Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[NH:13][C:14](=[O:16])[CH3:15].F[B-](F)(F)F.[O:22]=[N+:23]=[O:24].O>C(#N)C>[Br:1][C:2]1[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]2[C:3]=1[C:4]([N+:23]([O-:24])=[O:22])=[CH:5][CH:6]=[C:7]2[NH:13][C:14](=[O:16])[CH3:15]
Reactant: O=[N+]=O
Reactant: CC(=O)Nc1cccc2c(Br)ccc(C)c12
Agent: F[B-](F)(F)F
Solvent: CC#N
Solvent: O
Product: CC(=O)Nc1ccc([N+](=O)[O-])c2c(Br)ccc(C)c12

Procedure:
To a cold (-5° C.) suspension of 4.45 g (16.00 mmol) of compound (19) in 25 ml acetonitrile was added dropwise a suspension of 2.60 g (16.64 mmol) of nitronium tetrafluoroborate in 5 ml of acetonitrile. After ten minutes, the homogenous, light-yellow reaction mixture was poured into water and extracted twice with ethyl acetate. The combined organic layers were washed with saturated NaCl solution and then dried over anhydrous MgSO4. The solvent was then removed under reduced pressure, and the crude residue was recrystallized from methanol to give N-(5-bromo-8-methyl-4-nitro-naphthalen-1-yl)-acetamide (20) as a light-yellow solid, m.p. 216°-217° C. Another 0.80 g of compound (20) was obtained from the concentrated mother liquors after flash chromatography on silica, eluting hexanes:ethyl acetate (1:1). The overall yield was 2.00 g (39%).
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH:5]1[C:10]([OH:19])([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][CH:12]=2)[CH2:9][CH2:8][CH2:7][CH2:6]1)[CH3:3].Cl.[OH2:21]>>[CH3:3][N+:2]([O-:21])([CH2:4][CH:5]1[C:10]([OH:19])([C:11]2[CH:12]=[CH:13][CH:14]=[C:15]([O:17][CH3:18])[CH:16]=2)[CH2:9][CH2:8][CH2:7][CH2:6]1)[CH3:1].[CH3:3][N:2]([CH2:4][CH:5]1[C:10]([OH:19])([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][CH:12]=2)[CH2:9][CH2:8][CH2:7][CH2:6]1)[CH3:1]
Reactant: O
Agent: COc1cccc(C2(O)CCCCC2CN(C)C)c1
Agent: Cl
Product: COc1cccc(C2(O)CCCCC2C[N+](C)(C)[O-])c1

Procedure:
First, tramadol N-oxide was prepared as set forth hereinafter. Tramadol hydrochloride (0.5 mol) was converted its free base in basified water (pH >9) and then extracted with ether. The ether was evaporated to yield the crystalline hydrate of tramadol. The solid was then heated with steam under a high vacuum to remove as much water as possible to yield 131.5 g of material. The material was dissolved in methanol (500 mL) and 65 g of 30% H2O2 was added. The solution was stirred for 3 hours and then an additional 65 g of the 30% H2O2 was added. The reaction was then stirred for 2.5 days at room temperature. Approximately 10 mg of PtO2 (use of Pt/C is suggested for its ease of removal) on carbon was then added to the reaction mixture, and very gentle foaming took place. An additional 10 mg of PtO2 was added and the reaction mixture was stirred overnight and then filtered through filter aid. The filtrate was concentrated under vacuum while being heated to a temperature <40° C. The residue was taken up in methylene chloride. Since the methylene chloride solution contained some colloidial platinum, the solution was diluted with ethyl acetate to 1 L and filtered through a nylon filter membrane (0.45 μ pore size) to yield a clear colorless filtrate. The filtrate was concentrated to 600 mL, and then ethyl acetate was added continuously to maintain a volume of 800 mL while the solution was heated until a vapor temperature of 74° C. was reached. The solution was then cooled to room temperature. The solid was collected by filtration, washed with ethyl acetate and dried in vacuo to yield 126.6 g of the tramadol N-oxide (mp. 159.5°-160° C.).
Reaction SMILES: [C:1]([N:3]=[C:4](SC)[S:5][CH3:6])#[N:2].[CH3:9][C:10]([NH2:14])([C:12]#[CH:13])[CH3:11]>C(#N)C>[C:1]([NH:3][C:4](=[N:14][C:10]([CH3:11])([C:12]#[CH:13])[CH3:9])[S:5][CH3:6])#[N:2]
Reactant: CSC(=NC#N)SC
Reactant: C#CC(C)(C)N
Solvent: CC#N
Product: C#CC(C)(C)N=C(NC#N)SC

Procedure:
A solution of dimethyl cyanodithioimidocarbonate (9.0 g, 0.615 mole) and 1,1-dimethylpropargylamine (90% amine, remainder water, 5.68 g, 0.0615 mole) in acetonitrile (125 ml) was stirred at reflux temperature for 13 days. The reaction mixture was evaporated under reduced pressure and the residue chromatographed on silica gel. The appropriate fractions were combined and the product was recrystallized from toluene to give the title product, mp 128°-130.5° C.
Reaction SMILES: C([O:3][C:4](=[O:29])[CH:5]([CH2:11][C:12]1[C:20]2[C:15](=[C:16]([C:21](=[O:28])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)[C:6]([O:8]CC)=[O:7])C.C>[OH-].[Na+]>[C:21]([C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:15]=1[NH:14][CH:13]=[C:12]2[CH2:11][CH:5]([C:6]([OH:8])=[O:7])[C:4]([OH:29])=[O:3])(=[O:28])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CCOC(=O)C(Cc1c[nH]c2c(C(=O)c3ccccc3)cccc12)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Product: O=C(c1ccccc1)c1cccc2c(CC(C(=O)O)C(=O)O)c[nH]c12
Yield: 71.1 %

Procedure:
A mixture of 10.0 g (0.025 mole) of 2-[(7-benzoyl-1H-indol-3-yl)methyl]propanedioic acid diethyl ester in 150 ml of 3N sodium hydroxide was heated at reflux for 18 hr, then treated with charcoal, cooled and filtered. The dark yellow filtrate was acidified by the dropwise addition of 50 ml of concentration hydrochloric acid. The addition of 20 ml of methylene chloride caused by formation of a ppt., which was collected and recrystallized from chloroform-methanol to give 6.0 g (70%) of off-white crystals, m.p. 188°-189° C.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:6]([O:10][CH3:11])=[CH:5][C:3]=1[NH2:4].[H-].[Na+].Cl[C:15]1[C:20]([C:21]#[N:22])=[CH:19][N:18]=[C:17]2[S:23][C:24]([I:26])=[CH:25][C:16]=12>O1CCCC1>[Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:6]([O:10][CH3:11])=[CH:5][C:3]=1[NH:4][C:15]1[C:20]([C:21]#[N:22])=[CH:19][N:18]=[C:17]2[S:23][C:24]([I:26])=[CH:25][C:16]=12
Reactant: COc1cc(N)c(Cl)cc1Cl
Reactant: N#Cc1cnc2sc(I)cc2c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(Nc2c(C#N)cnc3sc(I)cc23)c(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 18.8 %

Procedure:
A mixture of 2,4-dichloro-5-methoxyaniline (1.1 g, 5.7 mmol) and 60% sodium hydride (285 mg, 9.9 mmol) in 30 mL of tetrahydrofuran is heated at reflux for 1 hour. The solution is cooled and 4-chloro-2-iodothieno[2,3-b]pyridine-5-carbonitrile (1.0 g, 3.12 mmol) is added. The reaction mixture is heated at reflux for 5 hours then allowed to stir at room temperature overnight. The resultant dark solution is partitioned between ethyl acetate and water. The organic layer is washed with water, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is purified by flash column chromatography eluting with 0.5:9.5 methanol:dichloromethane to provide 0.28 g of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-2-iodothieno[2,3-b]pyridine-5-carbonitrile as an off white solid, mp 231-233° C. An additional 0.09 g is obtained by chromatography of a mixture of unreacted starting material and product using a gradient of 9:1 to 1:1 hexane:ethyl acetate. 1H NMR (DMSO-d6) δ 3.87 (s, 3H), 7.36 (s, 1H), 7.76 (s, 1H), 8.11 (s, 1H), 8.39 (s, 1H), 9.76 (s, 1H); MS 473.8 (M−H)−.
Reaction SMILES: [C:1]([CH2:3][CH2:4][C@@:5]1([C:31]([O:33]C)=O)[CH2:9][CH2:8][C@H:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16]CC3C=CC=CC=3)=[CH:12][CH:11]=2)[N:6]1C(OC(C)(C)C)=O)#[N:2].C(O)(C(F)(F)F)=O>CO.[Ni].ClCCl>[OH:16][C:13]1[CH:14]=[CH:15][C:10]([CH:7]2[CH2:8][CH2:9][C@:5]3([CH2:4][CH2:3][CH2:1][NH:2][C:31]3=[O:33])[NH:6]2)=[CH:11][CH:12]=1
Reactant: COC(=O)[C@]1(CCC#N)CC[C@H](c2ccc(OCc3ccccc3)cc2)N1C(=O)OC(C)(C)C
Agent: [Ni]
Solvent: ClCCl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: O=C1NCCC[C@]12CCC(c1ccc(O)cc1)N2
Temperature: 0 °C
Reaction time: 4.5 h
Yield: 19.4 %

Procedure:
To a solution of 1-(1,1-dimethylethyl) 2-methyl (2R,5R)-2-(2-cyanoethyl)-5-{4-[(phenylmethyl)oxy]phenyl}-1,2-pyrrolidinedicarboxylate (D49, 215 mg, 0.46 mmol) in methanol (20 mL) was added Raney Nickel (slurry in water, 1 spatula) and the mixture was stirred under a hydrogen atmosphere (6 atm) for 4.5 hours. The catalyst was filtered off, the solvent removed under reduced pressure, and the residue treated with toluene (3×20 mL) and dried under vacuum. The crude oil obtained was dissolved in dichloromethane and the resulting solution cooled to 0° C. and TFA (0.2 mL) was added dropwise. After 1 h at room temperature the solvent was removed under vacuum and the residue purified by SCX column and by chromatography on silica gel using dichloromethane/methanol (95:5) to afford the title compound (22 mg, 19%) as a 66/33 mixture of epimers at the benzylic position. Rt (HPLC) 2.16 min; MS: (ES/+) m/z: 247 [MH+]; C14H18N2O2 requires 246.
Reaction SMILES: [C:1]([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH2:28])[C:13]([N:14]3[CH2:19][CH2:18][CH2:17][C@H:16]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=[O:3])[CH3:2].[F:29][C:30]1[CH:35]=[C:34]([S:36]([CH3:39])(=[O:38])=[O:37])[CH:33]=[C:32]([F:40])[C:31]=1[C:41]1[N:46]=[C:45]([C:47](O)=[O:48])[CH:44]=[CH:43][C:42]=1[F:50].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH:28][C:47]([C:45]3[CH:44]=[CH:43][C:42]([F:50])=[C:41]([C:31]4[C:32]([F:40])=[CH:33][C:34]([S:36]([CH3:39])(=[O:38])=[O:37])=[CH:35][C:30]=4[F:29])[N:46]=3)=[O:48])[C:13]([N:14]3[CH2:19][CH2:18][CH2:17][C@H:16]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC1CCc2c1ncc(N)c2N1CCC[C@H](NC(=O)OC(C)(C)C)C1
Reactant: CS(=O)(=O)c1cc(F)c(-c2nc(C(=O)O)ccc2F)c(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)OC1CCc2c1ncc(NC(=O)c1ccc(F)c(-c3c(F)cc(S(C)(=O)=O)cc3F)n1)c2N1CCC[C@H](NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 40.7 %

Procedure:
A mixture of 3-amino-4-{(3S)-3-[(tert-butoxycarbonyl)amino]piperidin-1-yl}-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl acetate (15.0 mg, 0.0384 mmol), 6-[2,6-difluoro-4-(methylsulfonyl)phenyl]-5-fluoropyridine-2-carboxylic acid (15.3 mg, 0.0461 mmol), HATU (36.5 mg, 0.0960 mmol) in DMF (0.09 mL) and DIPEA (14.9 mg, 0.115 mmol) was stirred at room temperature for 16 h. The mixture was filtered, concentrated under reduced pressure and purified by preparative LC-MS (method; XBridge™ preparative C18 5 μm OBD™ column, 30×10 mm, 60 mL/min., eluting with a gradient of MeCN and water with 0.1% NH4OH) to give the sub-title compound as a colorless gum (11.0 mg, 41%). LCMS calc. for C33H37F3N5O7S (M+H)+: m/z=704.2. Found: 704.2.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:32][CH2:31][CH2:30][C@@:7]2([CH2:11][C@H:10]([O:12][Si:13]([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:9][CH2:8]2)[C:6]1=[O:33])=[O:4].FC(F)(F)C(O)=O.C([SiH](CC)CC)C.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.O>[CH3:1][O:2][C:3]([CH:5]1[CH2:32][CH2:31][CH2:30][C@@:7]2([CH2:11][C@H:10]([O:12][Si:13]([C:26]([CH3:29])([CH3:27])[CH3:28])([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:9][CH2:8]2)[CH:6]1[OH:33])=[O:4]
Reactant: COC(=O)C1CCC[C@]2(CC[C@@H](O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C2)C1=O
Agent: CC[SiH](CC)CC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)C1CCC[C@]2(CC[C@@H](O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C2)C1O
Yield: 106.2 %

Procedure:
To a solution of the crude (2R,5R)-2-(tert-butyldiphenylsilanyloxy)-6-oxo-spiro[4.5]de cane-7-carboxylic acid methyl ester (1.65 g) obtained in Step 4 in toluene (1.6 mL) were added trifluoroacetic acid (5 mL) and triethylsilane (0.52 mL) under ice-cooling, followed by stirring the mixture under ice-cooling for 3 hours. Then, to the reaction mixture was added dropwise a solution of potassium carbonate (4.95 g) in water (20 mL), and the mixture was stirred under ice-cooling for 10 minutes, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried and concentrated to give (2R,5R)-2-(tert-butyldiphenylsilanyloxy)-6-hydroxy-spiro[4.5]decane-7-carboxylic acid methyl ester (1.76 g) as a crude product.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]([O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH:21]([OH:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C>ClCCl>[CH2:6]([O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH:21]([O:27][S:2]([CH3:1])(=[O:4])=[O:3])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CCOC(=O)C(O)Cc1ccc(OCc2ccccc2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C(Cc1ccc(OCc2ccccc2)cc1)OS(C)(=O)=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Methanesulfonyl chloride (0.94 ml) was added to a solution of ethyl 3-(4-benzyloxyphenyl)lactate (3.32 g), which is the product of Reference example 1(b), in anhydrous dichloromethane (30 ml). To this mixture triethylamine (2.47 ml) was added dropwise in an ice bath. The mixture was stirred at ambient temperature for 3 hours. The reaction mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water. The ethyl acetate layer was separated and dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was crystallized from hexane to afford the desired product (3.60 g) as colorless crystals.
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=3[Cl:28])=[CH:17][CH:16]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:29](Cl)(=[O:31])[CH3:30].C(N(CC)C(C)C)(C)C>C1COCC1.C(Cl)Cl>[CH2:1]([C@H:8]1[CH2:9][N:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=3[Cl:28])=[CH:17][CH:16]=2)[CH2:11][CH2:12][N:13]1[C:29](=[O:31])[CH3:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)Cl
Reactant: Cc1ccc(Cl)c(-c2ccc(CN3CCN[C@@H](Cc4ccccc4)C3)cc2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(=O)N1CCN(Cc2ccc(-c3cc(C)ccc3Cl)cc2)C[C@@H]1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
This compound was made in the following manner: 50 mg of 3-(S)-benzyl-1-(2′-chloro-5′-methyl-biphenyl-4-ylmethyl)-piperazine was dissolved in THF, 2 equiv. of acetylchloride and 2 equiv. of N,N-diisopropylethylamine were added. The reaction was stirred at room temperature overnight. The reaction was diluted with DCM, washed with saturated aqueous sodium bicarbonate solution, then dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by column chromatography to afford the title compound as the free base. Treatment with 1 equiv 1M HCl in dioxane and concentration in vacuo afforded 46 mg of the corresponding hydrochloride salt. Yield 77%, ES MS m/z 433
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[C:7]([CH3:12])[C:3]=1[C:4]([OH:6])=[O:5].Cl(O)(=O)(=O)=O>C(OC(C)(C)C)(=O)C.C(Cl)Cl>[Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[C:7]([CH3:12])[C:3]=1[C:4]([O:6][C:3]([CH3:7])([CH3:4])[CH3:2])=[O:5]
Reactant: Cc1cc(Cl)nc(Cl)c1C(=O)O
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC(=O)OC(C)(C)C
Solvent: ClCCl
Product: Cc1cc(Cl)nc(Cl)c1C(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 190.4 %

Procedure:
To a solution of 2,6-dichloro-4-methylnicotinic acid (1.00 g, 4.85 mmol, 1 equiv) in tert-butyl acetate (24 mL) was added 70% perchloric acid (0.88 mL, 14.56 mmol, 3 equiv). After 1 h, reaction was diluted with DCM, washed cautiously with saturated aqueous sodium bicarbonate solution, dried (Na2SO4), and concentrated in vacuo to provide the product (1.21 g, 95%) as a pale yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.15 (s, 1H), 2.37 (d, J=0.5 Hz, 3H), 1.62 (s, 9H); LCMS (ESI, M+1): 262.1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=O)[C:6]([O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[C:5]2[C:20]([F:23])([F:22])[F:21].BrC1C=C2C(=CC=1)NC(=O)C(OC1C=CC([Cl:43])=CC=1)=C2C(F)(F)F>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([Cl:43])[C:6]([O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[C:5]2[C:20]([F:23])([F:22])[F:21]
Reactant: O=c1[nH]c2ccc(Br)cc2c(C(F)(F)F)c1Oc1ccc(Cl)cc1
Reactant: O=c1[nH]c2ccc(Br)cc2c(C(F)(F)F)c1Oc1ccccc1
Product: FC(F)(F)c1c(Oc2ccccc2)c(Cl)nc2ccc(Br)cc12

Procedure:
The title compound was prepared using 6-bromo-3-phenoxy-4-(trifluoromethyl)quinolin-2(1H)-one (Intermediate 8, step a) in place of 6-bromo-3-(4-chlorophenoxy)-4-(trifluoromethyl)quinolin-2(1H)-one (Intermediate 7, step c) according to the procedure described in Intermediate 7, step d.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[C:9](=[O:19])[NH:10][C:11](=[O:18])[N:12]([CH2:14][CH2:15][CH:16]=O)[CH:13]=2)=[CH:4][CH:3]=1.[F:20][C:21]([F:35])([F:34])[C:22]1[CH:27]=[CH:26][C:25]([C@:28]23[CH2:33][C@H:32]2[CH2:31][NH:30][CH2:29]3)=[CH:24][CH:23]=1.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[OH-].[Na+].[Cl:56]C(Cl)C>>[ClH:56].[ClH:56].[CH3:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[C:9](=[O:19])[NH:10][C:11](=[O:18])[N:12]([CH2:14][CH2:15][CH2:16][N:30]3[CH2:31][C@H:32]4[C@:28]([C:25]5[CH:24]=[CH:23][C:22]([C:21]([F:20])([F:35])[F:34])=[CH:27][CH:26]=5)([CH2:33]4)[CH2:29]3)[CH:13]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(-c2cn(CCC=O)c(=O)[nH]c2=O)cn1
Reactant: CC(Cl)Cl
Reactant: FC(F)(F)c1ccc([C@@]23CNC[C@@H]2C3)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Cc1ccc(-c2cn(CCCN3C[C@@H]4C[C@]4(c4ccc(C(F)(F)F)cc4)C3)c(=O)[nH]c2=O)cn1
Product: Cl
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 40 %

Procedure:
To a solution of 3-[5-(6-Methyl-pyridin-3-yl)-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl]-propionaldehyde (Prep59, 90 mg, 0.35 mmol), (1S,5R)-1-(4-trifluoromethyl-phenyl)-3-aza-bicyclo[3.1.0]hexane (Prep4, 71 mg, 0.31 mmol) and AcOH (21 mg, 0.35 mmol) in dichloroethane (2 mL), NaBH(AcO)3 (77 mg, 0.36 mmol) was added portionwise at 0° C. The mixture was stirred at 0° C. for further 45 minutes, then a 1N solution of NaOH was added and the mixture extracted with EtOAc. The organic phase was dried and evaporated, the residue redissolved in DCM and treated with PS-isocyanate resin (400 mg) under stirring for 4 h. After filtration, the solvent was evaporated under vacuum, and the crude was purified by flash chromatography with DCM-MeOH—NH4OH (95-5-0.5) to give the title compound (65 mg, 40% yield) as free base.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C:9](=[O:13])[CH2:10]2)=[CH:5][CH:4]=1.[NH:14]1CC[CH2:16][CH2:15]1.C1C=CC=CC=1.ClCC#N>O>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C:9](=[O:13])[CH:10]2[CH2:16][C:15]#[N:14])=[CH:5][CH:4]=1
Reactant: C1CCNC1
Reactant: COc1ccc2c(c1)CC(=O)CC2
Agent: N#CCCl
Solvent: O
Solvent: c1ccccc1
Product: COc1ccc2c(c1)C(CC#N)C(=O)CC2
Reaction time: 8 h

Procedure:
A mixture of 7-methoxy-2-tetralone (472 g., 2.68 mole), pyrrolidine (241 g., 3.40 mole) and benzene (2.5l) was refluxed under nitrogen with water separation (Dean-Stark trap) for 2 hrs. and then distilled for a further 1 hr. (1.2l) of distillate). Chloroacetonitrile (324 g., 4.30 mole) was added during 15 mins. and the mixture was refluxed for 4 hrs. and then left at room temperature overnight. Water (1.5l) was added and the mixture was refluxed for 3 hrs. The organic layer was separated while still hot, washed with 3N sulphuric acid (500 ml.) and filtered with suction through a pad of magnesium sulphate. The product crystallized from benzene and from benzene-ether (two crops) as yellow prisms (484 g., 84%); m.p. 97°-99° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH2:8])[S:5][C:6]=1[CH3:7].[Br:9][CH2:10][CH2:11][O:12][CH2:13][C:14]([F:17])([F:16])[F:15]>>[BrH:9].[CH3:1][C:2]1[N:3]([CH2:10][CH2:11][O:12][CH2:13][C:14]([F:17])([F:16])[F:15])[C:4](=[NH:8])[S:5][C:6]=1[CH3:7]
Reactant: FC(F)(F)COCCBr
Reactant: Cc1nc(N)sc1C
Product: Br
Product: Cc1sc(=N)n(CCOCC(F)(F)F)c1C
Temperature: 65 °C

Procedure:
4,5-Dimethyl-thiazol-2-ylamine and 2-(2-bromo-ethoxy)-1,1,1,-trifluoro-ethane were mixed and heated at 65° C. for 4 hours. The residue was triturated with hexane to afford the title compound. MS (ESI+) m/z 255 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:9]([O:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[C:18]([NH:23][C:24](=[O:36])[CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=4)[CH:17]=3)[CH:8]=[CH:7][C:5]=2[N:6]=1.N1C=CC=CC=1.[CH:43]1([C:46](Cl)=[O:47])[CH2:45][CH2:44]1>O1CCCC1.C(OCC)(=O)C>[CH:43]1([C:46]([NH:1][C:2]2[S:3][C:4]3[C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:9]([O:15][C:16]4[CH:21]=[CH:20][C:19]([F:22])=[C:18]([NH:23][C:24](=[O:36])[CH2:25][C:26]5[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:34])([F:35])[F:33])[CH:27]=5)[CH:17]=4)[CH:8]=[CH:7][C:5]=3[N:6]=2)=[O:47])[CH2:45][CH2:44]1
Reactant: COC(=O)c1c(Oc2ccc(F)c(NC(=O)Cc3cccc(C(F)(F)F)c3)c2)ccc2nc(N)sc12
Reactant: O=C(Cl)C1CC1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1c(Oc2ccc(F)c(NC(=O)Cc3cccc(C(F)(F)F)c3)c2)ccc2nc(NC(=O)C3CC3)sc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 79.6 %

Procedure:
To a solution of methyl 2-amino-6-[4-fluoro-3-({[3-(trifluoromethyl)phenyl]acetyl}amino)phenoxy]-1,3-benzothiazole-7-carboxylate (2.50 mg, 4.81 mmol) in tetrahydrofuran (20 mL) were added pyridine (770 μL, 9.62 mmol) and cyclopropanecarbonyl chloride (790 μL, 8.66 mmol), and the mixture was stirred at room temperature for 12 hr. The reaction mixture was diluted with ethyl acetate (80 mL), washed successively with saturated aqueous sodium hydrogen carbonate solution (50 ml) and saturated brine (50 mL), and the organic layer was dried over anhydrous magnesium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=40/60→80/20), and a fraction containing the object product was concentrated under reduced pressure. The obtained pale-yellow residue was recrystallized from ethyl acetate/n-hexane (3/2) to give the title compound (2.25 g, 80%) as a white powder.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:13])OCC)[CH:5]=[CH:4][C:3]=1[Cl:14].[CH3:15][NH:16][CH3:17]>C(O)C>[CH3:15][N:16]([CH3:17])[C:9]([NH:8][C:6]1[CH:5]=[CH:4][C:3]([Cl:14])=[C:2]([NH2:1])[N:7]=1)=[O:13]
Reactant: CNC
Reactant: CCOC(=O)Nc1ccc(Cl)c(N)n1
Solvent: CCO
Product: CN(C)C(=O)Nc1ccc(Cl)c(N)n1

Procedure:
A mixture of ethyl N-(6-amino-5-chloro-2-pyridyl)carbamate (64.7 g., 0.3 mole), dimethylamine (45 g., 1.0 mole) and 300 ml. of ethanol is heated at 120° C. for 24 hours in a pressure vessel. The reaction mixture is then concentrated in vacuo and 68 g. of brown solid is obtained. Recrystallization from n-butyl chloride gives pure material, m.p. 139°-141°
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[C:15](=[O:16])[NH:14][C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[NH:11][C:10]1=[O:21])=[O:7])([CH3:4])([CH3:3])[CH3:2].[S:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[C:27]([CH2:29]Cl)=[O:28]>>[S:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[C:27]([CH2:29][N:14]1[C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[N:11]([CH2:29][C:27]([C:23]2[S:22][CH:26]=[CH:25][CH:24]=2)=[O:28])[C:10](=[O:21])[CH:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C:15]1=[O:16])=[O:28]
Reactant: CC(C)(C)OC(=O)NC1C(=O)Nc2ccccc2NC1=O
Reactant: O=C(CCl)c1cccs1
Product: CC(C)(C)OC(=O)NC1C(=O)N(CC(=O)c2cccs2)c2ccccc2N(CC(=O)c2cccs2)C1=O

Procedure:
Compound 14g is prepared in a manner similar to that used for preparation of Compound 14 h using previously prepared Compound 13 and 2-thienylcarbonylmethyl chloride.