Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([CH:10]([F:12])[F:11])[CH:5]=[CH:4][C:3]=1[N+:13]([O-])=O>C(O)C.[Pd]>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([CH:10]([F:11])[F:12])[CH:5]=[CH:4][C:3]=1[NH2:13]
Reactant: COc1c(C(F)F)ccc([N+](=O)[O-])c1Cl
Agent: [Pd]
Solvent: CCO
Product: COc1c(C(F)F)ccc(N)c1Cl

Procedure:
A solution of crude 2-chloro-4-difluoromethyl-3-methoxy-1-nitro-benzene in ethanol (50 mL) containing 5% palladium on charcoal (250 mg) was hydrogenated (50 psi) for 5 hours. The solution was filtered and concentrated to give 2-chloro-4-difluoromethyl-3-methoxyaniline (1.3 g, 48 mmol): LC/MS (m/z=207).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([CH2:9][CH2:10][CH:11]=[CH:12]2)=[CH:7][CH:6]=1)=O.Cl>O1CCCC1.C1(C)C=CC=CC=1.[H-].COCCO[Al+]OCCOC.[Na+].[H-]>[OH:2][CH2:3][C:5]1[CH:14]=[C:13]2[C:8]([CH2:9][CH2:10][CH:11]=[CH:12]2)=[CH:7][CH:6]=1
Reactant: COC(=O)c1ccc2c(c1)C=CCC2
Agent: COCCO[Al+]OCCOC
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: OCc1ccc2c(c1)C=CCC2
Temperature: 25 °C
Yield: 88.8 %

Procedure:
In 80 ml of tetrahydrofuran, 20 g of a 70% toluene solution of sodium bis(2-methoxyethoxy)aluminum hydride was dissolved and cooled with ice. To the solution, 20 ml of a tetrahydrofuran solution containing 10 g of 7-methoxycarbonyl-3,4-dihydronaphthalene was dropwise added and stirred for an hour at room temperature. Successively, 100 ml of a 3N aqueous hydrochloric acid solution was added with caution under ice cooling to make the solution acid, and the organic layer was extracted with ether. The ether solution was dried with anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The concentrated residue was mixed with hexane. Formed crystals were filtered to give 7.56 g of 7-hydroxymethyl-3,4-dihydronaphthalene.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[N:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][CH2:16][N:17]2[C:21](=[O:22])[C:20]3[CH:23]=[CH:24][C:25]([N+:27]([O-])=O)=[CH:26][C:19]=3[S:18]2(=[O:31])=[O:30])[CH2:9][CH2:8]1.Cl[Sn]Cl.O>Cl>[N:3]1[CH:4]=[CH:5][CH:6]=[N:1][C:2]=1[N:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][CH2:16][N:17]2[C:21](=[O:22])[C:20]3[CH:23]=[CH:24][C:25]([NH2:27])=[CH:26][C:19]=3[S:18]2(=[O:30])=[O:31])[CH2:9][CH2:8]1
Reactant: O=C1c2ccc([N+](=O)[O-])cc2S(=O)(=O)N1CCCCN1CCN(c2ncccn2)CC1
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: O
Product: Nc1ccc2c(c1)S(=O)(=O)N(CCCCN1CCN(c3ncccn3)CC1)C2=O
Reaction time: 0.5 h
Yield: 71 %

Procedure:
0.03 mol of 2-(4-(4-(2-pyrimidinyl)-1-piperazinyl)butyl)-6-nitro-1,2-benzoisothiazol-3(2H)one 1,1-dioxide is dissolved in 50 ml of concentrated hydrochloric acid, and a solution of 0.13 mol of SnCl2.2 H2O in 100 ml of concentrated hydrochloric acid is added. After the exothermic reaction is complete, the mixture is stirred for 30 minutes. The mixture is poured onto ice, filtered and the crystals are washed with water. After treatment with dilute sodium hydroxide solution, the base is extracted by shaking with methylene chloride, the solvent is evaporated off and the product is obtained as colourless crystals. Yield: 71% of theory; melting point: 150°-151° C.
Reaction SMILES: FC(F)(F)[C:3]([NH:5][C:6]1[CH:14]=[CH:13][C:9]2[N:10]=[CH:11][S:12][C:8]=2[CH:7]=1)=O.CI.[OH-].[K+]>CC(C)=O>[CH3:3][NH:5][C:6]1[CH:14]=[CH:13][C:9]2[N:10]=[CH:11][S:12][C:8]=2[CH:7]=1
Reactant: O=C(Nc1ccc2ncsc2c1)C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: CI
Product: CNc1ccc2ncsc2c1
Yield: 19 %

Procedure:
To 6-Trifluoroacetamidobenzothiazole (1.97 g, 8 mmol) in 40 ml dry acetone was added methyl iodide (4.54 g, 32 mmol) and then KOH (2.1 g, 32 mmol). The mixture was refluxed for 40 min. and concentrated in vacuo. The product was taken up in 40 ml H2O, refluxed for 40 min. and extracted with methylene chloride. The organic phase was washed with water, dried over Na2SO4 and concentrated in vacuo. The product was purified by flash chromatography (silica gel, methylene chloride) to give 250 mg 6-methylamino-benzothiazole.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@H:9]([OH:10])[C@@H:8]([CH2:11][OH:12])[O:7][C@H:6]1[C:13]1[Se:14][CH:15]=[C:16]([C:18]([NH2:20])=[O:19])[N:17]=1)(=[O:3])[CH3:2].P(Cl)(Cl)(Cl)=O.C([O:28][P:29](OCC)([O:31]CC)=[O:30])C.[OH-].[Na+]>>[C:1]([O:4][C@@H:5]1[C@H:9]([OH:10])[C@@H:8]([CH2:11][O:12][P:29]([OH:31])([OH:30])=[O:28])[O:7][C@H:6]1[C:13]1[Se:14][CH:15]=[C:16]([C:18]([NH2:20])=[O:19])[N:17]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1c1nc(C(N)=O)c[se]1
Reactant: CCOP(=O)(OCC)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: CC(=O)O[C@@H]1[C@H](O)[C@@H](COP(=O)(O)O)O[C@H]1c1nc(C(N)=O)c[se]1

Procedure:
2-(2-O-Acetyl-β-D-ribofuranosyl)selenazole-4-carboxamide is treated with 1 to 5 equivalents of phosphoryl chloride in the presence of triethylphosphate at 0 degrees C. Afer complete dissolution is obtained, the solution is poured over crushed ice and adjusted with sodium hydroxide solution to pH 7, extracted with chloroform, and placed on a column of ion exchange resin (Dowex AG 1×8, formate). The column is first washed with water, then the product is eluted with a gradient of water-formic acid. The fractions containing pure product are pooled and evaporated to dryness. The residue is recrystallized from ethanol-water to provide the free acid of the title compound as a crystalline solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][S:5]([C:8]1[CH:13]=[CH:12][C:11](B(O)O)=[CH:10][CH:9]=1)(=[O:7])=[O:6].Br[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH:26]2[CH2:31][CH2:30][N:29]([C:32]3[O:36][N:35]=[C:34]([CH:37]([CH3:39])[CH3:38])[N:33]=3)[CH2:28][CH2:27]2)=[CH:20][N:19]=1.C([O-])([O-])=O.[Na+].[Na+]>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.COCCOC>[OH:1][CH2:2][CH2:3][NH:4][S:5]([C:8]1[CH:13]=[CH:12][C:11]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH:26]3[CH2:31][CH2:30][N:29]([C:32]4[O:36][N:35]=[C:34]([CH:37]([CH3:39])[CH3:38])[N:33]=4)[CH2:28][CH2:27]3)=[CH:20][N:19]=2)=[CH:10][CH:9]=1)(=[O:7])=[O:6]
Reactant: O=S(=O)(NCCO)c1ccc(B(O)O)cc1
Reactant: CC(C)c1noc(N2CCC(COc3ccc(Br)nc3)CC2)n1
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
Product: CC(C)c1noc(N2CCC(COc3ccc(-c4ccc(S(=O)(=O)NCCO)cc4)nc3)CC2)n1
Yield: 15 %

Procedure:
The title compound (30 mg, 15%) was prepared as an off-white solid from (4-{[(2-hydroxyethyl)amino]sulfonyl}phenyl)boronic acid (98 mg, 0.4 mmol), 2-bromo-5-[({1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}methyl)oxy]pyridine (153 mg, 0.4 mmol), Pd(PPh3)4 (100 mg, 0.14 mmol), 2M Na2CO3 (2 mL) and DME (4 mL) in a manner similar to Example 21, Step 3. 1H NMR (400 MHz, CDCl3): δ 8.39 (s, 1H), 8.07 (d, 2H, J=8.2 Hz), 7.93 (d, 2H, J=8.2 Hz), 7.72 (d, 1H, J=8.6 Hz), 7.30 (d, 1H, J=6.5 Hz), 5.07 (t, 1H, J=5.8 Hz), 4.28-4.18 (m, 2H), 3.94 (d, 2H, J=6.0 Hz), 3.73-3.65 (m, 2H), 3.17-3.04 (m, 4H), 2.96-2.80 (m, 1H), 2.06-1.92 (m, 3H), 1.57-1.40 (m, 2H), 1.28 (d, 6H, J=6.9 Hz); LRMS (ESI), m/z 502 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:29])=[C:6]([C:8]2(O)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH2:17][C:18]3[O:19][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=3)[C:9]2=[O:27])[CH:7]=1.OC1C=CC2OCC(=O)N(C)C=2C=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:29])=[C:6]([CH:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH2:17][C:18]3[O:19][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=3)[C:9]2=[O:27])[CH:7]=1
Reactant: O=C1N(Cc2ccc(C(F)(F)F)o2)c2ccccc2C1(O)c1cc(Br)ccc1O
Agent: CN1C(=O)COc2ccc(O)cc21
Product: O=C1C(c2cc(Br)ccc2O)c2ccccc2N1Cc1ccc(C(F)(F)F)o1

Procedure:
Following the procedure as described in PREPARATION 17B, and making non-critical variations using 3-(5-bromo-2-hydroxyphenyl)-3-hydroxy-1-((5-(trifluoromethyl)furan-2-yl)methyl)indolin-2-one to replace 741-(diphenylmethyl)-3-hydroxy-2-oxo-2,3-dihydro-1H-indol-3-yl]-6-hydroxy-4-methyl-2H-1,4-benzoxazin-3(4H)-one, 3-(5-bromo-2-hydroxyphenyl)-1-{[5-(trifluoromethyl)furan-2-yl]methyl}-1,3-dihydro-2H-indol-2-one was obtained (89%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ8.78 (br s, 1H), 7.44-7.36 (m, 1H), 7.36-7.19 (m, 3H), 7.08 (d, J=7.9 Hz, 1H), 6.99 (d, J=2.3 Hz, 1H), 6.94 (d, J=8.5 Hz, 1H), 6.73-6.68 (m, 1H), 6.37-6.32 (m, 1H), 5.10 (s, 1H), 5.00-4.85 (m, 2H); MS (ES+) m/z 452.0 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:20][CH2:21][C:22]([O:25][C:26]([F:39])([F:38])[C:27]([F:37])([F:36])[O:28][C:29]([F:35])([F:34])[C:30]([F:33])([F:32])[F:31])([F:24])[F:23])=[CH:10][CH:9]=2)=[N:6][CH:7]=1.[CH2:40]([O:44][CH2:45][CH2:46][CH2:47][CH2:48]Cl)[CH2:41][CH2:42][CH3:43]>>[CH2:40]([O:44][CH2:45][CH2:46][CH2:47][CH2:48][O:1][C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:20][CH2:21][C:22]([O:25][C:26]([F:39])([F:38])[C:27]([F:36])([F:37])[O:28][C:29]([F:34])([F:35])[C:30]([F:31])([F:32])[F:33])([F:24])[F:23])=[CH:12][CH:13]=2)=[N:4][CH:3]=1)[CH2:41][CH2:42][CH3:43]
Reactant: CCCCOCCCCCl
Reactant: Oc1cnc(-c2ccc(OCCCCCOCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)F)cc2)nc1
Product: CCCCOCCCCOc1cnc(-c2ccc(OCCCCCOCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)F)cc2)nc1

Procedure:
The title compound was prepared essentially as in Example 12 by combining 5-hydroxy-2-[4-(5-(2-(2-(pentafluoroethoxy)tetrafluoroethoxy)-2,2-difluoroethoxy)pentoxy)phenyl]pyrimidine (3.0 g, 5.1 mmol) with 4-butoxybutyl chloride (1.0 g, 6.1 mmol). The reaction mixture was quenched with water, and the crude product was further purified by recrystallization from ethanol, followed by Kugelrohr distillation (230-40° C. at 0.5 torr), to provide a yield of 2.4 g.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:9]([C:10]2[NH:14][CH:13]=[C:12]([CH2:15][N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:11]=2[F:25])=[CH:8][CH:7]=[CH:6][N:5]=1.C1OCCOCCOCCOCCOC1.Cl[S:42]([C:45]1[CH:49]=[CH:48][S:47][C:46]=1[C:50]([O:52][CH3:53])=[O:51])(=[O:44])=[O:43]>O1CCCC1>[C:19]([O:18][C:17]([N:16]([CH2:15][C:12]1[C:11]([F:25])=[C:10]([C:9]2[C:4]([F:3])=[N:5][CH:6]=[CH:7][CH:8]=2)[N:14]([S:42]([C:45]2[CH:49]=[CH:48][S:47][C:46]=2[C:50]([O:52][CH3:53])=[O:51])(=[O:43])=[O:44])[CH:13]=1)[CH3:24])=[O:23])([CH3:21])([CH3:22])[CH3:20]
Reactant: CN(Cc1c[nH]c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Reactant: COC(=O)c1sccc1S(=O)(=O)Cl
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1sccc1S(=O)(=O)n1cc(CN(C)C(=O)OC(C)(C)C)c(F)c1-c1cccnc1F
Reaction time: 0.08 h
Yield: 97 %

Procedure:
To a suspension of sodium hydride (60% in oil, 14.8 mg) in tetrahydrofuran (3 mL) was added tert-butyl {[5-(2-fluoropyridin-3-yl)-4-fluoro-1H-pyrrol-3-yl]methyl}methylcarbamate (100 mg) under ice-cooling, and the mixture was stirred for 5 min. 15-Crown-5 (81.7 mg) and methyl 3-(chlorosulfonyl)thiophene-2-carboxylate were added dropwise and the mixture was further stirred under ice-cooling for 2 hr. The reaction mixture was concentrated under reduced pressure, diluted with water, and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=6:1→2:1) to give the title compound as a pale-yellow oil (yield 158 mg, 97%).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[C:6]([O:16][C:17]3[CH:22]=[CH:21][C:20](/[CH:23]=[CH:24]/[C:25]([OH:27])=[O:26])=[CH:19][CH:18]=3)[C:7]3[C:12]([CH:13]=2)=[CH:11][C:10]([O:14]C)=[CH:9][CH:8]=3)[CH2:3][CH2:2]1.B(Br)(Br)Br>C(Cl)Cl>[CH:1]1([C:4]2[C:5]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[C:6]([O:16][C:17]3[CH:22]=[CH:21][C:20](/[CH:23]=[CH:24]/[C:25]([OH:27])=[O:26])=[CH:19][CH:18]=3)[C:7]3[C:12]([CH:13]=2)=[CH:11][C:10]([OH:14])=[CH:9][CH:8]=3)[CH2:3][CH2:2]1
Reactant: COc1ccc2c(Oc3ccc(/C=C/C(=O)O)cc3)c(-c3ccccc3)c(C3CC3)cc2c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(O)/C=C/c1ccc(Oc2c(-c3ccccc3)c(C3CC3)cc3cc(O)ccc23)cc1
Yield: 51 %

Procedure:
Methyl ether (155) (0.14 g, 0.32 mmol) was treated with BBr3 in CH2Cl2 to give the crude product as a yellow viscous oil, which was purified by reverse phase preparation HPLC on Agilent 1100 to afford 69 mg (51%) of the title compound (156) as an off-white solid. mp 242-243° C. 1H NMR (400 MHz, CH3OH-d4): δ 0.75-0.85 (m, 4H), 1.60-1.70 (m, 1H), 6.26 (d, J=15.9 Hz, 1H), 6.57 (d, J=8.6 Hz, 2H), 7.02 (dd, J1=9.0 Hz, J2=2.0 Hz, 1H), 7.12 (d, J=1.9 Hz, 1H), 7.16-7.28 (m, 6H), 7.34 (d, J=8.6 Hz, 2H), 7.52 (d, J=15.9 Hz, 1H), 7.58 (d, J=9.0 Hz, 1H). LCMS (APCI): m/z 423 (M+H)+, m/z 421 (M−H)−. Anal. Calc for C28H22O4.1.25H2O: C, 75.58; H, 5.55. Found: C, 75.34; H, 5.34.
Reaction SMILES: [O:1]=[C:2]([C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[C:34]([O:37][CH3:38])[CH:35]=2)[N:30]=[CH:29][CH:28]=1)[CH2:3][CH2:4][C@@H:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]#[C:13][C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[C:15]=2[F:22])[CH2:7][C@@H:6]1[C:23]([O:25]C)=[O:24].Cl.O.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[O:1]=[C:2]([C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[C:34]([O:37][CH3:38])[CH:35]=2)[N:30]=[CH:29][CH:28]=1)[CH2:3][CH2:4][C@@H:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]#[C:13][C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[C:15]=2[F:22])[CH2:7][C@@H:6]1[C:23]([OH:25])=[O:24]
Reactant: COC(=O)[C@H]1CN(CC#Cc2cc(F)cc(F)c2F)CC[C@H]1CCC(=O)c1ccnc2ccc(OC)cc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: COc1ccc2nccc(C(=O)CC[C@@H]3CCN(CC#Cc4cc(F)cc(F)c4F)C[C@@H]3C(=O)O)c2c1
Yield: 59.9 %

Procedure:
A solution of 1 g of methyl (3R,4R)-4-[3-oxo-3-(6-methoxyquinolin-4-yl)propyl]-1-[3-(2,3,5-trifluorophenyl)prop-2-ynyl]piperidine-3-carboxylate in 10 cm3 of a 5N aqueous hydrochloric acid solution is stirred for 4 hours at a temperature in the region of 80° C. After cooling to a temperature in the region of 20° C., 10 cm3 of water, then 10 cm3 of chloroform, and then 1.9 g of powdered sodium hydrogen carbonate are added. The mixture is extracted with 3 times 10 cm3 of chloroform. The organic phases are pooled, dried over sodium sulfate, filtered, and then concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C. The residue obtained is purified by chromatography under a nitrogen pressure of 50 kPa, on a column of silica gel (particle size 20–45μ; diameter 2.5 cm; 30 g), eluting with a mixture of dichloromethane-methanol (96/4 by volume) and collecting first a fraction of 150 cm3, and then fractions of 10 cm3. Fractions 5 to 22 are pooled, and then concentrated as above. 0.583 g of (3R,4R)-4-[3-oxo-3-(6-methoxyquinolin-4-yl)propyl]-1-[3-(2,3,5-trifluorophenyl)prop-2-ynyl]piperidine-3-carboxylic acid, in the form of a green-colored solid which melts at around 70° C., is obtained.
Reaction SMILES: Br[C:2]1[S:3][C:4]([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[C:5]([C:7](=[O:31])[NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:30])[C:13]=2[N:14]2[CH2:20][CH2:19][C@@H:18]([F:21])[C@H:17]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:16][CH2:15]2)[N:6]=1.[CH3:40][C:41]1[CH:46]=[CH:45][N:44]=[CH:43][C:42]=1B(O)O.CC([O-])=O.[K+].C([O-])([O-])=O.[Na+].[Na+]>C(#N)C.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Fe]>[C:26]([O:25][C:23]([NH:22][C@H:17]1[C@H:18]([F:21])[CH2:19][CH2:20][N:14]([C:13]2[N:12]([CH3:30])[N:11]=[CH:10][C:9]=2[NH:8][C:7]([C:5]2[N:6]=[C:2]([C:42]3[CH:43]=[N:44][CH:45]=[CH:46][C:41]=3[CH3:40])[S:3][C:4]=2[NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:31])[CH2:15][CH2:16]1)=[O:24])([CH3:29])([CH3:28])[CH3:27]
Reactant: Cc1ccncc1B(O)O
Reactant: Cn1ncc(NC(=O)c2nc(Br)sc2NC(=O)OC(C)(C)C)c1N1CC[C@@H](F)[C@H](NC(=O)OC(C)(C)C)CC1
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: CC(=O)[O-]
Solvent: CC#N
Product: Cc1ccncc1-c1nc(C(=O)Nc2cnn(C)c2N2CC[C@@H](F)[C@H](NC(=O)OC(C)(C)C)CC2)c(NC(=O)OC(C)(C)C)s1
Yield: 58.9 %

Procedure:
In a microwave reaction vial, tert-butyl N-[2-bromo-4-[[5-[(4R,5R)-4-(tert-butoxycarbonylamino)-5-fluoro-azepan-1-yl]-1-methyl-pyrazol-4-yl]carbamoyl]thiazol-5-yl]carbamate (161 mg, 0.25 mmol), (4-methyl-3-pyridyl)boronic acid (105 mg, 0.76) and PD(DPPF)CL2 (19 mg, 0.025 mmol) were dissolved in acetonitrile (3 mL). 1.0M KOAc (0.38 mL, 0.38 mmol) and 1.0M Na2CO3 (0.38 mL, 0.38 mmol) were added and the reaction was irradiated with microwave at 125° C. for 30 min. The mixture was cooled, filtered through Celite, concentrated and purified via flash chromatography, EA/heptane 0% to 100% to afford tert-butyl N-[4-[[5-[(4R,5R)-4-(tert-butoxycarbonylamino)-5-fluoro-azepan-1-yl]-1-methyl-pyrazol-4-yl]carbamoyl]-2-(4-methyl-3-pyridyl)thiazol-5-yl]carbamate (95 mg, 58%). This compound was stirred with 4N HCl in dioxane (3 mL, 12 mmol) and methanol (2 mL) at room temperature for 3 h. Solvent was removed under reduced pressure. The residue was basified with saturated NaHCO3 and extracted with EA 3×. The combined organic layers were dried over MgSO4 and the solvent removed under reduced pressure and the residue purified by preparative HPLC to afford 428 (38 mg, 58%). 1H NMR (400 MHz, DMSO) δ 8.83 (s, 1H), 8.79 (s, 1H), 8.43 (d, J=5.0 Hz, 1H), 7.49 (s, 2H), 7.47 (s, 1H), 7.37 (d, J=4.9 Hz, 1H), 4.42 (dt, J=8.4, 5.0 Hz, 1H), 3.64 (s, 3H), 3.26-3.02 (m, 5H), 2.63 (s, 3H), 2.18-2.02 (m, 1H), 2.02-1.88 (m, 1H), 1.87-1.75 (m, 1H), 1.66-1.53 (m, 1H). LCMS (ES+) m/z 445 (M+1)
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]([CH3:22])[C:11]([CH3:21])=[C:12]([C:18](=[O:20])[CH:19]=2)[C:13]([O:15]CC)=[O:14])=[CH:5][CH:4]=1.[OH-].[Na+]>O>[Br:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:10]([CH3:22])[C:11]([CH3:21])=[C:12]([C:18](=[O:20])[CH:19]=2)[C:13]([OH:15])=[O:14])=[CH:7][CH:8]=1
Reactant: CCOC(=O)c1c(C)n(C)c(-c2ccc(Br)cc2)cc1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1c(C(=O)O)c(=O)cc(-c2ccc(Br)cc2)n1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.7 %

Procedure:
5.3 g (0.014 mol) of ethyl 6-(4-bromophenyl)-1,2-dimethyl-4-oxonicotinate hydrochloride is suspended in 100 ml of water and to it there is added 5 g (0.0625 mol) of 50% aqueous sodium hydroxide. The mixture is refluxed and stirred for 1 hr. and the solution formed is cooled to room temperature. The solution is extracted with methylenedichloride and the aqueous solution is acidified to pH 1 with 12N hydrochloric acid. The suspension formed is vacuum filtered and the filter cake is washed with water and dried to afford 4 g (89% yield) of 6-(4-bromophenyl)-1,2-dimethyl-4-oxonicotinic acid, mp 269°-271° C. dec.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH:8]1[O:13][C:11](=[O:12])[CH2:10][CH2:9]1.[CH:14]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]([CH3:25])[CH3:24])[C:18]=1[N:26]=[C:27]=[O:28])([CH3:16])[CH3:15].C([N-]C(C)C)(C)C.[Li+]>>[CH3:16][CH:14]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]([CH3:24])[CH3:25])[C:18]=1[NH:26][C:27]([CH:10]1[CH2:9][CH:8]([CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1])[O:13][C:11]1=[O:12])=[O:28])[CH3:15]
Reactant: CCCCCCCC1CCC(=O)O1
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: CCCCCCCC1CC(C(=O)Nc2c(C(C)C)cccc2C(C)C)C(=O)O1

Procedure:
The title compound, mp 95°-98° C., was prepared from undecanoic γ-lactone (5.0 g, 0.027 mol), 2,6-diisopropylphenyl isocyanate (5.50 g, 0.027 mol) and lithium diisopropylamide (0.027 mol) using the procedure described in Example 1.
Reaction SMILES: Br[C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][C@@H:7]([NH:12][C:13](=[O:16])[CH2:14][CH3:15])[C:6]=2[CH:5]=[N:4][CH:3]=1.[F:17][C:18]([F:38])([F:37])[C:19]1[CH:24]=[C:23]([CH:25]2[CH2:27][CH2:26]2)[C:22](B2OC(C)(C)C(C)(C)O2)=[CH:21][CH:20]=1>>[CH:25]1([C:23]2[CH:24]=[C:19]([C:18]([F:17])([F:37])[F:38])[CH:20]=[CH:21][C:22]=2[C:2]2[C:11]3[CH2:10][CH2:9][CH2:8][C@@H:7]([NH:12][C:13](=[O:16])[CH2:14][CH3:15])[C:6]=3[CH:5]=[N:4][CH:3]=2)[CH2:26][CH2:27]1
Reactant: CC1(C)OB(c2ccc(C(F)(F)F)cc2C2CC2)OC1(C)C
Reactant: CCC(=O)N[C@@H]1CCCc2c(Br)cncc21
Product: CCC(=O)N[C@@H]1CCCc2c(-c3ccc(C(F)(F)F)cc3C3CC3)cncc21
Yield: 84 %

Procedure:
In analogy to the procedure described for the preparation of example 1, (R)—N-(4-bromo-5,6,7,8-tetrahydroisoquinolin-8-yl)propionamide (intermediate A-16) was reacted with 4-trifluoromethyl-6-cyclopropylphenylboronic acid pinacol ester acid to give the title compound as colorless oil in 84% yield. MS: 389.2 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([C:15]3[CH:20]=CN=CC=3)[C:13](C)=[C:12]([C:22](OCC)=O)[C:11]=2[CH:27]([CH3:29])[CH3:28])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:38][CH2:39][CH3:40])C>>[Cl:8][C:6]1[CH:5]=[C:4]([S:9][C:10]2[N:14]([CH2:13][C:12]3[CH:22]=[CH:10][N:14]=[CH:13][CH:12]=3)[C:15]([CH3:20])=[C:40]([CH2:39][OH:38])[C:11]=2[CH:27]([CH3:28])[CH3:29])[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: CCOC(=O)c1c(C(C)C)c(Sc2cc(Cl)cc(Cl)c2)n(-c2ccncc2)c1C
Reactant: CCOCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: Cc1c(CO)c(C(C)C)c(Sc2cc(Cl)cc(Cl)c2)n1Cc1ccncc1
Temperature: 2.5 °C
Reaction time: 1 h

Procedure:
A solution containing 0.1 g of ethyl 5-(3,5-dichlorophenylsulphanyl)-4-isopropyl-2-methyl-1-pyridin-4-yl-1H-pyrrole-3-carboxylate in 0.5 ml of anhydrous diethyl ether was added dropwise to 0.54 ml of a 1M solution of lithium aluminum hydride which was stirred and cooled at 0-5° C. The mixture was stirred at 5° C. for 1 h then at room temperature for 1 h. The mixture was cooled again to 5° C. and quenched with saturated ammonium chloride solution, then extracted three times with 10 ml of ethyl acetate. The combined extracts were washed with 10 ml of brine, then dried over anhydrous magnesium sulphate, filtered and evaporated. The residue was purified by flash chromatography on silica gel using methanol/dichloromethane (1:19) for the elution to give 70 mg of 5-(3,5-dichlorophenylthio)-4-isopropyl-2-methyl-1-[(4-pyridyl)methyl]-1H-pyrrole-3-methanol as a pale orange gum. Mass spectrum (ESI) m/z 421 [M+H]+. 1H NMR (CDCl3) 1.31 (d, 6H), 2.21 (s, 3H), 3.24 (m, 1H), 4.66 (s, 2H), 5.10 (s, 2H), 6.68 (d, 2H), 6.74 (m, 2H), 6.98 (t, 1H), 8.44 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][CH:5](O)[C:6]1[CH:7]=[CH:8][C:9]([CH3:12])=[N:10][CH:11]=1.C(OC(=O)C)(=O)C.CO.[H][H]>C1(C)C=CC=CC=1.C(O)(=O)C.[Pd]>[CH3:1][O:2][C:3](=[O:14])[CH2:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([CH3:12])=[N:10][CH:11]=1
Reactant: COC(=O)CC(O)c1ccc(C)nc1
Reactant: [H][H]
Agent: [Pd]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)CCc1ccc(C)nc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 114 %

Procedure:
80.0 g (0.35 mol) of recrystallized 3-hydroxy-3-(2-methyl-5-pyridyl)-propionic acid methyl ester was dissolved in 100 ml of toluene. 60.0 g (0.588 mol) of acetic anhydride and 0.1 g (0.0009 mol) of 4-dimethyl-aminopyridine were added, and the solution was stirred for 1 hour at 60° C. Then 20 ml of methanol was added. After 15 minutes, the solution was diluted with 250 ml of acetic acid, 1.5 g of 5 percent palladium on activated carbon was added, and the solution was poured into the autoclave. The hydrogenation was performed under 8 bars of hydrogen at 65° C. for 5.5 hours. At the end of the hydrogenation, the autoclave was cooled, and the solution was filtered and evaporated. The evaporation residue was dissolved in 100 ml of water and 100 ml of methylene chloride and adjusted to pH 7 with 87.9 g of 40 percent sodium hydroxide solution. The phases were separated, the aqueous phase was extracted with methylene chloride, and the combined organic extracts were evaporated. 71.5 g of raw 2-methylpyridine-5-propionic acid methyl ester was obtained. (Content according to GC, 91.5 percent; yield, 92.1 percent in relation to the 3-hydroxy-3-(2-methyl-5-pyridyl)-propionic acid methyl ester used.) The product was distilled to obtain a 97 percent product having with a boiling point of 100°-113° C./1-2 mbar. The yield of distilled product was 88.5 percent, in relation to the 3-hydroxy-3-(2-methyl-5-pyridyl)propionic acid methyl ester used.