Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[NH2:10][C:11]1[C:16](Br)=[N:15][C:14]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:13][N:12]=1>CN(C=O)C>[NH2:10][C:11]1[C:16]([S:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[N:15][C:14]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:13][N:12]=1
Reactant: Nc1ncc(-c2ccccc2)nc1Br
Reactant: Sc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ncc(-c2ccccc2)nc1Sc1ccccc1
Temperature: 7.5 °C
Reaction time: 0.25 h
Yield: 78.8 %

Procedure:
To a cooled solution of thiophenol (0.10 mL, 1.00 mmol) in dry DMF (10 mL), sodium hydride (NaH) (0.025 g, 1.00 mmol) was added the resulting mixture was stirred for 15 min at 5-10° C. After this time 2-amino-3-bromo-5-phenylpyrazine 17b (0.25 g, 1.00 mmol) was added and the mixture refluxed for 20 h, cooled and extracted with EtOAc. The organic layer was washed with water, dried over Na2SO4, filtered and the solvent removed under reduced pressure to get a crude that was purified by flash chromatography using petroleum ether-EtOAc (60:40 v/v) as eluent, to obtain 0.22 g of the title compound 18b as a brown solid (mp 109-112° C., 79% yield). 1H-NMR (CDCl3): 4.92 (br s, 2H), 7.29-7.50 (m, 8H), 7.74-7.77 (m, 2H), 8.35 (s, 1H). MS (ESI): m/z 280 (M+H1).
Reaction SMILES: [SH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13].[CH3:15]I.O=O.[OH-].[Na+]>O.C(O)C>[CH3:15][S:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13]
Reactant: O=C(O)CCCCCCCCCCS
Reactant: CI
Agent: O=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CSCCCCCCCCCCC(=O)O
Yield: 58.7 %

Procedure:
Into a 3-neck round-bottom flask fitted with a condenser and an addition funnel were added 20 g of 11-mercaptoundecanoic acid, 13 g of methyl iodide and 200 mL of ethanol. A slow flow of nitrogen through the reactor was started to exclude oxygen because mercaptans can be converted into disulfides in the presence of air and strong alkali. A solution of 7.33 g of sodium hydroxide in 14.66 g of water was added dropwise to the reaction mixture via the addition funnel. Any unreacted methyl iodide, the ethanol and the water were removed using a rotovap. The residue was acidified using a mixture of concentrated hydrochloric acid and ice. After isolation the product was distilled. After a small amount of a low boiling fraction was collected, the crude product was collected at ~1 mm of Hg at 180° C. weighing 22.75 g. The crude product was distilled to yield 12.5 g of desired product representing 58.7% of theoretical based upon the weight of starting 11-mercaptoundecanoic acid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.[C:10]([C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[C:17](=[O:18])[O:16][CH2:15]2)#[N:11].[NH4+].[Cl-]>O1CCCC1.COCCOC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:17]([C:19]2[CH:20]=[CH:21][C:12]([C:10]#[N:11])=[CH:13][C:14]=2[CH2:15][OH:16])=[O:18])=[CH:4][CH:3]=1
Reactant: N#Cc1ccc2c(c1)COC2=O
Reactant: Fc1ccc([Mg]Br)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: COCCOC
Product: N#Cc1ccc(C(=O)c2ccc(F)cc2)c(CO)c1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
1048 g of a 10% solution of 4-fluorophenylmagnesium bromide in tetrahydrofuran are added to a suspension of 60.0 g of 5-cyanophthalide in 390 ml of 1,2-dimethoxyethane at −10° C. within three hours. After stirring for 30 minutes at −10° C., the cold reaction mixture is poured into 1 L of aqueous NH4Cl (180 g in 1000 ml of water, 20° C.) in about 5 minutes. The layers are separated and the aqueous layer is extracted with 300 ml of tetrahydrofuran. The organic layers are combined and volatiles are removed under reduced pressure at 45° C. The residue is dissolved in a mixture of 1000 mL of CH2Cl2 and 200 ml of water containing 2.5 g of sodium carbonate (pH of 9). The layers are separated and the organic phase is dried with 40 g of sodium carbonate. The dry CH2Cl2 solution is treated with 6 g of charcoal, stirred for 10 minutes and the charcoal is removed by filtration. The filter cake is washed with 50 mL of CH2Cl2. Filtrate and washing liquid are combined and the solvent is removed under reduced pressure. 300 mL of diisopropylether are added to the residue. After stirring for 1 hour at 22° C. the crystal suspension is cooled to 0° C. and stirred for another two hours, then cooled to −10° C. and stirred for 14 hours. The product is isolated by filtration and washed with 40 mL of chilled diisopropylether, 80 mL of a 1:1 mixture of diisopropylether/cyclohexane and 80 mL of cyclohexane. After drying for 3 hours at 50° C. in vacuo 83.0 g (86.2% of theory, purity (HPLC): 99.8 area %) white, crystalline powder of the title compound are obtained (mp. 85° C.).
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.C(N(CC)C(C)C)(C)C.Br[C:26]1[S:30][C:29]([C:31]#[N:32])=[N:28][N:27]=1.[NH4+].[Cl-]>O1CCOCC1>[Br:1][C:2]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:3]=1[O:4][CH:5]1[CH2:6][CH2:7][N:8]([C:26]2[S:30][C:29]([C:31]#[N:32])=[N:28][N:27]=2)[CH2:9][CH2:10]1
Reactant: N#Cc1nnc(Br)s1
Reactant: Fc1ccc(Br)c(OC2CCNCC2)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1nnc(N2CCC(Oc3cc(F)ccc3Br)CC2)s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(2-bromo-5-fluorophenoxy)piperidine (15.16 g, 52.5 mmol) in 1,4-dioxane (80 mL) was added N,N-diisopropylethylamine (Hünig's base or DIPEA) (20 mL, 115 mmol) followed by 5-bromo-1,3,4-thiadiazole-2-carbonitrile (10.02 g, 52.7 mmol). The mixture was stirred 1 h at room temperature. The reaction mixture was then poured into saturated aqueous NH4Cl, extracted with EtOAc, washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The crude material was purified by column chromatography on silica gel (eluting with 10-40% EtOAc/hexanes) to afford the desired product as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:57]=[CH:58][CH:59]=1)[CH2:5][N:6]1[C:10]([CH3:11])=[C:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:22]=[CH:23][C:24]([O:32][CH2:33][CH2:34][CH2:35][O:36]CC5C=CC(OC)=CC=5)=[C:25]([NH:27][S:28]([CH3:31])(=[O:30])=[O:29])[CH:26]=4)[CH:19]=3)[N:14]([S:46]([C:49]3[CH:55]=[CH:54][C:52]([CH3:53])=[CH:51][CH:50]=3)(=[O:48])=[O:47])[CH:13]=2)[C:8]([CH3:56])=[N:7]1.C(O)(C(F)(F)F)=O.C1(C)C=CC=CC=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:57]=[CH:58][CH:59]=1)[CH2:5][N:6]1[C:10]([CH3:11])=[C:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:22]=[CH:23][C:24]([O:32][CH2:33][CH2:34][CH2:35][OH:36])=[C:25]([NH:27][S:28]([CH3:31])(=[O:29])=[O:30])[CH:26]=4)[CH:19]=3)[N:14]([S:46]([C:49]3[CH:50]=[CH:51][C:52]([CH3:53])=[CH:54][CH:55]=3)(=[O:47])=[O:48])[CH:13]=2)[C:8]([CH3:56])=[N:7]1
Reactant: COc1ccc(COCCCOc2ccc(-c3cnc4c(c3)c(-c3c(C)nn(Cc5cccc(F)c5)c3C)cn4S(=O)(=O)c3ccc(C)cc3)cc2NS(C)(=O)=O)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)n2cc(-c3c(C)nn(Cc4cccc(F)c4)c3C)c3cc(-c4ccc(OCCCO)c(NS(C)(=O)=O)c4)cnc32)cc1
Temperature: 25 °C

Procedure:
A stirred solution of N-(5-(3-(1-(3-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(3-((4-methoxybenzyl)oxy)prop oxy)phenyl)methanesulfonamide (120 mg, 0.1 mmol), TFA/toluene (169 mg/3 mL) was heated to 80° C. for overnight. TLC showed reaction completion. Reaction mass was cooled to RT and solvents evaporated under reduced pressure. This afforded 60 mg of the crude titled compound. MS: m/z=718.2 (M+1).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:3]=1.[NH:12]1[C:20]2[C:15](=[CH:16][C:17]([CH2:21][N:22]3[CH2:27][CH2:26][CH:25]([C:28]4[CH:29]=[C:30]([NH:34][C:35](=[O:39])[CH:36]([CH3:38])[CH3:37])[CH:31]=[CH:32][CH:33]=4)[CH2:24][CH2:23]3)=[CH:18][CH:19]=2)[CH:14]=[CH:13]1>>[CH3:37][CH:36]([CH3:38])[C:35]([NH:34][C:30]1[CH:31]=[CH:32][CH:33]=[C:28]([CH:25]2[CH2:24][CH2:23][N:22]([CH2:21][C:17]3[CH:16]=[C:15]4[C:20](=[CH:19][CH:18]=3)[N:12]([C:2]3[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:3]=3)[CH:13]=[CH:14]4)[CH2:27][CH2:26]2)[CH:29]=1)=[O:39]
Reactant: FC(F)(F)c1cccc(I)c1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccc4[nH]ccc4c3)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccc4c(ccn4-c4cccc(C(F)(F)F)c4)c3)CC2)c1

Procedure:
Prepared by Procedure C and Scheme Q1, with CuBr in place of Cu, using 1-iodo-3-(trifluoromethyl)benzene and N-{3-[1-(1H-indol-5-ylmethyl)-4-piperidinyl]phenyl}-2-methylpropanamide: 1H NMR (400 MHz, CDCl3) δ 7.80-6.94 (m, 12H), 6.69 (d, 1H, J=3.6 Hz), 3.36 (s, 2H), 3.10-3.00 (m, 2H), 2.58-2.42 (m, 2H), 2.16-2.02 (m, 2H), 1.85-1.75 (m, 4H), 1.25 (d, 6H, J=7.2 Hz); ESMS m/e: 520.2 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8](OS(C(F)(F)F)(=O)=O)=[CH:7][CH:6]=2.C(N(C(C)C)CC)(C)C.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[CH3:71][C:72]1[CH:73]=[CH:74][C:75]2[N:76]([C:78]([SH:81])=[N:79][N:80]=2)[N:77]=1.C>CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([S:81][C:78]1[N:76]3[N:77]=[C:72]([CH3:71])[CH:73]=[CH:74][C:75]3=[N:80][N:79]=1)=[CH:7][CH:6]=2
Reactant: O=S(=O)(Oc1ccc2ncc(Br)cc2c1)C(F)(F)F
Reactant: Cc1ccc2nnc(S)n2n1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc2nnc(Sc3ccc4ncc(Br)cc4c3)n2n1
Temperature: 100 °C
Reaction time: 1 h
Yield: 57.6 %

Procedure:
A solution of trifluoromethanesulfonic acid 3-bromo-quinolin-6-yl ester (973 mg, 2.74 mmol), diisopropylethylamine (0.87 mL, 4.98 mmol) in DMF (9 mL) under nitrogen was degassed by bubbling in nitrogen for 20 min. Tris(dibenzylideneacetone)dipalladium (114 mg, 0.124 mmol, Strem catalyst) and Xantphos (144 mg, 0.249 mmol) were added together in one portion, followed by 6-methyl-[1,2,4]triazolo[4,3-b]pyridazine-3-thiol (450 mg, 2.49 mmol) under a stream of nitrogen. The reaction mixture was stirred at 100° C. for 1 h. The reaction mixture was cooled to room temperature and 500 mg of activated decolorizing charcoal were added. The suspension was stirred for 2.5 h, and the mixture was directly filtered through a plug of silica gel, using DMF as eluent. The solvent was evaporated in vacuo, and the residue was partitioned between water and 10% methanol/dichloromethane. The organic layer was separated and adsorbed on silica gel. Purification by flash chromatography on silica gel using a gradient of 0-5% methanol/dichloromethane afforded 534 mg of 3-bromo-6-(6-methyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylsulfanyl)-quinoline as a cream-colored solid (58% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:18]=[CH:17][C:7]([O:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[CH:6][CH:5]=1)([O-])=O>C(O)C.[Pd]>[N:11]1([CH2:10][CH2:9][O:8][C:7]2[CH:17]=[CH:18][C:4]([NH2:1])=[CH:5][CH:6]=2)[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1
Reactant: O=[N+]([O-])c1ccc(OCCN2CCOCC2)cc1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(OCCN2CCOCC2)cc1

Procedure:
8.1 g (32 mMol) of 4-[2-(4-Nitro-phenoxy)-ethyl]-morpholine is dissolved in 100 mL of ethanol and subjected to catalytic hydration at rt using 681 mg of Pd/C. After filtration trough HYFLO and removal of the solvent under reduced pressure, the crude product is purified by bulb-to-bulb distillation (0.13 mbar: 200° C.) to obtain 4-(2-morpholin-4-yl-ethoxy)-phenylamine. Title compound: ES-MS: 223 [M+H]+; single peak at tR=3 min (System 2).
Reaction SMILES: C([O:3][C:4](=[O:18])[CH2:5][CH:6]1[C:15](=[O:16])[N:14]([CH3:17])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7]1)C.O.[OH-].[Li+:21]>C1COCC1.O>[CH3:17][N:14]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]([CH2:5][C:4]([O-:18])=[O:3])[C:15]1=[O:16].[Li+:21]
Reactant: CCOC(=O)CC1Nc2ccccc2N(C)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CN1C(=O)C(CC(=O)[O-])Nc2ccccc21
Temperature: 0 °C
Reaction time: 6 h

Procedure:
4-Methyl-3-oxo-1,2,3,4-tetrahydro-quinoxalin-2-yl-acetic acid ethyl ester (1.05 g, 4.23 mmol) was dissolved in a mixed solvent THF/H2O (1:1, 39 mL) and cooled to 0° C. in an ice-bath. Lithium hydroxide monohydrate (174 mg, 4.15 mmol) was then added and the resulting mixture was stirred at 0° C. for 6 h (monitored by TLC). Solvent was removed under reduced pressure and the residue was triturated with EtOAc to give the title compound as a gray solid: 1H NMR (D2O) δ=7.03–6.79 (m, 4H), 4.06 (dd, 1H, J=4.5, 9.6 Hz), 3.21 (s, 3H), 2.48 (dd, 1H, J=9.3, 15.6 Hz), 2.33 (dd, 1H, J=4.5, 15.6 Hz).
Reaction SMILES: [C:1]([C:5]1[C:10]([OH:11])=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:8]=[C:7]([CH3:16])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(OC1C(OC(=O)C(F)(F)F)=C(I)C=CC=1)=[O:20].O>C(#N)C.O>[CH3:16][C:7]1([OH:20])[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:10](=[O:11])[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:8]1
Reactant: O=C(Oc1cccc(I)c1OC(=O)C(F)(F)F)C(F)(F)F
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: CC#N
Solvent: O
Product: CC1(O)C=C(C(C)(C)C)C(=O)C(C(C)(C)C)=C1
Temperature: 0 °C

Procedure:
To a solution of 5.0 g of 2,6-di-t-butyl-p-cresol in 90 ml of acetonitrile/water (5/1) was added 10.5 g of bistrifluoroacetoxyiodobenzene with stirring at 0° C. After stirring for 30 minutes, 90 ml of water was added and the reaction solution was extracted three times with 50 ml of dichloromethane and washed four times with 60 ml of water. Organic layers were dried over anhydrous sodium sulfate, then concentrated under reduced pressure and the precipitating crystal was filtered to give a crude crystal, which was recrystallized from hexane to give 4-methyl-4-hydroxy-2,6-di-t-butylcyclohexa-2,5-diene-1-one as a pale yellow solid. The yield was 3.0 g (55%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:13]([CH3:17])[C:14]([OH:16])=O)[CH:5]=[CH:6][C:7]=1[CH2:8][S:9]([CH3:12])(=[O:11])=[O:10].[C:18]([C:22]1[CH:26]=[C:25]([CH2:27][NH2:28])[N:24]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[CH:30]=2)[N:23]=1)([CH3:21])([CH3:20])[CH3:19].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>C1COCC1>[C:18]([C:22]1[CH:26]=[C:25]([CH2:27][NH:28][C:14](=[O:16])[CH:13]([C:4]2[CH:5]=[CH:6][C:7]([CH2:8][S:9]([CH3:12])(=[O:10])=[O:11])=[C:2]([F:1])[CH:3]=2)[CH3:17])[N:24]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[CH:30]=2)[N:23]=1)([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)c1cc(CN)n(-c2cccc(Cl)c2)n1
Reactant: CC(C(=O)O)c1ccc(CS(C)(=O)=O)c(F)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C(=O)NCc1cc(C(C)(C)C)nn1-c1cccc(Cl)c1)c1ccc(CS(C)(=O)=O)c(F)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 80.4 %

Procedure:
To a stirred solution of 2-(3-fluoro-4-(methylsulfonylmethyl)phenyl)propanoic acid (60 mg, 0.231 mmol) and (3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methanamine (60 mg, 0.231 mmol) in THF (1.8 mL) were added O-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluorborat (73 mg, 0.231 mmol), 1-hydroxybenzotriazole (30 mg, 0.231 mmol) and N-ethyldiisopropylamine (0.078 mL, 0.462 mmol). The reaction mixture was stirred for 48 h at room temperature, concentrated in vacuo and the residue was purified by CC (eluent: ethyl acetate/cyclohexane (3:2)) to give N-[[5-tert-butyl-2-(3-chlorophenyl)-2H-pyrazol-3-yl]-methyl]-2-[3-fluoro-4-(methylsulfonyl-methyl)-phenyl]-propionamide (94 mg, 80%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[Sn](Cl)(Cl)(Cl)Cl.[C:23](Cl)(=[O:25])[CH3:24].O>C(Cl)Cl>[C:23]([C:8]1[C:7]([O:9][CH3:10])=[CH:6][C:5]([NH:11][C:12](=[O:17])[C:13]([F:14])([F:16])[F:15])=[CH:4][C:3]=1[O:2][CH3:1])(=[O:25])[CH3:24]
Reactant: COc1cc(NC(=O)C(F)(F)F)cc(OC)c1
Reactant: CC(=O)Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: COc1cc(NC(=O)C(F)(F)F)cc(OC)c1C(C)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 12.7 %

Procedure:
To a solution of N-(3,5-dimethoxyphenyl)-2,2,2-trifluoroacetamide (31.8 g, 130 mmol) in anhydrous methylene chloride (450 mL), cooled in an ice bath, is added a solution of tin (IV) chloride (29.9 mL, 260 mmol dissolved in 30 mL anhydrous methylene chloride) dropwise over 10 minutes. Acetyl chloride (9.1 mL, 130 mmol) is added slowly, maintaining the temperature of the reaction below 5° C. After stirring 3 hours at room temperature, the reaction is cooled in an ice bath. Water (300 mL) is added, maintaining the temperature of the reaction below 25° C., and the reaction is stirred at room temperature for 18 hours. The reaction mixture is extracted with methylene chloride, and the organic layer is separated, washed with water, dried, filtered and evaporated under reduced pressure. The residue is purified by silica gel column chromatography eluting with 20% to 30% hexanes/ethyl acetate to yield N-(4-acetyl-3,5-dimethoxyphenyl)-2,2,2-trifluoroacetamide (4.8 g, 13%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH:9][CH2:10][CH:11]([F:13])[F:12])=[CH:4][C:3]=1[F:14].[CH2:15]1[C:20](=[O:21])[O:19][CH2:18][C:16]1=O>C(O)(=O)C>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]([CH2:10][CH:11]([F:13])[F:12])[C:16]2[CH2:18][O:19][C:20](=[O:21])[CH:15]=2)=[CH:4][C:3]=1[F:14]
Reactant: O=C1COC(=O)C1
Reactant: Fc1cc(CNCC(F)F)cnc1Cl
Solvent: CC(=O)O
Product: O=C1C=C(N(Cc2cnc(Cl)c(F)c2)CC(F)F)CO1
Temperature: 25 °C
Reaction time: 6 h
Yield: 73.1 %

Procedure:
317 mg (1.41 mmol) of N-[(6-chloro-5-fluoropyridin-3-yl)methyl]-2,2-difluoroethylamine (III-1) are added to 173 mg (1.69 mmol) of tetronic acid in 400 μA of acetic acid, and the mixture is stirred at room temperature for 6 hours. The reaction mixture is concentrated under reduced pressure, and the residue is then partitioned between dichloromethane and water. The aqueous phase is extracted two more times with dichloromethane. The combined organic phases are washed with 1 N aqueous sodium hydroxide solution and concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel (silica gel 60-Merck, particle size: 0.04 to 0.063 mm) using the mobile phase mixture ethyl acetate:cyclohexane (3:1) gives 316 mg (64% of theory) of 4-[[(6-chloro-5-fluoropyridin-3-yl)methyl](2,2-difluoroethyl)amino]furan-2(5H)-one.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]2[N:7]=[C:8]([NH:10][C@H:11]3[CH2:16][CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12]3)[S:9][C:5]=2[CH:4]=1.Cl.O1CCOCC1>CO.O1CCOCC1>[CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]2[N:7]=[C:8]([NH:10][C@H:11]3[CH2:16][CH2:15][CH2:14][NH:13][CH2:12]3)[S:9][C:5]=2[CH:4]=1
Reactant: COc1ccc2nc(N[C@H]3CCCN(C(=O)OC(C)(C)C)C3)sc2c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: COc1ccc2nc(N[C@H]3CCCNC3)sc2c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of (S)-tert-butyl 3-(6-methoxybenzo[d]thiazol-2-ylamino)piperidine-1-carboxylate (3.35 g, 9.22 mmol) in methanol/dioxane (3 ml/3 ml) was added slowly 4M HCl in dioxane (60 ml, 240 mmol) [Caution: gas development!]. The reaction mixture was stirred 2.5 hours at ambient temperature and concentrated in vacuo in order to remove methanol and half of dioaxane. The residue was suspended in diethylether (50 ml). The solids were filtered off, washed with diethylether (50 ml) and dried in vacuo to give (S)-6-methoxy-N-(piperidin-3-yl)benzo[d]thiazol-2-amine as its hydrochloride salt as white solid. Yield: 4.29 g. ES/MS m/z 264.1 (MH+), Rt=1.62 min.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH:8]([NH2:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:6]([N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:5]=[CH:4][CH:3]=1.[CH2:22]([O:24][C:25]1[CH:26]=[C:27]([CH2:36][C:37](O)=[O:38])[CH:28]=[CH:29][C:30]=1[C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH3:23]>>[CH2:22]([O:24][C:25]1[CH:26]=[C:27]([CH2:36][C:37]([NH:15][CH:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:7]2[C:2]([CH3:1])=[CH:3][CH:4]=[CH:5][C:6]=2[N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:38])[CH:28]=[CH:29][C:30]=1[C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH3:23]
Reactant: Cc1cccc(N2CCCCC2)c1C(N)c1ccccc1
Reactant: CCOC(=O)c1ccc(CC(=O)O)cc1OCC
Product: CCOC(=O)c1ccc(CC(=O)NC(c2ccccc2)c2c(C)cccc2N2CCCCC2)cc1OCC

Procedure:
Prepared from 6-methyl-α-phenyl-2-piperidino-benzylamine and 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid.
Reaction SMILES: C[Si](C)(C)[C:3]1[S:7][C:6]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:5][C:4]=1[O:12][CH3:13].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH3:13][O:12][C:4]1[CH:5]=[C:6]([S:8]([NH2:11])(=[O:10])=[O:9])[S:7][CH:3]=1
Reactant: COc1cc(S(N)(=O)=O)sc1[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COc1csc(S(N)(=O)=O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.7 %

Procedure:
To a solution of 5-trimethylsilyl-4-methoxythiophene-2-sulfonamide (770 mg, 2.90 mmol) in THF (10 mL) is added a solution of tetra-butylammonium fluoride (17.4 mL of 1 M in THF, 17.4 mmol). The reaction mixture is stirred at room temperature for 2 hr. The THF is removed under reduced pressure. The residue is dissolved in EtOAc (200 mL). The organic layer is washed with brine then dried (Na2SO4), filtered and concentrated in vacuo. The crude product is chromatographed on silica gel, eluting with Hex:EtOAc (3:1) to afford the title compound (480 mg, 86%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl.[CH2:8]([N:11]([CH2:15][CH2:16][C:17]1[CH:18]=[CH:19][C:20]2[O:25][CH2:24][CH2:23][NH:22][C:21]=2[CH:26]=1)[CH2:12][CH2:13][CH3:14])[CH2:9][CH3:10].[Cl:27][CH2:28][C:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][CH:30]=1.O>CN(C=O)C>[ClH:27].[CH2:8]([N:11]([CH2:15][CH2:16][C:17]1[CH:18]=[CH:19][C:20]2[O:25][CH2:24][CH2:23][N:22]([CH2:28][C:29]3[C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH:32]=[CH:31][CH:30]=3)[C:21]=2[CH:26]=1)[CH2:12][CH2:13][CH3:14])[CH2:9][CH3:10]
Reactant: CCCN(CCC)CCc1ccc2c(c1)NCCO2
Reactant: ClCc1cccc2ccccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCN(CCC)CCc1ccc2c(c1)N(Cc1cccc3ccccc13)CCO2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Potassium carbonate (316 mg, 2.29 mmol) was added to a solution of 3,4-dihydro-6-[2-(N,N-dipropylamino)ethyl]-2H-1,4-benzoxazine hydrochloride (200 mg, 0.76 mmol) obtained in Example 134 and 1-chloromethyl naphthalene (400 mg, 2.29 mmol) in DMF (15 ml). After the reaction solution was stirred at room temperature for 2 hours, water was added to the reaction solution which was then extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate and concentrated. The residues were purified by silica gel column chromatography (developing solvent; hexane:ethyl acetate=3:1), treated with 4 N hydrochloric acid in ethyl acetate and crystallized from acetone-pentane, whereby the title compound (80 mg) was obtained as crystals with a mp of 177 to 178° C.