Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].[Cl:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]1[C:21]([N+:22]([O-])=O)=[C:20]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:19]=[C:18]([CH3:32])[C:17]=1[CH3:33]>O.C(O)C>[Cl:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]1[C:17]([CH3:33])=[C:18]([CH3:32])[N:19]=[C:20]([O:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:21]=1[NH2:22]
Reactant: Cc1nc(Oc2ccccc2)c([N+](=O)[O-])c(NCCCCCCl)c1C
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1nc(Oc2ccccc2)c(N)c(NCCCCCCl)c1C
Reaction time: 5 h
Yield: 99.9 %

Procedure:
A solution of sodium dithionite (90.5 g, 520 mmol), available as approximately 85% pure sodium hydrosulfite, in water (200 mL) was added to a solution of (5-chloropentyl)-(2,3-dimethyl-5-nitro-6-phenoxy-pyridin-4-yl)amine (37.8 g, 104 mmol) in ethanol (575 mL), and the mixture was stirred rapidly for five hours. The mixture did not become homogeneous, and additional ethanol (200 mL) was added. The mixture remained heterogeneous and was separated into two batches. A solution of sodium dithionite (40 g, 230 mmol) in water (150 mL) was partitioned evenly between the two batches, and the reactions were stirred for an additional hour. An analysis by TLC indicated that the reactions were complete. A white solid was removed from the reaction mixtures by filtration and was washed with methanol. The solvents were removed under reduced pressure, and the residue was partitioned between dichloromethane (400 mL) and water (100 mL). Saturated aqueous sodium bicarbonate was added to the aqueous layer until it was basic, and the resulting solution was extracted with dichloromethane (2×100 mL). The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide 34.7 g of N4-(5-chloropentyl)-5,6-dimethyl-2-phenoxypyridine-3,4-diamine as an orange-red liquid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]=[CH:7][C:6]([C:14]#[N:15])=[C:5]2[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Br:23])[CH:18]=1.CN1CCOCC1.[C:31](Cl)(=[O:34])[CH:32]=[CH2:33]>O1CCCC1.C(OCC)(=O)C>[Br:23][C:19]1[CH:18]=[C:17]([NH:16][C:5]2[C:4]3[C:9](=[CH:10][C:11]([O:12][CH3:13])=[C:2]([NH:1][C:31](=[O:34])[CH:32]=[CH2:33])[CH:3]=3)[N:8]=[CH:7][C:6]=2[C:14]#[N:15])[CH:22]=[CH:21][CH:20]=1
Reactant: C=CC(=O)Cl
Reactant: COc1cc2ncc(C#N)c(Nc3cccc(Br)c3)c2cc1N
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Product: C=CC(=O)Nc1cc2c(Nc3cccc(Br)c3)c(C#N)cnc2cc1OC
Reaction time: 1 h
Yield: 29.1 %

Procedure:
To a solution of 1.5 g (4.06 mmol) of 6-Amino-4-[(3-bromophenyl)amino]-7-methoxy-3-quinolinecarbonitrile and 0.45 ml of N-methylmorpholine in 30 ml of tetrahydrofuran was added at 0° C., under nitrogen, with stirring, 0.42 g (4.7 mmol) of acryloyl chloride of a 15 minute period. After 1 hour at 0° C., the solution was diluted with 200 ml ethyl acetate. The mixture was washed with saturated sodium bicarbonate solution and then dried over magnesium sulfate. The solvent was removed. The residue was chromatographed on silica gel eluted with chloroform-ethyl acetate mixtures to give 0.5 g of the tide compound as a light yellow solid powder: mass spectrum (electrospray, m/e): M+H 423.1,425.1
Reaction SMILES: [C:1]([C:3]1[CH:15]=[C:14]2[C:6]([C:7]3[C:8](=[O:25])[C:9]4[CH:21]=[CH:20][C:19]([C:22](O)=[O:23])=[CH:18][C:10]=4[C:11]([CH3:17])([CH3:16])[C:12]=3[NH:13]2)=[CH:5][CH:4]=1)#[N:2].[O:26]1[CH2:29][CH:28]([NH2:30])[CH2:27]1>>[O:26]1[CH2:29][CH:28]([NH:30][C:22]([C:19]2[CH:20]=[CH:21][C:9]3[C:8](=[O:25])[C:7]4[C:6]5[C:14](=[CH:15][C:3]([C:1]#[N:2])=[CH:4][CH:5]=5)[NH:13][C:12]=4[C:11]([CH3:16])([CH3:17])[C:10]=3[CH:18]=2)=[O:23])[CH2:27]1
Reactant: CC1(C)c2cc(C(=O)O)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Reactant: NC1COC1
Product: CC1(C)c2cc(C(=O)NC3COC3)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21

Procedure:
Under the same conditions as the method for synthesizing Compound B3-15, the title compound was prepared from Compound B2-28 and oxetan-3-yl amine.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].CC[N:14](C(C)C)[CH:15]([CH3:17])[CH3:16].C(N)(C)C>C(#N)C>[F:8][C:6]1[CH:5]=[CH:4][C:3]([N+:9]([O-:11])=[O:10])=[C:2]([NH:14][CH:15]([CH3:17])[CH3:16])[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: CCN(C(C)C)C(C)C
Solvent: CC(C)N
Solvent: CC#N
Product: CC(C)Nc1cc(F)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.3 %

Procedure:
2,4-Difluoro-1-nitrobenzene (2.00 g, 12.57 mmol) was dissolved in acetonitrile (20 mL) and DIPEA (2.2 mL, 12.57 mmol) added, followed by isopropylamine (1.07 mL, 12.57 mmol). The bright yellow mixture was stirred at RT overnight. The resultant mixture was concentrated in vacuo and the residue purified by column chromatography (silica gel, gradient 0-5% EtOAc in cyclohexane) to afford the title compound as a yellow gum (2.1 g, 99%). Contaminated with some unreacted 2,4-difluoro-1-nitrobenzene, but used in the next step without any further purification. 1H NMR (CDCl3, 400 MHz): δ 8.20 (1H, dd, J=9.53, 6.21 Hz), 6.48 (1H, dd, J=11.71, 2.63 Hz), 6.33 (1H, m), 3.80-3.64 (1H, m), 1.33 (6H, d, J=6.36 Hz)
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([CH3:22])[C:5]2=[C:6]([CH2:8][C@H:9]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=3[Br:21])[NH:10]/[C:11]/2=[N:12]\[OH:13])[N:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH:30]1[CH2:34][CH2:33][O:32][C:31]1=[O:35]>CN(C=O)C>[NH2:1][C:2]1[N:3]=[C:4]([CH3:22])[C:5]2=[C:6]([CH2:8][C@H:9]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=3[Br:21])[NH:10]/[C:11]/2=[N:12]\[O:13][CH:30]2[CH2:34][CH2:33][O:32][C:31]2=[O:35])[N:7]=1
Reactant: Cc1nc(N)nc2c1/C(=N/O)N[C@@H](c1ccc(F)cc1Br)C2
Reactant: O=C1OCCC1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1nc(N)nc2c1/C(=N/OC1CCOC1=O)N[C@@H](c1ccc(F)cc1Br)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.7 %

Procedure:
To a solution of (R,Z)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one oxime (0.3 mmol, 109 mg) in DMF (2.0 mL) was added Cs2CO3 (0.45 mmol, 146 mg) and 3-bromodihydrofuran-2(3H)-one (0.36 mmol, 33.6 μL). The reaction mixture was stirred overnight at r.t. and LCMS shows completion of the reaction. The reaction mixture was poured on crushed ice and the resultant solid was filtered and dried to afford 3-((Z)—((R)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)dihydrofuran-2(3H)-one (105 mg, 78%) as off white solid. MS (ES). [M+H] calculated for C18H18BrFN5O3, 450.05. found 450.30.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:21]=[CH:20][C:12]([C:13]([CH:15]([C:18]#[N:19])[C:16]#[N:17])=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22](=O)(O)[O-].[Na+].S(OC)(OC)(=O)=O>O1CCOCC1.O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([O:14][CH3:22])=[C:15]([C:18]#[N:19])[C:16]#[N:17])=[CH:20][CH:21]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])O
Reactant: N#CC(C#N)C(=O)c1ccc(OCc2ccccc2)cc1
Agent: [Na+]
Solvent: O
Solvent: COS(=O)(=O)OC
Solvent: C1COCCO1
Product: COC(=C(C#N)C#N)c1ccc(OCc2ccccc2)cc1
Yield: 79.7 %

Procedure:
Compound 31B (3.7 g, 13.39 mmol) was dissolved in 1,4-dioxane (30 mL) and water (5 mL). To this solution was added to sodium bicarbonate (9.0 g, 107 mmol) portionwise to control the gas formation. To the resulting suspension was added dimethyl sulfate (8.96 mL, 94 mmol). The reaction was heated under reflux for 2 hours. The reaction mixture was concentrated, and partitioned between water and EtOAc. The aqueous layer was extracted with additional EtOAc. The combined organic layers were washed with brine, dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with 7:3/hexanes: EtOAc to provide 3.1 g of the desired product: 1H NMR (DMSO-d6): δ 7.64-7.68 (m, 2H), 7.34-7.69 (m, 5H), 7.22-7.26 (m, 2H), 5.22 (s, 2H), 3.92 (s, 3H). MS (DCI(+)): m/z 308 (M+NH4).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1.C(N(CC)CC)C.[OH:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[CH2:27][C@H:26]([NH:31][S:32]([CH:35]([CH3:37])[CH3:36])(=[O:34])=[O:33])[CH2:25]2>C(Cl)Cl.O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=1)[O:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[CH2:27][C@H:26]([NH:31][S:32]([CH:35]([CH3:37])[CH3:36])(=[O:34])=[O:33])[CH2:25]2
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: CC(C)S(=O)(=O)N[C@H]1Cc2ccc(O)cc2C1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)S(=O)(=O)N[C@H]1Cc2ccc(Oc3cccc(C(F)(F)F)c3)cc2C1

Procedure:
To a mixture of the 3-trifluoromethyphenyl boronic acid (0.274 mmol, 52 mg), copper (II) acetate (0.137 mmol, 25 mg), triethylamine (0.685 mmol, 96 μL) and 4A molecular sieves (100 mg) in DCM (1 mL) was added (S)-N-(5-hydroxy-2,3-dihydro-1H-inden-2-yl)propane-2-sulfonamide (0.137 mmol, 35 mg) and the resultant mixture stirred at room temperature overnight. The reaction mixture was diluted with DCM (1 mL) before water (0.5 mL) was added and the organic layers separated using hydrophobic frits. The aqueous was extracted with a further 1 mL DCM, and the combined organics concentrated using to dryness. The residue was taken up in DMSO and purified by preparative HPLC to give the title compound as a clear film (21.9 mg, 40%). MS (ESI): m/z [M+H]+ 400.0
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[CH:7]=[CH2:8])([CH3:4])([CH3:3])[CH3:2].[OH:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][OH:19]>C1COCC1>[C:1]([O:5][C:6](=[O:9])[CH2:7][CH2:8][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][OH:19])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: OCCOCCOCCO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CCOCCOCCOCCO
Reaction time: 8 h

Procedure:
Na metal (catalytic) was added to a stirring solution of acrylic acid tert-butyl ester (6.7 mL, 46 mmol), and 2-[2-(2-hydroxy-ethoxy)-ethoxy]-ethanol (20.7 g, 138 mmol) in THF (100 mL) at 0° C. and the mixture was stirred overnight. Solvent was removed and the remaining oil dissolved in EtOAc (100 mL). The organic layer was washed with water (3×50 mL), and dried over Na2SO4 and the solvent removed in vacuo to give an oil which corresponds to the title compound that would be used as is for the next step. (M+1)=279.
Reaction SMILES: [Mg].[CH:2]1(Br)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[C:9]([C:17]([O:19][C:20]([CH3:24])([CH3:23])[C:21]#[CH:22])=[O:18])(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Cl-].[NH4+]>C1COCC1.O>[CH:2]1([C:9]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)([OH:16])[C:17]([O:19][C:20]([CH3:24])([CH3:23])[C:21]#[CH:22])=[O:18])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: BrC1CCCCC1
Reactant: C#CC(C)(C)OC(=O)C(=O)c1ccccc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: C#CC(C)(C)OC(=O)C(O)(c1ccccc1)C1CCCCC1
Reaction time: 18 h

Procedure:
A Grignard reagent, prepared from 3.38 g magnesium and 2.27 g cyclohexyl bromide in anhydrous THF in the usual way, was added dropwise under a nitrogen gas stream to a solution of 1,1-dimethyl-2-propynyl benzoylformate in anyhdrous THF under ice cooling, and stirring was continued for 18 hours under cooling with water. A solution of 7.5 g ammonium chloride in 30 ml water was then added under ice cooling. The separated organic layer was collected, washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The oily residue was purified by silica gel column chromatography (Wako Gel C-200; 1:15 mixture of ethyl acetate and n-hexane), giving 17.6 g of the objective compound as oil.
Reaction SMILES: [OH:1][CH:2]([CH3:9])[CH2:3][NH:4][C:5](=[O:8])[O:6][CH3:7].[Br:10][CH:11]([CH3:15])[C:12](Br)=[O:13]>>[Br:10][CH:11]([CH3:15])[C:12]([O:1][CH:2]([CH3:9])[CH2:3][NH:4][C:5](=[O:8])[O:6][CH3:7])=[O:13]
Reactant: CC(Br)C(=O)Br
Reactant: COC(=O)NCC(C)O
Product: COC(=O)NCC(C)OC(=O)C(C)Br

Procedure:
by using methyl 2-hydroxypropylcarbamate and 2-bromopropionyl bromide there is obtained methyl 2-(2-bromopropionyloxy)-propylcarbamate, nD20 1.4764;
Reaction SMILES: C1(C2C=CC(CNCCC3C=CC(F)=C(C(F)(F)F)C=3)=CC=2)CC1.[C:25]12([CH2:37][CH2:36]1)[C:33]1[C:28](=[CH:29][C:30]([CH:34]=O)=[CH:31][CH:32]=1)[CH2:27][CH2:26]2.[Cl:38][C:39]1[CH:40]=[C:41]([CH2:46][CH2:47][NH2:48])[CH:42]=[CH:43][C:44]=1[Cl:45].[BH4-].[Na+]>>[Cl:38][C:39]1[CH:40]=[C:41]([CH2:46][CH2:47][NH:48][CH2:34][C:30]2[CH:29]=[C:28]3[C:33](=[CH:32][CH:31]=2)[C:25]2([CH2:37][CH2:36]2)[CH2:26][CH2:27]3)[CH:42]=[CH:43][C:44]=1[Cl:45]
Reactant: O=Cc1ccc2c(c1)CCC21CC1
Reactant: NCCc1ccc(Cl)c(Cl)c1
Agent: Fc1ccc(CCNCc2ccc(C3CC3)cc2)cc1C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Product: Clc1ccc(CCNCc2ccc3c(c2)CCC32CC2)cc1Cl
Yield: 92.2 %

Procedure:
The title compound was synthesized in analogy to (4-cyclopropylbenzyl)-[2-(4-fluoro-3-trifluoromethylphenyl)-ethyl]-amine (described in example S53) using 2′,3′-dihydro-spiro-[cyclopropane-1,1′-[1H]indene]-5′-carboxaldehyde (62 mg, 0.36 mmol), 2-(3,4-dichloro-phenyl)-ethylamine (68 mg, 0.36 mmol) and sodium borohydride (20 mg, 0.54 mmol). The desired product (115 mg, 92%) was isolated without further purification as a colorless oil. MS (ISP) 346.2 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:19])[N:8]([CH3:18])[C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[C:11]([CH3:17])[N:10]=2)=[O:5])[CH3:2].[CH3:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C(=O)([O-])[O-].[Na+].[Na+].Cl>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:19])[N:8]([CH3:18])[C:9]2[C:14]([C:15]=1[N:24]1[CH2:25][CH2:26][N:21]([CH3:20])[CH2:22][CH2:23]1)=[CH:13][CH:12]=[C:11]([CH3:17])[N:10]=2)=[O:5])[CH3:2]
Reactant: CN1CCNCC1
Reactant: CCOC(=O)c1c(Cl)c2ccc(C)nc2n(C)c1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1c(N2CCN(C)CC2)c2ccc(C)nc2n(C)c1=O

Procedure:
A stirred mixture of 5.3 g. (0.019 mole) of 4-chloro-1,7-dimethyl-1,2-dihydro-2-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester, 1.9 g. (0.019 mole) of N-methylpiperazine and 1.9 g. (0.019 mole) of sodium carbonate in 100 ml. of ethanol was heated under reflux for 5 hours. The mixture was filtered and the filtrate was evaporated in a rotary evaporator. The residue was triturated with 150 ml. of 10% aqueous sodium carbonate and was extracted with 150 ml. of ether. The ether layer was dried over magnesium sulfate, filtered and was diluted with 30 ml. of ethanol. This solution was acidified with an ethereal hydrochloric acid solution. The precipitate which formed was collected and was recrystallized from ethanol to afford 1.0 g. of product as the hydrochloride, hemihydrate, m.p. 278°-280° C. dec.
Reaction SMILES: C(O)(=O)C.[C:5]([O:9][C:10]([N:12]1[CH2:17][C@H:16]([CH2:18][N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[N:15](CC2C=CC=CC=2)[CH2:14][C@H:13]1[CH3:32])=[O:11])([CH3:8])([CH3:7])[CH3:6]>CCO.[Pd]>[C:5]([O:9][C:10]([N:12]1[CH2:17][C@H:16]([CH2:18][N:19]2[CH2:20][CH2:21][O:22][CH2:23][CH2:24]2)[NH:15][CH2:14][C@H:13]1[CH3:32])=[O:11])([CH3:8])([CH3:6])[CH3:7]
Reactant: C[C@@H]1CN(Cc2ccccc2)[C@@H](CN2CCOCC2)CN1C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: C[C@@H]1CN[C@@H](CN2CCOCC2)CN1C(=O)OC(C)(C)C
Reaction time: 3 h
Yield: 95 %

Procedure:
Acetic acid (30.0 mL) and Pd/C (10%, 6.0 g) were added to a solution of (2R,5S)-4-benzyl-2-methyl-5-morpholin-4-ylmethyl-piperazine-1-carboxylic acid tert-butyl ester (9.0 g, 23.1 mmol) in EtOH (240 mL) and the resulting mixture was hydrogenated at 1 bar for 3 h. The catalyst was removed by filtration and the solvent was removed in vacuo. The residue was dissolved in DCM (150 mL), the organic solution was washed with saturated aqueous NaHCO3 (150 mL), water (150 mL), dried (MgSO4) and evaporated to give the title compound as a colourless gum (6.57 g, 95%). 1H NMR (CDCl3): 4.32-3.90 (1H, m), 3.77-3.64 (5H, m), 3.30 (1H, dd), 3.16-2.82 (2H, m), 2.67 (1H, dd), 2.59-2.49 (2H, m), 2.47-2.30 (2H, m), 2.21 (1H, dd), 2.17-2.07 (2H, m), 1.47 (9H, s), 1.27 (3H, d).
Reaction SMILES: CO[C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1[C:11]1[O:12]CC(C)(C)N=1.Br[CH2:19][CH2:20][C:21]1[CH:25]=[CH:24][S:23][CH:22]=1.[Mg]>>[CH3:10][O:9][C:8]1[C:3]([CH2:19][CH2:20][C:21]2[CH:25]=[CH:24][S:23][CH:22]=2)=[C:4]([CH2:11][OH:12])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cccc(C2=NC(C)(C)CO2)c1OC
Reactant: BrCCc1ccsc1
Agent: [Mg]
Product: COc1cccc(CO)c1CCc1ccsc1

Procedure:
Using the method of example 44, steps 1-3, with 2-(2,3-dimethoxyphenyl)-4,4-dimethyl-2-oxazoline (J. Org. Chem. 43, 1372 (1978) and the Grignard reagent prepared from 1-bromo-2-(3-thiophenyl)ethane and magnesium the title compound was prepared and the structure confirmed by NMR spectroscopy. 4. 3-[2-(2-Bromomethyl-6-methoxy-phenyl)-ethyl]-thiophene
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2F)(=[O:19])=[O:18])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].[NH:33]1[CH:37]=[CH:36][N:35]=[CH:34]1>CS(C)=O.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N:33]2[CH:37]=[CH:36][N:35]=[CH:34]2)(=[O:18])=[O:19])=[CH:13][CH:12]=1
Reactant: O=S(=O)(c1ccc(CCc2ccc(F)cc2F)cc1)c1ccccc1F
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: O=S(=O)(c1ccc(CCc2ccc(F)cc2F)cc1)c1ccccc1-n1ccnc1
Temperature: 150 °C
Yield: 77 %

Procedure:
2,4-Difluoro-1-(2-{4-[(2-fluorophenyl)sulfonyl]phenyl}ethyl)benzene (Example 124, 100 mg, 0.26 mmol), potassium carbonate (126 mg, 0.39 mmol) and imidazole (26 mg, 0.39 mmol) were combined in dimethylsulfoxide (1.3 mL) and heated in a microwave reactor at 150° C. for 20 minutes. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over Na2SO4 and evaporated in vacuo. The residue was purified by flash column chromatography on silica, eluting with 5% ethanol/ethyl acetate to yield the title compound as a white solid (85 mg, 77%). δH (400 MHz, d6 DMSO): 8.31-8.29 (1H, m), 7.87-7.79 (2H, m), 7.41-7.39 (2H, m), 7.31-7.23 (5H, m), 7.16-7.12 (1H, m), 6.99-6.95 (1H, m), 6.88 (1H, t, J=1.1 Hz), 6.85 (1H, t, J=1.3 Hz), 2.92-2.84 (4H, m). m/z (ES+) 425 [MH+].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](I)=[N:6][CH:7]=1.[F:9][C:10]1[CH:11]=[C:12](B(O)O)[CH:13]=[CH:14][C:15]=1[O:16][CH3:17].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[Br:1][C:2]1[CH:3]=[N:4][C:5]([C:12]2[CH:13]=[CH:14][C:15]([O:16][CH3:17])=[C:10]([F:9])[CH:11]=2)=[N:6][CH:7]=1
Reactant: Brc1cnc(I)nc1
Reactant: COc1ccc(B(O)O)cc1F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(-c2ncc(Br)cn2)cc1F
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a mixture of 5-bromo-2-iodopyrimidine (3.0 g, 10 mmol) and 3-fluoro-4-methoxyphenylboronic acid (2.0 g, 12 mmol) in dioxane (15 mL) and H2O (5 mL) was added Pd(dppf)Cl2—CH2Cl2 (0.1 g, 0.12 mmol) and Na2CO3 (2.0 g, 19 mmol) under argon. The mixture was stirred at RT for 20 h and was further heated at 80° C. for 20 h. The mixture was cooled to RT and was extracted with EtOAc. The organic layer was washed with H2O, NH4Cl (sat), dried (Na2SO4), and concentrated. The crude residue was partitioned in 1:1 ether-CH2Cl2 and filtered to provide the title compound as a flake. The filtrate was concentrated and was triturated with MeOH to provide a second batch of product solid. MS (ESI pos. ion) m/z: 283, 285. Calc'd for C11H8BrFN2O: 281.98.
Reaction SMILES: [O:1]1[C:19]2[C:4](=[CH:5][C:6]3[CH:11]([CH2:12][C:13]([O:15]CC)=[O:14])[O:10][CH2:9][CH2:8][C:7]=3[CH:18]=2)[O:3][CH2:2]1.[OH-].[Na+]>C(O)C.O>[O:1]1[C:19]2[C:4](=[CH:5][C:6]3[CH:11]([CH2:12][C:13]([OH:15])=[O:14])[O:10][CH2:9][CH2:8][C:7]=3[CH:18]=2)[O:3][CH2:2]1
Reactant: CCOC(=O)CC1OCCc2cc3c(cc21)OCO3
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)CC1OCCc2cc3c(cc21)OCO3
Temperature: 60 °C
Yield: 96.1 %

Procedure:
0.78 g of ethyl (7,8-dihydro-5H-1,3-dioxolo[4,5-g]-[2]benzopyran-5-yl)acetate was dissolved in 20 ml of ethanol. A solution of 0.35 g of sodium hydroxide in 4 ml of water was added thereto and the mixture was stirred under heating at 60° C. The solvent was distilled off and water was added to the residue. The mixture was washed with ethyl acetate and acidified with 1N hydrochloric acid. After extraction with chloroform, the extract was washed with a saturated aqueous common salt solution and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off and the residue was subjected to silica gel column chromatography (chloroform) to obtain 0.67 g of the intended compound in the form of colorless crystals.
Reaction SMILES: [CH3:1][S:2]([C:4]1[N:8]2[C:9](=[O:21])[C:10]3[NH:11][CH:12]=[N:13][C:14]=3[N:15]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:7]2=[N:6][N:5]=1)=[O:3].CS(C1N2C(=O)C3NC=NC=3N(CCCCC)C2=NN=1)(=O)=O.[Br:44]N1C(=O)CCC1=O>C1COCC1.O>[Br:44][C:12]1[NH:11][C:10]2[C:9](=[O:21])[N:8]3[C:4]([S:2]([CH3:1])=[O:3])=[N:5][N:6]=[C:7]3[N:15]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:14]=2[N:13]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCCCn1c2nc[nH]c2c(=O)n2c(S(C)=O)nnc12
Agent: CCCCCn1c2nc[nH]c2c(=O)n2c(S(C)(=O)=O)nnc12
Solvent: C1CCOC1
Solvent: O
Product: CCCCCn1c2nc(Br)[nH]c2c(=O)n2c(S(C)=O)nnc12
Temperature: 70 °C
Reaction time: 3 h

Procedure:
To a mixture of 3-(methylsulfinyl)-9-pentyl-6,9-dihydro-5h-[1,2,4]triazolo[4,3-a]purin-5-one and 3-(methylsulfonyl)-9-pentyl-6,9-dihydro-5h-[1,2,4]triazolo[4,3-a]purin-5-one (3:2, 125 mg, 0.40 mmol) in THF (3 mL) was added N-bromosuccinimide (82.3 mg, 0.462 mmol). The mixture was stirred at 70° C. for 3 hours. The reaction was diluted with water and extracted with ethyl acetate three times, dried with sodium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by Prep LCMS to yield the desired product. LCMS calculated for: C12H15BrN6O2S (M+H) 387.0; found: 387.0, 389.0.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].O1CCCC1.[F:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][C:20]=1[O:21][CH3:22])[CH:17]([CH2:23][CH2:24][NH2:25])[CH2:16][CH2:15]2.C(N(CC)CC)C>O>[F:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][C:20]=1[O:21][CH3:22])[CH:17]([CH2:23][CH2:24][NH:25][C:1](=[O:4])[CH2:2][CH3:3])[CH2:16][CH2:15]2
Reactant: COc1cc2c(cc1F)CCC2CCN
Reactant: CCC(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCC(=O)NCCC1CCc2cc(F)c(OC)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.2 %

Procedure:
Propionyl chloride (2.5 g, 27.0 mmols) was gradually and dropwise added to a tetrahydrofuran (20 ml) solution containing 2-(5-fluoro-6-methoxyindan-1-yl)ethylamine (4.35 g, 20.8 mmols) and triethylamine (4.21 g, 41.6 mmols) while cooling with ice. After having been stirred at room temperature for 2 hours, the reaction mixture was poured into water, and the organic substance was extracted out with ethyl acetate. The extract was washed with a saturated saline solution and water and then dried with anhydrous magnesium sulfate, and the solvent was removed through distillation under reduced pressure. The resulting residue was purified through silica-gel column chromatography (ethyl acetate/hexane=90/10) to obtain 4.87 g (yield: 88%) of the target compound.
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([N:15]1[CH2:20][CH2:19][CH2:18][C:17]([CH3:24])([C:21]([OH:23])=[O:22])[CH2:16]1)=O)(C)(C)C>C(Cl)Cl>[CH3:24][C:17]1([C:21]([OH:23])=[O:22])[CH2:18][CH2:19][CH2:20][NH:15][CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CCCC(C)(C(=O)O)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C(=O)O)CCCNC1
Reaction time: 3 h

Procedure:
TFA was added to a solution of 1-(tert-butoxycarbonyl)-3-methylpiperidine-3-carboxylic acid (1 eq) in CH2Cl2 (0.5 M). After stirring for 3 h at it the reaction mixture was concentrated in vacuo and azeotroped once with toluene to give 3-methylpiperidine-3-carboxylic acid (TFA salt). The crude product was used for the next step without further purification.