Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N:4][O:5][C:6]=1[C:7]1[CH2:16][CH2:15][C:10]2([O:14][CH2:13][CH2:12][O:11]2)[CH2:9][CH:8]=1>C(O)C.[Pd]>[CH3:1][C:2]1[C:3]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N:4][O:5][C:6]=1[CH:7]1[CH2:8][CH2:9][C:10]2([O:14][CH2:13][CH2:12][O:11]2)[CH2:15][CH2:16]1
Reactant: CCOC(=O)c1noc(C2=CCC3(CC2)OCCO3)c1C
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1noc(C2CCC3(CC2)OCCO3)c1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of ethyl 4-methyl-5-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)isoxazole-3-carboxylate (556 mg, 1.896 mmol) in ethanol (20 mL) was flushed with nitrogen and then treated with 10% Pd—C, 50% wet (Alfa Aesar, 38303) (303 mg, 2.84 mmol). The reaction mixture was stirred under an atmosphere of hydrogen at room temperature overnight. The resulting mixture was filtered through Celite®, washing with ethanol and DCM. The filtrate was concentrated under reduced pressure and the residue was passed through a 500 mg silica-TMT cartridge, eluting with ethanol:ether (1:1). The solvent was removed under reduced pressure to afford the title compound;
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[CH:4][C:3]=1[O:9][CH2:10][C:11]1[N:12]=[C:13]([NH:16][C:17](=[O:19])[CH3:18])[S:14][CH:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+].F[B-](F)(F)F.C(P(CCCC)CCCC)CCC.CCOC(C)=O>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:8][C:6]1[CH:7]=[C:2]2[C:3]([O:9][CH2:10][C:11]3[N:12]=[C:13]([NH:16][C:17](=[O:19])[CH3:18])[S:14][C:15]=32)=[CH:4][N:5]=1
Reactant: CC(=O)Nc1nc(COc2cnc(C)cc2Br)cs1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCCP(CCCC)CCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)Nc1nc2c(s1)-c1cc(C)ncc1OC2
Temperature: 115 °C
Reaction time: 7 h
Yield: 23.3 %

Procedure:
A mixture of 463 mg (1.53 mmol) N-[4-(4-bromo-6-methyl-pyridin-3-yloxymethyl)-thiazol-2-yl]-acetamide (Stage 40.3), 900 mg (2.71 mmol) cesium carbonate, 30.4 mg (0.135 mmol) palladium acetate and 81 mg (0.271 mmol) tributylphosphine tetrafluoroborate in 3 mL DMF was stirred at 115° C. for 7 h under argon. Then the reaction mixture was poured onto water, EtOAc was added and, after filtration over a layer of Hyflo Super Gel medium (Fluka 56678), the filtrate was extracted with EtOAc (2×). The combined organic layers were washed with water and brine, dried (MgSO4) and filtered. The filtrate was concentrated in vacuo to leave a residue that was purified on silica gel (=−100% EtOAc in heptane) to afford 93 mg of the title compound as a solid. LCMS: tR=0.27 min, M+H=262, M−H 260 (method J).
Reaction SMILES: [CH2:1]([C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:6]([CH2:15][C:16]#[CH:17])[C:5](=[O:18])[C:4]=1[O:19]C)[CH3:2]>O>[CH2:1]([C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:6]([CH2:15][C:16]#[CH:17])[C:5](=[O:18])[C:4]=1[OH:19])[CH3:2]
Reactant: C#CCn1c(-c2ccccc2)nc(CC)c(OC)c1=O
Solvent: O
Product: C#CCn1c(-c2ccccc2)nc(CC)c(O)c1=O
Reaction time: 1.5 h
Yield: 71.5 %

Procedure:
To an oven dried 3-neck round bottom flask, equipped with a magnetic stirrer, a thermometer, an addition funnel, a septum and a nitrogen inlet, was added 10 mL of 1M boron tribromide in methylene chloride, by syringe. The BBr3 was cooled to -65 C with a dry ice/acetone bath and 0.9 g (3.3 mmol) of 6-ethyl-5-methoxy-2-phenyl-3-propargyl-4(3H)-pyrimidinone (Compound 183) was added dropwise through an addition funnel. The reaction stirred at low temperature for 1.5 h. The reaction progress was checked by G.C. and was complete at this time. Water was slowly added and the reaction was left to stir for 1 h at room temperature. The reaction mixture was transferred to an addition funnel and extracted three times with methylene chloride. The organic layers were combined and dried over MgSO4, then concentrated to yield 0.6 g (72% yield) of 6-ethyl-5-hydroxy-2-phenyl-3-propargyl-4(3H)-pyrimidinone, as a white solid. M.p. 152°-154° C. 1H-NMR (CDCl3) 1.25(3H,t), 2.4(1H,t), 2.7(2H,q), 4.65(2H,d), 6.25(1H,s), 7.55(3H,m), 7.65(2H,m).
Reaction SMILES: [C:1]1([S:7]([NH:10][CH:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=O)[CH2:13][CH2:12]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.NN.[OH-].[K+]>>[C:1]1([S:7]([NH:10][CH:11]2[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][CH2:19][CH2:20][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:15][CH2:16]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(CCCN1CCC(NS(=O)(=O)c2ccccc2)CC1)c1ccccc1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=S(=O)(NC1CCN(CCCCc2ccccc2)CC1)c1ccccc1

Procedure:
4-Benzenesulphonamido-1-(4-phenyl-4-oxobutyl)piperidine may be reacted with hydrazine hydrate and potassium hydroxide under Wolff-Kishner reaction conditions to give the title compound.
Reaction SMILES: Cl[Si](C)(C)[CH3:3].[Cl:6][C:7]1[C:8]([C:15]([OH:17])=[O:16])=[N:9][C:10]([S:13][CH3:14])=[N:11][CH:12]=1>CO.ClCCl>[Cl:6][C:7]1[C:8]([C:15]([O:17][CH3:3])=[O:16])=[N:9][C:10]([S:13][CH3:14])=[N:11][CH:12]=1
Reactant: C[Si](C)(C)Cl
Reactant: CSc1ncc(Cl)c(C(=O)O)n1
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1nc(SC)ncc1Cl
Temperature: 25 °C
Reaction time: 20 h
Yield: 95.1 %

Procedure:
16.0 g of chloro(trimethyl)silane are added dropwise to a solution of 6.2 g of 5-chloro-2-(methylsulfanyl)pyrimidine-4-carboxylic acid 1 in 100 ml of methanol and 100 ml of dichloromethane. The mixture is stirred at ambient temperature for 20 h, and then concentrated under vacuum. The residue is taken up with water and extracted with dichloromethane. The organic phase is dried over magnesium sulfate and concentrated under vacuum so as to obtain 6.3 g of methyl 5-chloro-2-(methylsulfanyl)pyrimidine-4-carboxylate 2 in the form of a brown oil.
Reaction SMILES: [CH2:1]([O:17][CH2:18][CH:19]([O:22][CH3:23])[CH2:20][OH:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[Br:24][CH2:25][C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29](Cl)=[O:30].N1C=CC=CC=1>O1CCCC1>[Br:24][CH2:25][C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29]([O:21][CH2:20][CH:19]([O:22][CH3:23])[CH2:18][O:17][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:30]
Reactant: O=C(Cl)c1cccc(CBr)c1
Reactant: CCCCCCCCCCCCCCCCOCC(CO)OC
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCOCC(COC(=O)c1cccc(CBr)c1)OC
Reaction time: 48 h
Yield: 78.3 %

Procedure:
a mixture of 8 g of 3-(hexadecyloxy)-2-methoxypropanol, 6.22 g of m-bromomethylbenzoyl chloride, 2.11 g of pyridine and 80 ml of tetrahydrofuran was stirred for 48 hours, then filtered and evaporated. The residue was purified by chromatography and crystallized giving 10 g of 3-(bromomethyl)benzoic acid, 3-(hexadecyloxy)-2-methoxypropyl ester as white solid.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][C:9]2[CH:10]=[C:11]([CH:13]=[CH:14][CH:15]=2)[NH2:12])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl.Cl[C:18]1[N:23]=[C:22]([NH:24][C:25]2[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=2[C:27]([NH2:29])=[O:28])[C:21]([O:34][CH3:35])=[CH:20][N:19]=1.C(O)(C)C>C1COCC1.C(OCC)C>[CH3:35][O:34][C:21]1[C:22]([NH:24][C:25]2[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=2[C:27]([NH2:29])=[O:28])=[N:23][C:18]([NH:12][C:11]2[CH:13]=[CH:14][CH:15]=[C:9]([CH2:8][CH2:7][N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)[CH:10]=2)=[N:19][CH:20]=1
Reactant: COc1cnc(Cl)nc1Nc1ccccc1C(N)=O
Reactant: Nc1cccc(CCN2CCOCC2)c1
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CC(C)O
Product: COc1cnc(Nc2cccc(CCN3CCOCC3)c2)nc1Nc1ccccc1C(N)=O
Temperature: 100 °C
Reaction time: 0.08 h

Procedure:
3-[2-(4-Morpholinyl)ethyl]aniline (103 mg; 0.5 mmoles) was dissolved in THF (2 mL) and treated with 1 mL of a solution of 1M HCl in ethyl ether. The mixture was stirred for 5 min and then concentrated in vacuo. The residue was treated with 2-{[2-chloro-5-(methoxy)-4-pyrimidinyl]amino}benzamide (139 mg; 0.5 mmoles) and isopropanol (4 mL). The suspension was stirred in a vial, which was sealed and heated at 100° C. for 24 h. Upon cooling, the solid was collected by filtration, washed with cold isopropanol and dried in vacuo to afford the desired product. MS: (M+H)+=449.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.S(Cl)(Cl)=O.Cl.CN.C[CH2:19][N:20](C(C)C)C(C)C>C1(C)C=CC=CC=1.ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:20][CH3:19])=[O:10])=[N:6][CH:7]=1
Reactant: O=C(O)c1ccc(Br)cn1
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CNC(=O)c1ccc(Br)cn1
Temperature: 25 °C
Yield: 63.2 %

Procedure:
5-Bromo-pyridine-2-carboxylic acid (2.59 g, 12.8 mmol) and thionylchloride (2.79 ml) were heated at reflux in toluene (25 ml) for 16 hours. Excess reagents were removed in vacuo and the residue was diluted in dichloromethane (50 ml). A mixture of methyl amine hydrochloride (2.60 g, 38.5 mmol) and DIPEA (6.7 ml, 38.5 mmol) in dichloromethane (10 ml) was added dropwise to the stirred solution and the resulting mixture was maintained at room temperature for 5 hours. The solution was washed with saturated aqueous NaHCO3 (25 ml), dried (MgSO4), filtered and concentrated in vacuo. The resulting brown solid was recrystallised (Heptane/EtOAc) to provide the title compound as off-white needles (1.74 g, 63%).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:6]=1[C:15]1[C:20]([O:21][CH3:22])=[CH:19][CH:18]=[C:17]([CH2:23][C:24]#[N:25])[CH:16]=1)[CH3:2].[CH:26]1([C:29](Cl)=[O:30])[CH2:28][CH2:27]1>>[C:24]([CH2:23][C:17]1[CH:18]=[CH:19][C:20]([O:21][CH3:22])=[C:15]([C:6]2[CH:7]=[CH:8][C:9]([C:11]([F:12])([F:13])[F:14])=[CH:10][C:5]=2[CH2:4][N:3]([CH2:1][CH3:2])[C:29]([CH:26]2[CH2:28][CH2:27]2)=[O:30])[CH:16]=1)#[N:25]
Reactant: O=C(Cl)C1CC1
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cc(CC#N)ccc1OC
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(CC#N)ccc1OC)C(=O)C1CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: (2′-ethylaminomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetonitrile and cyclopropanecarbonyl chloride. M+H is 417.
Reaction SMILES: [CH3:1][CH:2]([CH3:30])[C@H:3]([NH:20][C:21]1[N:29]=[CH:28][N:27]=[C:26]2[C:22]=1[N:23]=[CH:24][NH:25]2)[C:4]([NH:6][C:7]1[C:8]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:9][CH:10]=[CH:11][CH:12]=1)=O>CC(O)=O>[CH3:1][CH:2]([CH3:30])[CH:3]([NH:20][C:21]1[N:29]=[CH:28][N:27]=[C:26]2[C:22]=1[N:23]=[CH:24][NH:25]2)[C:4]1[N:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2=[N:9][CH:10]=[CH:11][CH:12]=[C:7]2[N:6]=1
Reactant: CC(C)[C@H](Nc1ncnc2[nH]cnc12)C(=O)Nc1cccnc1Nc1ccccc1
Solvent: CC(=O)O
Product: CC(C)C(Nc1ncnc2[nH]cnc12)c1nc2cccnc2n1-c1ccccc1
Temperature: 25 °C
Yield: 47.5 %

Procedure:
A solution of (S)-3-methyl-N-(2-phenylaminopyridin-3-yl)-2-(9H-purin-6-ylamino)butyramide (821 mg, 2.0 mmol) in AcOH (10 mL) was heated at 100° C. for 2 h. After cooling to RT, the volatiles were removed under reduced pressure and the resulting residue partitioned between DCM and a saturated aqueous solution of NaHCO3. The aqueous phase was extracted with DCM and the combined organic fractions dried (MgSO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% 2M NH3/MeOH in DCM) to afford 196 as a light brown solid (365 mg, 46%). LCMS (Method K): RT 3.18 min [M+H]+ 385.1. 1H NMR (DMSO-d6, 400 MHz): δ 8.29-7.99 (4H, m), 7.78-7.42 (6H, m), 7.31 (1H, dd, J=8.01, 4.75 Hz), 5.40 (1H, br s), 2.45-2.34 (1H, m), 0.95 (3H, d, J=6.69 Hz), 0.81 (3H, br d, J=6.59 Hz). Signals split due to presence of rotamers/tautomers
Reaction SMILES: C(O)(=O)/C=C\C(O)=O.[CH3:9][CH:10]([N:17]1[CH2:20][CH:19]([OH:21])[CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[H-].[Na+].[Cl:24][C:25]1[CH:26]=[C:27](F)[CH:28]=[CH:29][CH:30]=1.[C:32]([OH:37])(=[O:36])[C:33]([OH:35])=[O:34]>[K].CN(C)C=O>[C:32]([OH:37])(=[O:36])[C:33]([OH:35])=[O:34].[Cl:24][C:25]1[CH:30]=[C:29]([CH:28]=[CH:27][CH:26]=1)[O:21][CH:19]1[CH2:20][N:17]([CH:10]([CH3:9])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:18]1
Reactant: CC(c1ccccc1)N1CC(O)C1
Reactant: Fc1cccc(Cl)c1
Agent: O=C(O)/C=C\C(=O)O
Agent: O=C(O)C(=O)O
Agent: [H-]
Solvent: CN(C)C=O
Product: CC(c1ccccc1)N1CC(Oc2cccc(Cl)c2)C1
Temperature: 90 °C

Procedure:
1-(α-Methylbenzyl)-3-hydroxyazetidine maleate (393 g., 1.3 moles) was partitioned in dilute potassium hydroxidebenzene. The separated dried benzene solution was concentrated, the residual oil dissolved in 250 ml. of dimethylformamide and added dropwise to a stirred suspension of 53 g. (1.1 moles) of 50% sodium hydride in 750 ml. of dimethylformamide at 90° C. The mixture was heated at 90° C. for 1 hr. and 130.5 g. (1-mole) of 3-chlorofluorobenzene added dropwise at 90° C. The mixture was refluxed for 3 hrs., cooled and partitioned between isopropyl ether and dilute sodium hydroxide. The isopropyl ether solution was dried, concentrated, and the residue added to 1200 ml. of isopropyl alcohol containing 90 g. (1 mole) of oxalic acid. The oxalate salt was recrystallized from ethanol. Yield 263 g. (69%); m.p. 141°-144° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[C:19]([CH:31]=[CH:32][CH:33]=2)[C:20]([NH:22][C:23]2[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=2[F:30])=[O:21])[CH:5]=[CH:4][N:3]=1.[N:34]1([CH:40]2[CH2:45][CH2:44][N:43]([C:46]3[CH:52]=[CH:51][C:49]([NH2:50])=[C:48]([CH3:53])[CH:47]=3)[CH2:42][CH2:41]2)[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.CCOCC>CC(O)C.C(Cl)Cl>[N:34]1([CH:40]2[CH2:45][CH2:44][N:43]([C:46]3[CH:52]=[CH:51][C:49]([NH:50][C:2]4[N:7]=[C:6]([C:8]5[N:12]6[CH:13]=[CH:14][CH:15]=[CH:16][C:11]6=[N:10][C:9]=5[C:17]5[CH:18]=[C:19]([CH:31]=[CH:32][CH:33]=5)[C:20]([NH:22][C:23]5[C:24]([F:30])=[CH:25][CH:26]=[CH:27][C:28]=5[F:29])=[O:21])[CH:5]=[CH:4][N:3]=4)=[C:48]([CH3:53])[CH:47]=3)[CH2:42][CH2:41]2)[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]1
Reactant: O=C(Nc1c(F)cccc1F)c1cccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)c1
Reactant: Cc1cc(N2CCC(N3CCCCC3)CC2)ccc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)O
Solvent: ClCCl
Product: Cc1cc(N2CCC(N3CCCCC3)CC2)ccc1Nc1nccc(-c2c(-c3cccc(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Temperature: 175 °C
Reaction time: 48 h

Procedure:
To 3-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-benzamide (Intermediate Example 1) (120 mg, 0.25 mmol) and 4-(1,4′-bipiperidin-1′-yl)-2-(methyl)aniline (68 mg, 0.25 mmol) in iPrOH (2 mL) in a microwave vial was added p-toluenesulfonic acid monohydrate (110 mg, 0.60 mmol). The reaction was heated in a microwave at 175° C. for 800 seconds. After cooling to rt, the solvent was removed on a rotovap and the residue taken up in DCM. Silica gel was added and the solvent removed on the rotovap. The preabsorbed solids were purified by flash chromatography. The desired fractions were combined and the solvent removed on the rotovap to give product contaminated with an impurity. The material was dissolved in DCM, and ether was added until the solution just turned cloudy. After two days, the solids were collected by vacuum filtration and washed with diethyl ether. The yellow crystals were separated from the beige powder using tweezers. The desired product was obtained as yellow crystals (23 mg, 0.033 mmol, 13% yield). 1H NMR (400 MHz, DMSO-d6) δ 10.24 (s, 1H), 9.35 (br s, 1H), 8.81 (s, 1H), 8.32 (s, 1H), 8.16 (d, J=5.4 Hz, 1H), 8.06 (d, J=7.9 Hz, 1H), 7.82 (d, J=7.7 Hz, 1H), 7.71 (d, J=9.0 Hz, 1H), 7.62 (dd, J=7.9, 7.7 Hz, 1H), 7.48-7.34 (m, 2H), 7.25-7.14 (m, 3H), 6.85 (br s, 1H), 6.85 (s, 1H), 6.79 (dd, J=8.6, 2.6 Hz, 1H), 6.43 (d, J=5.3 Hz, 1H), 3.72 (d, J=12.5 Hz, 2H), 2.62 (dd, J=12.1, 10.6 Hz, 2H), 2.52-2.27 (m, 5H), 2.17 (s, 3H), 1.78 (d, J=11.8 Hz, 2H), 1.60-1.34 (m, 8H). MS (ESI) m/z=699 [M+1].
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([NH:33][C:34](=O)[C:35]2[C:40]([F:41])=[CH:39][CH:38]=[CH:37][C:36]=2[F:42])[CH:28]=[C:29]([O:31][CH3:32])[CH:30]=1>C1(C)C=CC=CC=1>[CH3:23][O:24][C:25]1[CH:26]=[C:27]([NH:33][C:34]([C:35]2[C:40]([F:41])=[CH:39][CH:38]=[CH:37][C:36]=2[F:42])=[S:10])[CH:28]=[C:29]([O:31][CH3:32])[CH:30]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COc1cc(NC(=O)c2c(F)cccc2F)cc(OC)c1
Solvent: Cc1ccccc1
Product: COc1cc(NC(=S)c2c(F)cccc2F)cc(OC)c1
Temperature: 120 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
20.3 g (50 mmol; 1.5 equivalents) of Lawesson's reagent is added to 9.8 g (33.4 mmol) of N-(3,5-dimethoxyphenyl)-2,6-difluorobenzamide in solution in 150 ml of anhydrous toluene. The reaction medium is maintained under stirring at 120° C. for 8 hours, then, after returning to ambient temperature, is washed with 3 times 75 ml of water. The resulting organic phase is dried over magnesium sulphate then the solvent is evaporated off under reduced pressure. The residue is purified by chromatography on a silica column (eluent: dichloromethane/methanol 98/2) and the expected product is obtained in the form of a green oil (10 g; yield=96%).
Reaction SMILES: [C:1]1([C:7]23[CH2:15][CH2:14][C:11]([CH2:16][C:17]([O:19][CH3:20])=[O:18])([CH2:12][CH2:13]2)[CH2:10][CH2:9][CH2:8]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[Al+3].[Cl-].[Cl-].[Br:25][C:26]([CH3:31])([CH3:30])[C:27](Br)=[O:28]>C(Cl)Cl>[Br:25][C:26]([CH3:31])([CH3:30])[C:27]([C:4]1[CH:3]=[CH:2][C:1]([C:7]23[CH2:15][CH2:14][C:11]([CH2:16][C:17]([O:19][CH3:20])=[O:18])([CH2:12][CH2:13]2)[CH2:10][CH2:9][CH2:8]3)=[CH:6][CH:5]=1)=[O:28]
Reactant: COC(=O)CC12CCCC(c3ccccc3)(CC1)CC2
Reactant: CC(C)(Br)C(=O)Br
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)CC12CCCC(c3ccc(C(=O)C(C)(C)Br)cc3)(CC1)CC2
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 25.6 %

Procedure:
To an ice water cooled solution of methyl (5-phenylbicyclo[3.2.2]non-1-yl)acetate (Intermediate 23; 229 mg, 0.79 mmol) in DCM (10 mL) was added aluminium chloride (318 mg, 2.38 mmol) followed by the dropwise addition of 2-bromoisobutyryl bromide (0.10 mL, 0.79 mmol). The reaction mixture was allowed to stir at 0° C. for 40 mins then poured onto ice-water (100 mL). The organic phase was separated and the aqueous phase washed with DCM (3×50 mL), the organic washings were combined, dried (MgSO4) and concentrated to leave a yellow gum. This was purified on a 12 g Crawford silicyle cartridge, loading in DCM and eluting with 0-10%-20% isohexane-EtOAc to provide the title compound (85 mg, 0.202 mmol, 26%) as a pale yellow gum; 1H NMR (CDCl3) δ 1.09 (d, 3H), 1.50-1.57 (m, 3H), 1.67-1.74 (m, 3H), 1.82-1.86 (m, 6H), 2.03 (s, 6H), 2.27 (q, 1H), 3.67 (s, 3H), 7.37 (d, 2H), 8.11 (d, 2H); GC-MS CI m/e MH+ 421.
Reaction SMILES: [CH:1]([N-:4]C(C)C)(C)[CH3:2].[Li+].CCCCCCC.O1CCCC1.C(C1C=CC=CC=1)C.C(#N)C.[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][CH:42]([C:45]#[N:46])[CH2:41][CH2:40]1)=[O:38])([CH3:35])([CH3:34])[CH3:33]>O1CCCC1>[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][CH:42]([C:45]([NH2:46])=[CH:2][C:1]#[N:4])[CH2:41][CH2:40]1)=[O:38])([CH3:35])([CH3:33])[CH3:34]
Reactant: CC(C)[N-]C(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)CC1
Agent: [Li+]
Solvent: CC#N
Solvent: CCc1ccccc1
Solvent: CCCCCCC
Product: CC(C)(C)OC(=O)N1CCC(C(N)=CC#N)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 64.4 %

Procedure:
47.7 ml (85.9 mmol) of 1.8 M lithium diisopropylamide-n-heptane/tetrahydrofuran/ethylbenzene solution was added to 50 ml of tetrahydrofuran and 4.14 ml (79.3 mmol) of acetonitrile was added dropwise under cooling with a dry ice-acetone bath, and the reaction solution was stirred for 3.0 hours. Under the same conditions, a solution of 13.9 g (66.1 mmol) of 4-cyanopiperidin-1-carboxylic acid tert-butyl ester in 30 ml of tetrahydrofuran was further added dropwise and then the reaction solution was stirred for 24 hours while the temperature of the reaction solution was slowly raised to room temperature. After completion of the reaction, ice water was added to the reaction solution and the reaction solution was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution and then dried with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was subjected to silica gel column chromatography [n-hexane/ethyl acetate=90/10-50/50 (V/V)], and the fraction including the desired compound was concentrated under reduced pressure to provide 10.7 g of the title compound as a yellow oil (yield: 64%).
Reaction SMILES: [N+:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2].[Cl-].[NH4+:15]>CN(C)C=O>[N+:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][C:5]=1[NH2:15])([O-:3])=[O:2]
Reactant: [NH4+]
Reactant: O=[N+]([O-])c1cccc2ccccc12
Agent: [Cl-]
Solvent: CN(C)C=O
Product: Nc1ccc2ccccc2c1[N+](=O)[O-]
Reaction time: 0.25 h

Procedure:
3.5 g of 1-nitronaphthalene and 3.7 g of benzthiazyl-2-sulphenamide, dissolved in 30 ml of dimethylformamide, are added dropwise to a stirred solution of 6 g of potassium tert.-butylate in 60 ml of dimethylformamide, while the temperature is kept at 20° to 25° C. After stirring further for 15 minutes the mixture is poured into 400 ml of a saturated aqueous ammonium chloride solution and then treated further as in Example 1. 1-Nitro-2-naphthylamine with a melting point of 123° to 125° C. is obtained in a yield of 2.9 g (72%). In addition, about 8% of 4-nitro-1-naphthylamine are obtained.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:9])=[CH:6][C:7]=1[NH2:8].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C1COCC1.[F:25][C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>[NH4+].[Cl-]>[Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:9])=[CH:6][C:7]=1[NH:8][S:32]([C:29]1[CH:30]=[CH:31][C:26]([F:25])=[CH:27][CH:28]=1)(=[O:34])=[O:33]
Reactant: Nc1cc(Cl)nnc1Cl
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=S(=O)(Nc1cc(Cl)nnc1Cl)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 86.7 %

Procedure:
To a 50 mL round-bottomed flask was added 3,6-dichloropyridazin-4-amine (148 mg, 902 μmol), sodium bis(trimethylsilyl)amide (365 μl, 1805 μmol) and THF (3 mL) at 0° C. The mixture was stirred at 0° C. for 30 min. 4-fluorobenzene-1-sulfonyl chloride (263 mg, 1354 μmol) was then added. The mixture was stirred at 0° C. for 1 hour. The reaction mixture was diluted with satd NH4Cl (10 mL) and extracted with EtOAc (3×30 mL). The combined organic extracts were washed with satd NaCl (5 mL), dried over Na2SO4, filtered and concentrated in vacuo and the residue was purified by silica gel chromatography (5% MeOH/EtOAc) to give N-(3,6-dichloropyridazin-4-yl)-4-fluorobenzenesulfonamide (252 mg, 86.7% yield). MS (ESI positive ion) m/z: 323 (M+1). 1H NMR (300 MHz, DMSO-d6) δ ppm 6.95 (s, 1H) 7.23-7.35 (m, 2H) 7.74-7.84 (m, 2H)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.O([Si](C)(C)C)S(C(F)(F)F)(=O)=O.C(N(CC)CC)C.[CH:30]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[S:39][CH:40]([C:44](O)=[O:45])[C:41](O)=[O:42])([CH3:32])[CH3:31]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:10][C:41](=[O:42])[C:40]([S:39][C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=3[CH:30]([CH3:31])[CH3:32])=[C:44]([OH:45])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: CC(C)c1ccccc1SC(C(=O)O)C(=O)O
Reactant: CC(=O)c1ccc(Cl)cc1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)c1ccccc1Sc1c(O)cc(-c2ccc(Cl)cc2)oc1=O

Procedure:
The title compound was prepared by Method A using 4'-chloroacetophenone (2.33 g, 15.1 mmol), trimethylsilyl triflate (3.5 mL, 18.1 mmol), triethylamine (4.26 mL, 30.6 mmol), methylene chloride (30 mL), and diethyl ester of [(2-isopropylphenyl)thio] propanedioic acid (3.11 g, 10.0 mmol) m.p. 148°-151° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.25 (d, 6H), 3.41 (m, 1H), 6.86 (s, 1H), 6.92 (m, 1H), 7.08 (m, 2H), 7.27 (m, 1H), 7.62 (m, 2H), 7.86 (m, 2H).