Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([O:19][CH3:20])=[CH:4][C:5]([OH:18])=[C:6]([C:8](=O)[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[CH:7]=1.[F:21][C:22]([F:34])([F:33])[C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30](O)=[O:31])=[CH:25][CH:24]=1.C(C1NC=CN=1)(C1NC=CN=1)=O.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][C:3]=1[O:19][CH3:20])[O:18][C:30](=[O:31])[C:29]([C:26]1[CH:25]=[CH:24][C:23]([C:22]([F:21])([F:33])[F:34])=[CH:28][CH:27]=1)=[C:8]2[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1
Reactant: COc1cc(O)c(C(=O)Cc2ccc(O)cc2)cc1Br
Reactant: O=C(O)Cc1ccc(C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2oc(=O)c(-c3ccc(C(F)(F)F)cc3)c(Cc3ccc(O)cc3)c2cc1Br
Temperature: 80 °C
Yield: 85.4 %

Procedure:
A mixture of 1-(5-bromo-2-hydroxy-4-methoxy-phenyl)-2-(4-hydroxy-phenyl)-ethanone (0.64 g, 1.9 mmol), 4-trifluoromethylphenylacetic acid (0.78 g, 3.8 mmol), carbonyl diimidazole (0.62 g, 3.8 mmol), N,N-dimethylaminopyridine (0.12 g, 1.0 mmol), and potassium carbonate (0.52 g, 3.8 mmol) in DMF (15 mL) was heated within an 80° C. oil bath overnight. The cooled reaction mixture was poured into water and extracted with EtOAc. Organic extracts were combined and washed with water and saturated sodium chloride in succession, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The resulting material purified using silica gel flash column chromatography (1:2 EtOAc:hexanes) to provide the title compound (0.82 g, 85%). MS (ESI) m/z 505.0 (M+1)+, 507.0 (M+1+2)+.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:24])[NH:5][C:6]([C:12]1[CH:17]=[C:16]([CH3:18])[C:15]([O:19][CH2:20][CH2:21]O)=[C:14]([CH3:23])[CH:13]=1)=[N:7]2.C(Br)(Br)(Br)[Br:26].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C>[Br:26][CH2:21][CH2:20][O:19][C:15]1[C:16]([CH3:18])=[CH:17][C:12]([C:6]2[NH:5][C:4](=[O:24])[C:3]3[C:8](=[CH:9][CH:10]=[CH:11][C:2]=3[Cl:1])[N:7]=2)=[CH:13][C:14]=1[CH3:23]
Reactant: BrC(Br)(Br)Br
Reactant: Cc1cc(-c2nc3cccc(Cl)c3c(=O)[nH]2)cc(C)c1OCCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Cc1cc(-c2nc3cccc(Cl)c3c(=O)[nH]2)cc(C)c1OCCBr
Temperature: 25 °C
Reaction time: 27 h
Yield: 88.8 %

Procedure:
To a solution of 5-chloro-2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one (0.40 g, 1.16 mmol) in anhydrous DMF (10 mL) was added carbon tetrabromide (0.42 g, 1.27 mmol) and triphenylphosphine (0.33 g, 1.27 mmol). The reaction mixture was stirred at room temperature for 27 hours. Solvent was evaporated to dryness in vacuo and the residue triturated with Et2O (15 mL)/EtOAc (15 mL) to give 2-(4-(2-bromoethoxy)-3,5-dimethylphenyl)-5-chloroquinazolin-4(3H)-one (0.42 g). It was used without further purification. The 1H NMR indicated a purity of about 45%.
Reaction SMILES: O1CCCCC1[O:7][NH:8][C:9]([C@H:11]([C@@H:21]([CH2:37][CH:38]([CH3:40])[CH3:39])[C:22]([NH:24][N:25]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:26](=[O:32])[CH2:27][NH:28][C:29]([NH2:31])=[O:30])=[O:23])[CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:10]>Cl.O1CCOCC1.C(OCC)C>[OH:7][NH:8][C:9]([C@H:11]([C@@H:21]([CH2:37][CH:38]([CH3:40])[CH3:39])[C:22]([NH:24][N:25]([CH2:33][CH:34]([CH3:35])[CH3:36])[C:26](=[O:32])[CH2:27][NH:28][C:29]([NH2:31])=[O:30])=[O:23])[CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:10]
Reactant: CC(C)C[C@@H](C(=O)NN(CC(C)C)C(=O)CNC(N)=O)[C@H](C/C=C/c1ccccc1)C(=O)NOC1CCCCO1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: CC(C)C[C@@H](C(=O)NN(CC(C)C)C(=O)CNC(N)=O)[C@H](C/C=C/c1ccccc1)C(=O)NO
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.1 %

Procedure:
A solution of 0.51 g of (E)-2(R)-[1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenyl-3-butenyl]-2′-isobutyl-4-methyl-2′-(2-ureidoacetyl)valerohydrazide dissolved in 5 ml of 4M hydrogen chloride in dioxan was stirred for 2 hours at room temperature and diluted with diethyl ether. The solid was filtered off, washed with diethyl ether and dried to give 0.36 g of (E)-2(R)-[1(S)-(hydroxycarbamoyl)-4-phenyl-3-butenyl]-2′-isobutyl-4-methyl-2′-(2-ureidoacetyl)valerohydrazide in the form of a white solid.
Reaction SMILES: [F:1][CH:2]([CH2:5][N:6]1[C:11](=[O:12])[CH:10]=[N:9][C:8]2[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[N:16][C:7]1=2)[CH:3]=O.[NH2:19][CH:20]1[CH2:24][N:23]([C:25]2[CH:26]=[CH:27][C:28]3[O:33][CH2:32][C:31](=[O:34])[NH:30][C:29]=3[CH:35]=2)[C:22](=[O:36])[CH2:21]1.C(O)(=O)C.S([O-])([O-])(=O)=O.[Na+].[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN(C)C=O.ClCCl>[F:1][CH:2]([CH2:3][NH:19][CH:20]1[CH2:21][C:22](=[O:36])[N:23]([C:25]2[CH:26]=[CH:27][C:28]3[O:33][CH2:32][C:31](=[O:34])[NH:30][C:29]=3[CH:35]=2)[CH2:24]1)[CH2:5][N:6]1[C:11](=[O:12])[CH:10]=[N:9][C:8]2[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[N:16][C:7]1=2
Reactant: NC1CC(=O)N(c2ccc3c(c2)NC(=O)CO3)C1
Reactant: COc1ccc2ncc(=O)n(CC(F)C=O)c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1ccc2ncc(=O)n(CC(F)CNC3CC(=O)N(c4ccc5c(c4)NC(=O)CO5)C3)c2n1
Reaction time: 12 h
Yield: 40.7 %

Procedure:
A crude product of 2-Fluoro-3-(6-methoxy-3-oxopyrido[2,3-b]pyrazin-4(3H)-yl)propanal (323 mg), 6-(4-amino-2-oxopyrrolidin-1-yl)-2H-1,4-benzoxazin-3(4H)-one (Reference Example 6; 227 mg, 0.917 mmol) were mixed in a mixed solution of dichloromethane (30 ml) and N,N-dimethylformamide (3 ml). Acetic acid (0.105 ml, 1.834 mmol) and anhydrous sodium sulfate (450 mg) were added to the solution and the mixture was stirred for 12 hours. Sodium triacetoxyborohydride (389 mg, 1.834 mmol) was added to the reaction solution, the mixture was stirred for 4 hours and then the solvent was removed under reduced pressure. A lower layer solvent of chloroform/methanol/water (7:3:1) was added to the residue and the resultant was alkalized by adding saturated sodium bicarbonate water under cooling on ice. The mixture was extracted with a lower layer solvent of chloroform/methanol/water (7:3:1), the extract was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol) and preparative layer chromatography (silica gel, chloroform/methanol=20:1) to yield 180 mg (41%) of the title compound in the form of a light orange solid.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][CH3:4].Cl[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([I:17])[CH:15]=2)[N:10]=[CH:9][C:8]=1[C:18]#[N:19].[H-].[K+]>C1COCC1>[CH2:1]([O:5][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([I:17])[CH:15]=2)[N:10]=[CH:9][C:8]=1[C:18]#[N:19])[CH2:2][CH2:3][CH3:4]
Reactant: N#Cc1cnc2ccc(I)cc2c1Cl
Reactant: CCCCO
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCCCOc1c(C#N)cnc2ccc(I)cc12

Procedure:
Similar procedure as described in example 28a was used, starting from butanol, 4-chloro-6-iodo-quinoline-3-carbonitrile (example 14c) and potassium hydride in a solvent system of THF to give 4-butoxy-6-iodo-quinoline-3-carbonitrile. LC-MS m/e 352 (MH+).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH2:7]([CH:14]1[CH2:18][NH:17][C:16]([C:19]2[S:23][C:22]([N:24]3[CH2:28][CH2:27][N:26]([CH2:29][C:30]4[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=4)[C:25]3=[O:37])=[CH:21][C:20]=2[CH3:38])=[N:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(N(CC)CC)C>ClCCl>[CH2:7]([C:14]1[N:15]=[C:16]([C:19]2[S:23][C:22]([N:24]3[CH2:28][CH2:27][N:26]([CH2:29][C:30]4[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=4)[C:25]3=[O:37])=[CH:21][C:20]=2[CH3:38])[NH:17][CH:18]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Cc1cc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C1=NC(Cc2ccccc2)CN1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1-c1nc(Cc2ccccc2)c[nH]1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 9 %

Procedure:
To a stirred solution of oxalyl chloride (0.05 mL, 0.62 mmol) in dichloromethane (1 mL) at −78° C. under nitrogen atmosphere was added dropwise N,N-dimethylsulfoxide (0.06 mL, 0.83 mmol). After 10 minutes, 1-(5-(4-benzyl-4,5-dihydro-1H-imidazol-2-yl)-4-methylthiophen-2-yl)-3-(4-fluorobenzyl)imidazolidin-2-one (0.06 g, 0.14 mmol) in dichloromethane (0.5 mL) was added dropwise. The resulting mixture was stirred at −78° C. for 40 minutes, then triethylamine (0.23 mL, 1.66 mmol) was added, and the cooling bath was removed. After stirred for 1 h, the reaction mixture was partitioned between water (25 mL) and dichloromethane (50 mL). The aqueous layer was extracted with dichloromethane (50 mL), and the combined organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by ion exchange chromatography eluted sequentially with methanol, 2.0 M ammonia in methanol solution, and further purified by preparative thin layer chromatography eluted with dichloromethane/methanol/triethylamine (95/5/0.5) to afford the title compound as a light yellow solid in 9% yield (0.01 g): 1H NMR (300 MHz, CDCl3) δ 7.34-7.21 (m, 8H), 7.06-6.99 (m, 2H), 6.72 (s, 1H), 6.13 (s, 1H), 4.41 (s, 2H), 3.98 (s, 2H), 3.81-3.73 (m, 2H), 3.44-3.37 (m, 2H), 2.42 (s, 3H); MS (ES+) m/z 447.2 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([N:19]([CH3:21])[CH3:20])=[O:18])[CH:15]=3)[C:10]([S:22]([CH3:24])=[O:23])=[CH:9]2)=[N:6][CH:7]=1.[F:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][C:27]=1B(O)O>>[F:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][C:27]=1[C:2]1[CH:3]=[N:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([N:19]([CH3:21])[CH3:20])=[O:18])[CH:15]=3)[C:10]([S:22]([CH3:24])=[O:23])=[CH:9]2)=[N:6][CH:7]=1
Reactant: CN(C)C(=O)c1ccc2c(S(C)=O)cn(-c3ncc(Br)cn3)c2c1
Reactant: COc1ccc(F)c(B(O)O)c1
Product: COc1ccc(F)c(-c2cnc(-n3cc(S(C)=O)c4ccc(C(=O)N(C)C)cc43)nc2)c1

Procedure:
Suzuki reaction of 1-(5-bromopyrimidin-2-yl)-N,N-dimethyl-3-(methylsulfinyl)-1H-indole-6-carboxamide (0.15 g, 0.37 mmol; intermediate in the preparation of synthesis example 267) with 2-fluoro-5-methoxyphenylboronic acid (0.13 g, 0.74 mmol) in analogy to the procedure detailed for example 261). White solid. Yield: 0.06 g (36% of theory)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[N:15]=[C:14]4[CH2:17][CH2:18][CH2:19][C:20]5[C:21]([CH2:27][C:28]6[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=6)([CH2:22][CH2:23][C:24](=[O:26])[CH:25]=5)[C:13]4=[CH:12][C:11]=3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[H][H]>C1COCC1.N1C=CC=CC=1.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[N:15]=[C:14]4[CH2:17][CH2:18][CH2:19][CH:20]5[CH2:25][C:24](=[O:26])[CH2:23][CH2:22][C:21]5([CH2:27][C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=5)[C:13]4=[CH:12][C:11]=3[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: O=C1C=C2CCCc3nc4c(cnn4-c4ccc(F)cc4)cc3C2(Cc2ccccn2)CC1
Agent: [Pd]
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=C1CCC2(Cc3ccccn3)c3cc4cnn(-c5ccc(F)cc5)c4nc3CCCC2C1
Yield: 59.5 %

Procedure:
9-(4-Fluorophenyl)-12b-(pyridin-2-ylmethyl)-1,5,6,7,9,12b-hexahydrobenzo[3,4]cyclohepta[1,2-b]pyrazolo[4,3-e]pyridin-3 (2H)-one (116, R1=4-Fluorophenyl, R2=Pyridin-2-ylmethyl) (9.28 g, 21.16 mmol) in THF (170 mL) and pyridine (22 mL) with palladium on carbon (10%) (0.690 g, 0.648 mmol) was hydrogenated in a Parr shaker at 50 psi hydrogen and rt for about 8 h. The mixture was filtered through a pad of Celite® and the pad was washed with DCM. The filtrate was concentrated under reduced pressure and the material was purified on silica gel (330 g) using a gradient from 0-100% EtOAc in DCM. Product fractions were combined and concentrated under reduced pressure to yield rac-(4aR,12bR)-9-(4-fluorophenyl)-12b-(pyridin-2-ylmethyl)-1,4,4a,5,6,7,9,12b-octahydrobenzo[3,4]cyclohepta[1,2-b]pyrazolo[4,3-e]pyridin-3(2H)-one (118, R1=4-Fluorophenyl, R2=Pyridin-2-ylmethyl) (5.55 g, 59.5%); LC/MS, method 3, Rt=2.46 min, MS m/z 441 (M+H)+. 1H NMR (400 MHz, DMSO) δ 8.40-8.37 (m, 2H), 8.31-8.29 (m, 1H), 8.19 (s, 1H), 7.80 (s, 1H), 7.47-7.38 (m, 3H), 7.09-7.05 (m, 1H), 6.61 (d, J=7.8 Hz, 1H), 3.83 (d, J=12.9 Hz, 1H), 3.63-3.56 (m, 1H), 3.40-3.35 (m, 1H), 2.97 (d, J=13.0 Hz, 1H), 2.62-1.81 (m, 9H), 1.75-1.65 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[N:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][CH2:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[CH:16][CH:15]=2)[C:5]2=[N:6][C:7]([CH3:11])=[CH:8][C:9]([CH3:10])=[C:4]2[N:3]=1.[CH3:28][N:29]1[CH2:34][CH2:33][C:32](=O)[CH2:31][CH2:30]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCCl>[CH3:1][C:2]1[N:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][CH2:21][CH:22]3[CH2:23][CH2:24][N:25]([CH:32]4[CH2:33][CH2:34][N:29]([CH3:28])[CH2:30][CH2:31]4)[CH2:26][CH2:27]3)=[CH:16][CH:15]=2)[C:5]2=[N:6][C:7]([CH3:11])=[CH:8][C:9]([CH3:10])=[C:4]2[N:3]=1
Reactant: Cc1cc(C)c2nc(C)n(Cc3ccc(NCC4CCNCC4)cc3)c2n1
Reactant: CN1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Product: Cc1cc(C)c2nc(C)n(Cc3ccc(NCC4CCN(C5CCN(C)CC5)CC4)cc3)c2n1
Reaction time: 0.33 h
Yield: 43.5 %

Procedure:
A solution of Compound 157 (0.250 g, 0.69 mmol) in 1,2-dichloroethane was added with 1-methyl-4-piperidone (0.128 mL, 1.04 mmol) followed by stirring for 20 minutes. The mixture was added with sodium triacetoxyborohydride (0.439 g, 2.07 mmol) followed by stirring at room temperature for 4 hours. The reaction mixture was added with a 2 mol/L aqueous sodium hydroxide solution and extracted with dichloromethane three times. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:2 mol/L ammonia-methanol solution=19:1). The obtained crystals were recrystallized from ethanol-diisopropyl ether to obtain Compound 160 (0.139 g, 0.30 mmol, 44%).
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:4][CH2:5][OH:6].C(N(CC)CC)C.[C:20]([Si:24]([CH3:27])([CH3:26])Cl)([CH3:23])([CH3:22])[CH3:21]>ClCCl>[Si:24]([O:6][CH2:5][CH2:4][C@H:3]([NH2:2])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:27])[CH3:26]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: N[C@@H](CCO)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCC[C@H](N)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.1 %

Procedure:
1.50 g of (S)-3-amino-3-phenylpropan-1-ol hydrochloride were initially charged in 20 ml of dichloromethane and then 2.77 ml of triethylamine and 1.30 g of tert-butyldimethylchlorosilane were added. After stirring at room temperature for 3 hours, the reaction solution was extracted three times with 30 ml of water, dried by means of a phase separator cartridge (Isolute®), concentrated by rotary evaporation and dried under high vacuum. This gave the product (2.06 g) with a molecular weight of 265.5 g/mol (C15H27NOSi); MS (ESI): m/e=266 (M+H+).
Reaction SMILES: FC(F)(F)[C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([OH:13])=[O:12])=[CH:8][C:7]=2[CH:14]=1.[F:17][C:18]([F:27])([F:26])C1C=C(O)C=CC=1>>[F:17][C:18]([F:27])([F:26])[C:4]1[CH:3]=[CH:14][C:7]2[CH:8]=[C:9]([C:11]([OH:13])=[O:12])[O:10][C:6]=2[CH:5]=1
Reactant: O=C(O)c1cc2cc(C(F)(F)F)ccc2o1
Reactant: Oc1cccc(C(F)(F)F)c1
Product: O=C(O)c1cc2ccc(C(F)(F)F)cc2o1

Procedure:
93 mg of 6-(trifluoromethyl)benzofuran-2-carboxylic acid were prepared as described for 5-(trifluoromethyl)benzofuran-2-carboxylic acid, using 3-(trifluoromethyl)phenol instead of 4-(trifluoromethyl)phenol.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[S:9][CH:10]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[N:12]=2)[CH:5]=[CH:6][CH:7]=1.Br[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][O:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][O:25]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[O:25]1[CH2:26][CH2:27][CH2:28][CH2:29][CH:24]1[O:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][O:1][C:2]1[CH:3]=[C:4]([C:8]2[S:9][CH:10]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[N:12]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: BrCCCCCOC1CCCCO1
Reactant: COC(=O)c1csc(-c2cccc(O)c2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1csc(-c2cccc(OCCCCCOC3CCCCO3)c2)n1
Temperature: 70 °C
Reaction time: 4 h

Procedure:
To a solution of methyl 2-(3-hydroxyphenyl)thiazole-4-carboxylate (24), (223 mg, 0.95 mmol, 1 eq.) and 2-(5-bromopentyloxy)tetrahydro-2H-pyran (357 mg, 1.42 mmol, 1.5 eq) in DMF (3 mL) was added powdered potassium carbonate (392 mg, 2.84 mmol, 3.0 eq.) The mixture was stirred vigorously for 4 h at 70° C., then concentrated in vacuo. The residue was diluted with ethyl acetate, washed with NaH2PO4 buffer (pH 5, 1M) and brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was purified by flash chromatography (ethyl acetate:hexanes gradient). Yield 250 mg (65%). TLC Rf=0.44 (ethyl acetate:hexanes 3:7), MS m/z 322 (M+H)+
Reaction SMILES: [F:1][C:2]1[C:7]([I:8])=[C:6]([CH3:9])[CH:5]=[CH:4][C:3]=1[CH2:10][OH:11]>C(Cl)Cl.O=[Mn]=O>[F:1][C:2]1[C:7]([I:8])=[C:6]([CH3:9])[CH:5]=[CH:4][C:3]=1[CH:10]=[O:11]
Reactant: Cc1ccc(CO)c(F)c1I
Agent: O=[Mn]=O
Solvent: ClCCl
Product: Cc1ccc(C=O)c(F)c1I
Reaction time: 8 h

Procedure:
A solution of (2-fluoro-3-iodo-4-methylphenyl)methanol (1.69 g, 6.35 mmol) in DCM (50 mL) at ambient temperature was treated with MnO2 (5.57 g, 63.5 mmol) and the resulting mixture was stirred overnight. The mixture was filtered through a pad of Celite® eluting with DCM. The filtrate was concentrated and the residue was loaded on an ISCO column (40 g, eluted with 15-35% ethyl acetate in hexanes) to provide 2-fluoro-3-iodo-4-methylbenzaldehyde as an off white solid. MS (ESI, pos. ion) m/z: 264.9 (M+1).
Reaction SMILES: [F:1][C:2]1[C:3]([N:9]=[CH:10][N:11]([CH3:13])[CH3:12])=[N:4][C:5]([OH:8])=[N:6][CH:7]=1.[C:14]1([S:20](Cl)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>N1C=CC=CC=1>[C:14]1([S:20]([N:6]2[CH:7]=[C:2]([F:1])[C:3]([N:9]=[CH:10][N:11]([CH3:13])[CH3:12])=[N:4][C:5]2=[O:8])(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CN(C)C=Nc1nc(O)ncc1F
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Product: CN(C)C=Nc1nc(=O)n(S(=O)(=O)c2ccccc2)cc1F
Temperature: 25 °C
Reaction time: 24 h
Yield: 18.8 %

Procedure:
To an 8 mL screw-cap vial were added pyridine (2 mL), N′-(5-fluoro-2-hydroxy-pyrimidin-4-yl)-N,N-dimethylformamidine (100 mg, 0.54 mmol), and benzenesulfonyl chloride (106 mg, 0.60 mmol), and the mixture was shaken at room temperature for 24 hours (h). The crude mixture was partitioned between ethyl acetate (EtOAc) and saturated aqueous sodium bicarbonate (satd aq NaHCO3), and the organic phase was dried over magnesium sulfate (MgSO4), filtered, and evaporated to yield 153 mg of crude material. Reverse phase chromatography furnished the title product as a white solid (33 mg, 19%): mp 203-204° C.; 1H NMR (300 MHz, CDCl3) δ 8.77 (s, 1H), 8.16-8.11 (m, 3H), 7.72-7.65 (m, 1H) 7.60-7.53 (m, 2H), 3.24 (s, 3H), 3.23 (s, 3H); ESIMS m/z 325 ([M+H]+).
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:3]=1[NH:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7](Cl)[N:6]=1.[OH:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1.Cl.C(OCC)C>CN1C(=O)CCC1>[F:1][C:2]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:3]=1[NH:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH:22][C:21]2[CH:23]=[CH:24][C:18]([OH:17])=[CH:19][CH:20]=2)[N:6]=1
Reactant: Cc1ccc(F)c(Nc2ccnc(Cl)n2)c1
Reactant: Nc1ccc(O)cc1
Agent: Cl
Solvent: CCOCC
Solvent: CN1CCCC1=O
Product: Cc1ccc(F)c(Nc2ccnc(Nc3ccc(O)cc3)n2)c1
Temperature: 100 °C

Procedure:
4-(2-Fluoro-5-methylanilino)-2-chloropyrimidine (Reference Example A-10, 1.00 g, 4.2 mmol) was dissolved in NMP (5 ml) and 4-hydroxyaniline (0.41 g, 3.7 mmol) and 1M HCl in diethyl ether (4.22 ml, 4.2 mmol) was added. The reaction mixture was heated at 100° C. for 15 hours, and then allowed to cool to ambient temperature. The mixture was evaporated under high vacuum to give the title product as a brown oil. The residue was purified by chromatography on a Mega Bond Elute column (10 g) eluting with DCM (4×25 ml), 2% NH3/MeOH in DCM (3×25 ml), 4% NH3/MeOH in DCM (3×25 ml), 6% NH3/MeOH in DCM (10×25 ml to give the title product as a white solid (0.80 g, 61%). NMR (300 MHz): 2.2 (s, 3H), 6.2 (d, 1H), 6.6 (d, 2H), 6.9 (m, 1H), 7.1 (m, 1H), 7.4 (d, 2H), 7.8 (d, 1H), 7.9 (d, 1H), 8.7 (s, 1H), 8.8 (s, 1H), 8.9 (s, 1H); m/z: (ES+) 311.0 (MH+).
Reaction SMILES: Br[C:2]1[NH:6][C:5]2[CH:7]=[C:8]([C:10]([O:12][CH3:13])=[O:11])[S:9][C:4]=2[C:3]=1[CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.[CH2:20]([O:27][C:28]1[CH:29]=[CH:30][C:31](B2OC(C)(C)C(C)(C)O2)=[C:32]([NH2:34])[CH:33]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O.C(=O)([O-])O.[Na+]>COCCOC.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>[NH2:34][C:32]1[CH:33]=[C:28]([O:27][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:29]=[CH:30][C:31]=1[C:2]1[NH:6][C:5]2[CH:7]=[C:8]([C:10]([O:12][CH3:13])=[O:11])[S:9][C:4]=2[C:3]=1[CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: COC(=O)c1cc2[nH]c(Br)c(C3CCCCC3)c2s1
Reactant: CC1(C)OB(c2ccc(OCc3ccccc3)cc2N)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)c1cc2[nH]c(-c3ccc(OCc4ccccc4)cc3N)c(C3CCCCC3)c2s1
Temperature: 110 °C
Reaction time: 8 h
Yield: 93.3 %

Procedure:
To a suspension of methyl 5-bromo-6-cyclohexyl-4H-thieno[3,2-b]pyrrole-2-carboxylate (4.73 g, 13.8 mmol) and 5-benzyloxy-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylamine (5.84 g, 17.9 mmol) produced by the method described in WO2005/080399 in 1,2-dimethoxyethane (50 ml) and water (50 ml) were added sodium hydrogen carbonate (1.72 g, 20.7 mol) and tetrakis(triphenylphosphine)palladium (799 mg, 0.691 mol), and the mixture was stirred overnight with heating at 110° C. The reaction mixture was allowed to cool to room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and filtered. The solvent was evaporated under reduced pressure and the residue was purified y silica gel column chromatography (hexane:ethyl acetate=3:1) to give methyl 5-(2-amino-4-benzyloxyphenyl)-6-cyclohexyl-4H-thieno[3,2-b]pyrrole-2-carboxylate (5.93 g, yield 93%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[N:3]=1.C([Li])CCC.[C:17]([N:24]1[CH2:29][CH2:28][C:27](=[O:30])[CH2:26][CH2:25]1)([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].O>O1CCCC1>[C:20]([O:19][C:17]([N:24]1[CH2:29][CH2:28][C:27]([OH:30])([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[N:3]=2)[CH2:26][CH2:25]1)=[O:18])([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: FC(F)(F)c1cccc(Br)n1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(c2cccc(C(F)(F)F)n2)CC1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 97.7 %

Procedure:
A mixture of 2-bromo-6-(trifluoromethyl)pyridine (300 mg, 1.33 mmol) in tetrahydrofuran (10 mL) under a nitrogen atmosphere cooled to −78° C. was treated with n-butyl lithium (2M solution in tetrahydrofuran, 0.83 mL, 1.33 mmol). The mixture was stirred at −78° C. for 15 min. At this time, the reaction was treated with 1-boc-4-piperidone (265 mg, 1.33 mmol). The mixture was then allowed to slowly warm to 25° C. and was stirred at 25° C. for 1 h. At this time, the reaction was poured into water. The aqueous layer was extracted with ethyl acetate. The organics were washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated in vacuo to afford 4′-hydroxy-6-trifluoromethyl-3′,4′,5′,6′-tetrahydro-2′H-[2,4′]bipyridinyl-1′-carboxylic acid tert-butyl ester (450 mg, 98%) as a yellow oil; LRMS for C16H21F3N2O3 (M+H)+ at m/z=346. The NMR spectrum obtained on the sample is compatible with its structure.