetophenone (20 g, 148.1 mmol) in DMF (60 mL) in drops through the pressure equalizing addition funnel under nitrogen atmosphere at 0° C. and the contents were stirred for 2 hours at 25° C. Then to the stirred solution was added 1,2-dibromoethane (97.48 g, 518.5 mmol) in drops and the contents were further stirred for another 18 hours at 90° C. The reaction mixture was cooled to 25-35° C. and was carefully added to cold water (650 mL) while stirring. The organics were extracted with ethylacetate (3×200 mL) and combined organics were washed with water (2×100 mL) followed by a brine wash. The separated organics were dried over Na2SO4 and concentrated under reduced pressure. The crude was chromatographed over silicagel by using 15-20% ethyl acetate/pet. ether (3 Lit), affording the title compound 5.1 g (14%) as a pale yellow solid. Mp: 92-94° C.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([NH:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:26]=1)=[C:5]([CH3:19])[C:6]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[N:7]2.[N:33]1[CH:38]=[CH:37][C:36]([C:39](O)=[O:40])=[N:35][CH:34]=1>>[F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([NH:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:26]=1)=[C:5]([CH3:19])[C:6]([N:13]1[CH2:14][CH2:15][N:16]([C:39]([C:36]3[CH:37]=[CH:38][N:33]=[CH:34][N:35]=3)=[O:40])[CH2:17][CH2:18]1)=[N:7]2
Reactant: O=C(O)c1ccncn1
Reactant: Cc1c(N2CCNCC2)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1
Product: Cc1c(N2CCN(C(=O)c3ccncn3)CC2)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1

Procedure:
Prepared according to Procedure Q using 5,7-difluoro-3-methyl-N-(5-morpholinopyridin-3-yl)-2-(piperazin-1-yl)quinolin-4-amine (40.0 mg, 0.09 mmol) and pyrimidine-4-carboxylic acid to give (4-(5,7-difluoro-3-methyl-4-(5-morpholinopyridin-3-ylamino)quinolin-2-yl)piperazin-1-yl)(pyrimidin-4-yl)methanone. 1H NMR (DMSO-d6) δ ppm 2.10 (br s, 3H), 3.05 (t, J=4.4 Hz, 4H), 3.30-3.35 (m, 2H), 3.36-3.40 (m, 2H), 3.53-3.56 (m, 2H), 3.67-3.69 (m, 4H), 3.84-3.86 (m, 2H), 6.51 (s, 1H), 7.14-7.19 (m, 1H), 7.28-7.31 (m, 1H), 7.51 (s, 1H), 7.74 (d, J=5.2 Hz, 1H), 7.78 (d, J=3.2 Hz, 1H), 8.37 (s, 1H), 9.00 (d, J=5.2 Hz, 1H), 9.28 (s, 1H). Mass Spectrum (ESI) m/e=546.9 (M+1).