Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[S:10][C:9](I)=[CH:8][C:6]=2[N:7]=1.[CH2:18]([OH:21])[C:19]#[CH:20].C(N(CC)CC)C>[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[S:10][C:9]([C:20]#[C:19][CH2:18][OH:21])=[CH:8][C:6]=2[N:7]=1
Reactant: C#CCO
Reactant: Clc1nc(N2CCOCC2)c2sc(I)cc2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: OCC#Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reaction time: 240 h

Procedure:
A mixture of 2-chloro-6-iodo-4-morpholin-4-yl-thieno[3,2-d]pyrimidine 19, prepared according to Example 12, (1.57 g), propargyl alcohol (288 μL), copper iodide (39 mg), bis(triphenylphosphine)palladium(II) chloride (146 mg), triethylamine (25 ml), and tetrahydrofuran (30 ml) were stirred under nitrogen for 10 days. The reaction mixture was then partitioned between chloroform and brine, the combined organics were then dried (MgSO4). The solvents were removed in vacuo. The crude product was then purified using flash chromatography to yield 3-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl)-prop-2-yn-1-ol (1.2 g).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[C:11]1[CH:12]=[C:13]2[C:19]([CH:20]=C)=[CH:18][N:17]([C:22]3[CH:27]=[CH:26][C:25]([CH:28]([CH3:30])[CH3:29])=[CH:24][CH:23]=3)[C:14]2=[CH:15][N:16]=1)[CH3:2].C1C[O:34]CC1.O>O=[Os](=O)(=O)=O>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[C:11]1[CH:12]=[C:13]2[C:19]([CH:20]=[O:34])=[CH:18][N:17]([C:22]3[CH:27]=[CH:26][C:25]([CH:28]([CH3:30])[CH3:29])=[CH:24][CH:23]=3)[C:14]2=[CH:15][N:16]=1)[CH3:2]
Reactant: C=Cc1cn(-c2ccc(C(C)C)cc2)c2cnc(-c3c(CC)cccc3CC)cc12
Reactant: C1CCOC1
Agent: O=[Os](=O)(=O)=O
Solvent: O
Product: CCc1cccc(CC)c1-c1cc2c(C=O)cn(-c3ccc(C(C)C)cc3)c2cn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 5-(2,6-diethyl-phenyl)-1-(4-isopropyl-phenyl)-3-vinyl-1H-pyrrolo[2,3-c]pyridine (400 mg, 1.0 mmol) in a THF/water mixture (3:1, 10 mL), NaIO4 (0.65 g, 3.0 mmol) and OsO4 (4% in water, 3 drops) are added and the mixture is stirred for 18 hours at room temperature. The solvent is removed under reduced pressure, and the residue is extracted with EtOAc. The combined organic extracts are washed with brine, dried (Na2SO4), and concentrated under reduced pressure. The residue is purified by chromatography on silica gel (Hexane/EtOAc, 6:1) to afford 5-(2,6-diethyl-phenyl)-1-(4-isopropyl-phenyl)-1H-pyrrolo[2,3-c]pyridine-3-carbaldehyde as a colorless oil.
Reaction SMILES: Cl.Cl.[CH2:3]([C@@H:10]1[NH:15][CH2:14][CH2:13][N:12]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH:25]3[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]3)[CH:17]=2)[CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:32](OC(=O)C)(=[O:34])[CH3:33]>N1C=CC=CC=1>[CH2:3]([C@H:10]1[CH2:11][N:12]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH:25]3[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]3)[CH:17]=2)[CH2:13][CH2:14][N:15]1[C:32](=[O:34])[CH3:33])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(N2CCN[C@@H](Cc3ccccc3)C2)cc1OC1CCN(C)CC1
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccc(N2CCN(C(C)=O)[C@@H](Cc3ccccc3)C2)cc1OC1CCN(C)CC1

Procedure:
Prepared using the same procedure described in Example 338 from (S)-3-benzyl-1-[4-methoxy-3-(1-methyl-piperidin-4-yloxy)-phenyl]-piperazine dihydrochloride (103 mg, 0.22 mmol) and acetic anhydride (200 μL, 2.11 mmol), and pyridine (2 mL) to afford the title compound as brown waxy solid (47 mg, 49%). LC/MS (Method B) 2.32 min, [M+1]+ 338.
Reaction SMILES: [Na].Cl[C:3]1[N:4]=[N:5][C:6]([S:9][CH2:10][CH:11]=[CH2:12])=[CH:7][CH:8]=1.[C:13]1([CH3:20])[C:18]([OH:19])=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH3:20][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=1[O:19][C:3]1[N:4]=[N:5][C:6]([S:9][CH2:10][CH:11]=[CH2:12])=[CH:7][CH:8]=1
Reactant: C=CCSc1ccc(Cl)nn1
Reactant: Cc1ccccc1O
Agent: [Na]
Product: C=CCSc1ccc(Oc2ccccc2C)nn1
Temperature: 100 °C
Reaction time: 5 h

Procedure:
0.23 g(0.01 mol) of metallic sodium was dissolved in 30 ml of dry o-cresol. To the resulting solution was added 1.87 g(0.01 mol) of 3-chloro-6-allylthiopyridazine. The reaction solution was stirred for 5 hours at 100±5° C. and then treated according to the same manner as Example 23 to obtain the title compound as a pale white needle crystal.
Reaction SMILES: [Li+].[OH-:2].[O:3]=[C:4]1[N:10]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][CH:21](C(OC)=O)[C:22]3[CH:31]=[C:30]([CH3:32])[C:25]4[O:26][CH2:27][CH2:28][O:29][C:24]=4[CH:23]=3)=[O:18])[CH2:13][CH2:12]2)[CH2:9][CH2:8][C:7]2[CH:37]=[CH:38][CH:39]=[CH:40][C:6]=2[NH:5]1.C1[CH2:45][O:44]CC1>O>[O:3]=[C:4]1[N:10]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C@@H:20]([C:45]([OH:44])=[O:2])[CH2:21][C:22]3[CH:31]=[C:30]([CH3:32])[C:25]4[O:26][CH2:27][CH2:28][O:29][C:24]=4[CH:23]=3)=[O:18])[CH2:13][CH2:12]2)[CH2:9][CH2:8][C:7]2[CH:37]=[CH:38][CH:39]=[CH:40][C:6]=2[NH:5]1
Reactant: [OH-]
Reactant: C1CCOC1
Reactant: COC(=O)C(COC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1)c1cc(C)c2c(c1)OCCO2
Agent: [Li+]
Solvent: O
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc2c1OCCO2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
151 mg (6.3 mmol) LiOH in 50 mL water were metered into a solution of 2.2 g (4.2 mmol) (R)-1-(methoxycarbonyl-2-(8-methyl-2,3-dihydro-1,4-benzodioxin-6-yl)-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate in 50 mL THF and the reaction mixture was stirred for 2 h at RT. After the end of the reaction the mixture was evaporated to dryness i.vac. The residue was combined with 100 mL water and 100 mL EtOAc, the aqueous phase was separated off, acidified with 2 M HCl, extracted with 200 mL EtOAc and the organic phase was dried. After the desiccant and solvent had been eliminated the residue was evaporated to dryness i.vac. and reacted further without purification.
Reaction SMILES: O.C[N+]1([O-])CCOCC1.[Cl:10][CH:11]=[C:12]1[CH:18]=[CH:17][C:16]2[CH:19]=[C:20]([CH2:23][OH:24])[CH:21]=[CH:22][C:15]=2[O:14][CH2:13]1>ClCCl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[Cl:10][CH:11]=[C:12]1[CH:18]=[CH:17][C:16]2[CH:19]=[C:20]([CH:23]=[O:24])[CH:21]=[CH:22][C:15]=2[O:14][CH2:13]1
Reactant: OCc1ccc2c(c1)C=CC(=CCl)CO2
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Solvent: O
Product: O=Cc1ccc2c(c1)C=CC(=CCl)CO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.4 %

Procedure:
84 mg (0.62 mmol) of 4-methylmorpholine N-oxide monohydrate and 207 mg of 4 Å molecular sieve are added to 92 mg (0.415 mmol) of [3-(chloromethylene)-2,3-dihydro-1-benzoxepin-7-yl]methanol, prepared according to example 71, in solution in 1 ml of dichloromethane. 14.6 mg (0.041 mmol) of tetrapropylammonium perruthenate are added to the suspension at 0° C. After stirring at ambient temperature for 1 hour, the reaction medium is purified by chromatography on silica gel (ethyl acetate/heptane 30/70) to give 70 mg (76%) of 3-(chloromethylene)-2,3-dihydro-1-benzoxepin-7-carbaldehyde in the form of a mixture of 2 Z/E isomers in an 85/15 ratio; 1H NMR (300 MHz, CDCl3) Z isomer: 4.90 (s, 2H), 6.41 (m, 3H), 7.14 (d, J=8.3 Hz, 1H), 7.70 (dd, J=8.3 and 2 Hz, 1H), 7.75 (d, J=2.07 Hz, 1H), 9.91 (s, 1H).
Reaction SMILES: Cl.O.[NH:3]1[CH2:8][CH2:7][C:6](=O)[CH2:5][CH2:4]1.Cl.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19]N)=[CH:15][CH:14]=1>C(O)C>[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]2[NH:19][C:6]3[CH2:5][CH2:4][NH:3][CH2:8][C:7]=3[C:15]=2[CH:14]=1
Reactant: COc1ccc(NN)cc1
Reactant: O=C1CCNCC1
Agent: Cl
Solvent: CCO
Solvent: O
Product: COc1ccc2[nH]c3c(c2c1)CNCC3

Procedure:
A suspension of 4-piperidone monohydrate hydrochloride (1.0 g, 6.5 mmol) and 4-methoxyphenylhydrazine hydrochloride (1.14 g, 6.5 mmol) in ethanol (17 ml) is kept stirring at reflux overnight. The resulting solid is filtered off and washed with diethyl ether to afford crude sub-title compound, which is used without further purification: tR (LC-1) 0.38; ESI-MS (positive ion): m/z 203.19 [M+H]+ (calcd 202.25 for C12H14N2O).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:6][C:5]([NH:14][C:15](=[O:19])[O:16][CH2:17][CH3:18])=[C:4]([F:20])[CH:3]=1.[OH:21]C(C(C)=C)C(OCC(C)C)=O.Cl.[C:34]1([CH3:40])C=CC=C[CH:35]=1>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:1][C:2]1[C:7]([O:8][CH:9]2[CH2:10][CH2:11][CH2:12][CH2:13]2)=[CH:6][C:5]([N:14]2[C:18](=[O:21])[C:17](=[C:34]([CH3:40])[CH3:35])[O:16][C:15]2=[O:19])=[C:4]([F:20])[CH:3]=1
Reactant: C=C(C)C(O)C(=O)OCC(C)C
Reactant: CCOC(=O)Nc1cc(OC2CCCC2)c(Cl)cc1F
Reactant: Cc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [Cl-]
Product: CC(C)=C1OC(=O)N(c2cc(OC3CCCC3)c(Cl)cc2F)C1=O
Temperature: 25 °C
Reaction time: 9 h
Yield: 37.8 %

Procedure:
Ethyl N-(4-chloro-5-cyclopentyloxy-2-fluorophenyl)carbamate (3.01 g, 10 mmol), isobutyl 2-hydroxy-3-methyl-3-butenoate (4.22 g, 24.5 mmol) and tetrabutylammonium chloride (278 mg, 1.0 mmol) were introduced into a flask (25 cc) equipped with a distillation unit, and the reaction was conducted at 200° C. for 9 hours. After the reaction solution was cooled to room temperature, toluene (20 mL) was added, and then the reaction solution was washed with water (20 mL), then 1N sodium hydroxide (20 mL) and 1N hydrochloric acid (20 mL). The organic layer was dried over magnesium sulfate. After the drying agent was filtered off, the filtrate was concentrated under reduced pressure. To the resulting oily crude product, acidic methanol (3.5 mL) was added to form a homogeneous solution. Then, 6N hydrochloric acid (0.4 mL) was further added, and the solution was left to stand at room temperature. The precipitated crystals were collected by filtration, then washed with a mixed solvent consisting of methanol (8 mL) and 6N hydrochloric acid (0.8 mL) and then water (10 mL) and dried to obtain 3-(4-chloro-5-cyclopentyloxy-2-fluorophenyl)-5-isopropylidene-1,3-oxazolidine-2,4-dione (1.34 g, yield 37.8%).
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:6]([OH:8])=[O:7])[CH2:4][SH:5].[C:9](Cl)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[OH-:18].[K+].Cl>O>[C:9]([NH:2][C@H:3]([C:6]([OH:8])=[O:7])[CH2:4][S:5][C:9](=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: N[C@@H](CS)C(=O)O
Reactant: O=C(Cl)c1ccccc1
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Solvent: O
Product: O=C(N[C@@H](CSC(=O)c1ccccc1)C(=O)O)c1ccccc1
Yield: 80.7 %

Procedure:
63.0 g (0.4 mole) of cysteine hydrochloride were suspended in 400 ml of water, and 112.5 g (0.8 mole) of benzoyl chloride were added. A solution of 89.8 g (1.6 moles) of potassium hydroxide in 1 liter of water was added dropwise to the stirred mixture, while cooling at 0°-5° C. Stirring was continued for a further hour at room temperature, after which the mixture was rendered strongly acidic with aqueous 2N HCl, the precipitate was filtered off under suction and washed neutral with water, and the product was recrystallized twice from methanol/water. 106.3 g (81%) of N,S-dibenzoylcysteine of melting point 183°-185° C. were obtained; Rf=0.43 in system I, [α]D20 =-85.7° (c=1 in absolute ethanol).
Reaction SMILES: [CH2:1]([C@H:8]([NH:30][C:31](=[O:50])[C@H:32]([CH:47]([CH3:49])[CH3:48])[NH:33][C:34]([N:36]([CH2:38][C:39]1[N:40]=[C:41]([CH:44]([CH3:46])[CH3:45])[S:42][CH:43]=1)[CH3:37])=[O:35])[CH2:9][C@H:10]([OH:29])[C@@H:11]([NH:19][C:20]([O:22][CH2:23][C:24]1[S:28][CH:27]=[N:26][CH:25]=1)=[O:21])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:51]([S:53][CH2:54][CH3:55])[CH3:52].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(#N)C.C(OCC)(=O)C>[CH2:1]([C@H:8]([NH:30][C:31](=[O:50])[C@H:32]([CH:47]([CH3:49])[CH3:48])[NH:33][C:34]([N:36]([CH2:38][C:39]1[N:40]=[C:41]([CH:44]([CH3:45])[CH3:46])[S:42][CH:43]=1)[CH3:37])=[O:35])[CH2:9][C@H:10]([O:29][CH:51]([S:53][CH2:54][CH3:55])[CH3:52])[C@@H:11]([NH:19][C:20]([O:22][CH2:23][C:24]1[S:28][CH:27]=[N:26][CH:25]=1)=[O:21])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCSCC
Reactant: CC(C)c1nc(CN(C)C(=O)N[C@H](C(=O)N[C@@H](Cc2ccccc2)C[C@H](O)[C@H](Cc2ccccc2)NC(=O)OCc2cncs2)C(C)C)cs1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCSC(C)O[C@@H](C[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)N(C)Cc1csc(C(C)C)n1)C(C)C)[C@H](Cc1ccccc1)NC(=O)OCc1cncs1
Yield: 75 %

Procedure:
To a solution of the compound of Example 1 (0.50 g, 0.69 mmol) and ethyl sulfide (1.9 mL) in acetonitrile (5 mL) at 0° C. was added benzoyl peroxide (0.84 g) in three portions over 3 hours. The reaction was diluted with ethyl acetate and washed with 10% Na2CO3 and brine. The organic was dried over MgSO4, filtered and evaporated. The residue was chromatographed on silica gel, eluting with a gradient of 50-100% ethyl acetate in chloroform to give the title compound (0.42 g, 75% yield).
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.[F:7][C:8]([F:37])([C:12]([F:36])([F:35])[C:13]([F:34])([F:33])[C:14]([F:32])([F:31])[C:15]([F:30])([F:29])[C:16]([F:28])([F:27])[C:17]([F:26])([F:25])[C:18]([F:24])([F:23])[C:19]([F:22])([F:21])[F:20])[C:9](O)=[O:10].[ClH:38]>>[F:7][C:8]([F:37])([C:12]([F:36])([F:35])[C:13]([F:34])([F:33])[C:14]([F:32])([F:31])[C:15]([F:30])([F:29])[C:16]([F:28])([F:27])[C:17]([F:26])([F:25])[C:18]([F:24])([F:23])[C:19]([F:22])([F:21])[F:20])[C:9]([Cl:38])=[O:10]
Reactant: Cl
Reactant: O=C(O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: O=C(Cl)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Yield: 70 %

Procedure:
Phosphorus pentachloride (PCl5), (10.53 g, 50 mmol) was added in small portions to perfluorodecanoic acid (25 g, 49 mmol). Although the ensuing reaction was not too exothermic, HCl gas evolution was vigorous. The resulting solution was refluxed for three hours then a second portion of PCl5 (10.53 g, 50 mmol) was added and the mixture refluxed an additional two hours. Distillation afforded 18.25 g (70%) of perfluorodecanoyl chloride as a colorless liquid.
Reaction SMILES: [CH3:1]CCCCC.C[Si](C=[N+]=[N-])(C)C.[Cl:14][C:15]1[CH:23]=[C:22]([C:24]([OH:26])=[O:25])[CH:21]=[C:20]([Cl:27])[C:16]=1[C:17](O)=[O:18].[CH3:28][OH:29]>>[CH3:28][O:29][C:17](=[O:18])[C:16]1[C:15]([Cl:14])=[CH:23][C:22]([C:24]([O:26][CH3:1])=[O:25])=[CH:21][C:20]=1[Cl:27]
Reactant: O=C(O)c1cc(Cl)c(C(=O)O)c(Cl)c1
Reactant: CCCCCC
Reactant: CO
Agent: C[Si](C)(C)C=[N+]=[N-]
Product: COC(=O)c1cc(Cl)c(C(=O)OC)c(Cl)c1

Procedure:
A hexane solution containing 2M trimethylsilyldiazomethane was added to the mixture of 500 mg of 2,6-dichloro-4-carboxybenzoic acid (Maybridge) and 15 ml of methanol until the end point of the reaction. The reaction mixture was concentrated and purified by silica gel chromatography (ethyl acetate/hexane) to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:16]2[S:17][CH:18]=[CH:19][N:20]=2)[C:9]2[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[CH3:21][C:22]1([CH3:30])[O:27][C:26](=[O:28])[CH2:25][C:24](=[O:29])[O:23]1.[CH:31](OCC)(OCC)OCC>C(O)(C)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:16]2[S:17][CH:18]=[CH:19][N:20]=2)[C:9]2[CH:15]=[CH:14][C:12]([NH:13][CH:31]=[C:25]3[C:26](=[O:28])[O:27][C:22]([CH3:30])([CH3:21])[O:23][C:24]3=[O:29])=[CH:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: Nc1ccc(C(c2ccc(Cl)cc2)c2nccs2)cc1
Reactant: CCOC(OCC)OCC
Reactant: CC1(C)OC(=O)CC(=O)O1
Solvent: CC(C)O
Product: CC1(C)OC(=O)C(=CNc2ccc(C(c3ccc(Cl)cc3)c3nccs3)cc2)C(=O)O1
Temperature: 100 °C

Procedure:
To a suspension of 4-((4-chlorophenyl)(thiazol-2-yl)methyl)aniline (220 mg, 0.731 mmol, 1 equip) in isopropanol (6 mL) was added 2,2-dimethyl-1,3-dioxane-4,6-dione (140 mg, 0.951 mmol, 1.3 equip) and triethyl orthoformate (443 mg, 2.925 mmol, 4 equip) and the resulting mixture was heated at 100° C. for 3 h. The reaction mixture was cooled to room temperature and concentrated. The residue was purified by MPLC using dichloromethane-methanol as eluent to yield 5-(((4-((4-chlorophenyl)(thiazol-2-yl)methyl)phenyl)amino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione as a pale yellow foam. 1H NMR (400 MHz, d6-DMSO) δ 11.25 (1H, d), 8.55 (1H, d), 7.82 (1H, d), 7.69 (1H, d), 7.52 (2H, d), 7.38 (2H, d), 7.38-7.30 (4H, m), 6.19 (1H, s), 1.67 (6H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:30]=C)[C:5]2[C:6]([CH:29]=1)=[N:7][N:8]([CH2:10][C:11]([NH:15][C:16](=[O:28])[C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=1)([C:13]#[N:14])[CH3:12])[N:9]=2.C(Cl)Cl.[O:35]=[O+][O-]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:30]=[O:35])[C:5]2[C:6]([CH:29]=1)=[N:7][N:8]([CH2:10][C:11]([NH:15][C:16](=[O:28])[C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]([F:25])([F:27])[F:26])=[CH:19][CH:18]=1)([C:13]#[N:14])[CH3:12])[N:9]=2
Reactant: O=[O+][O-]
Reactant: C=Cc1cc(Cl)cc2nn(CC(C)(C#N)NC(=O)c3ccc(OC(F)(F)F)cc3)nc12
Solvent: ClCCl
Solvent: CO
Product: CC(C#N)(Cn1nc2cc(Cl)cc(C=O)c2n1)NC(=O)c1ccc(OC(F)(F)F)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
A solution of N-[2-(6-Chloro-4-vinyl-2H-benzotriazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethoxybenzamide (0.29 g) in 35 mL of a 3 to 1 mixture of DCM and methanol was treated with ozone gas for 15 minutes. After stirring one hour at −78° C., the mixture was purged 10 minutes with oxygen and then quenched with dimethyl sulfide followed by a 10% solution of sodium thiosulfate, then diluted with DCM (100 mL). The mixture was separated, and the organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue that was purified by chromatography (SiO2, heptane/EA) to afford the title compound as a white solid (0.23 g, 79%). Rf=0.6 (1:1 EA/heptane). MS (ES): M/Z [M+H]=452. 1H NMR: (400 MHz, CHLOROFORM-d): 1.58 (s, 3H), 5.24 (d, J=13.8 Hz, 1H), 5.47 (d, J=13.8 Hz, 1H), 7.37 (d, J=8.1 Hz, 2H), 7.94 (br. s, 1H), 8.00 (d, J=1.8 Hz, 1H), 8.05 (m, 2H), 8.22 (d, J=1.9 Hz, 1H) and 10.34 (s, 1H). 19F NMR (376 MHz, CHLOROFORM-d): −58.1 (s, 3F).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[N:10]([C:13]([CH3:22])=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:15]=2)[C:11]=1[OH:12])=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[F:29][C:30]1[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[C:31]=1[CH2:32]Cl.[I-].[K+]>CN(C=O)C.O.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:11](=[O:12])[N:10]2[C:13]([CH3:22])=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:15]=[C:9]2[N:8]([CH2:32][C:31]2[C:30]([F:29])=[CH:37][CH:36]=[CH:35][C:34]=2[F:38])[CH:7]=1)=[O:5])[CH3:2]
Reactant: Fc1cccc(F)c1CCl
Reactant: CCOC(=O)c1cnc2nc(-c3ccccc3)c(C)n2c1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(Cc2c(F)cccc2F)c2nc(-c3ccccc3)c(C)n2c1=O
Temperature: 20 °C
Reaction time: 1 h
Yield: 90.9 %

Procedure:
To a solution of the compound obtained in Example 1 (157 mg, 0.53 mmol) in DMF (15 ml), potassium carbonate (80 mg, 0.58 mmol), 2,6-difluorobenzyl chloride (103 mg, 0.64 mmol) and potassium iodide (44 mg, 0.26 mmol) are added, followed by stirring at about 15 to 25° C. for 1 hour and stirring under heating at 80° C. for 1 hour. The brownish white crystalline substance obtained by concentration under reduced pressure of the reaction mixture is dispensed to ethyl acetate (30 ml) and water (30 ml). The water layer is extracted with ethyl acetate (10 ml), and the organic layers are combined and dried over sodium sulfate, after which the solvent is distilled off under reduced pressure to yield a crude brownish white crystalline product (204 mg), which is then purified by flush column chromatography to yield a white crystal (146 mg, 65%).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:19]=[CH:20][C:21]=2[O:22][CH3:23])[CH2:10][NH:11][C:12]2[C:16]([CH2:17][OH:18])=[CH:15][NH:14][N:13]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.O.[C:25]1(C)C=CC(S(O)(=O)=O)=CC=1.[OH-].[Na+]>CO>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:19]=[CH:20][C:21]=2[O:22][CH3:23])[CH2:10][NH:11][C:12]2[C:16]([CH2:17][O:18][CH3:25])=[CH:15][NH:14][N:13]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: COc1ccc(CNc2n[nH]cc2CO)cc1OC1CCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COCc1c[nH]nc1NCc1ccc(OC)c(OC2CCCC2)c1

Procedure:
A solution of 3-(3-cyclopentyloxy-4-methoxybenzylamino)-4-hydroxymethylpyrazole (1.0 g, 3.15 mmol) and p-toluenesulfonic acid monohydrate (0.2 g, 1.0 mmol) in methanol (100 mL) was kept at room temperature for 10 min. The reaction mixture was neutralized with 1 N aqueous sodium hydroxide and evaporated under reduced pressure at room temperature. The residue was partitioned between water (50 mL) and ethyl acetate (50 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (10 mL). The combined ethyl acetate layers were washed with water and evaporated under reduced pressure. The residue was taken up in a small volume of methylene chloride and applied to a 4 mm silica gel disk on a Chromatotron. Elution with 525 mL of methylene chloride and 275 mL of 1% methanol/methylene chloride removed some impure material. Continued elution with 75 mL of 1% methanol/methylene chloride afforded 380 mg (36%) of pure 3-(3-cyclopentyloxy-4-methoxybenzylamino)-4-methyoxymethylpurazole, mp. 112-115°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH3:11])[N:10]=2)[N:7]=1.[Br:12]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Br:12][C:8]1[N:6]2[N:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]2=[N:10][C:9]=1[CH3:11]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cn2nc(Cl)ccc2n1
Solvent: ClC(Cl)Cl
Product: Cc1nc2ccc(Cl)nn2c1Br
Temperature: 25 °C
Reaction time: 15 h
Yield: 90 %

Procedure:
To a solution of 6-chloro-2-methylimidazo[1,2-b]pyridazine (2.00 g, 11.9 mmol, 1.0 equiv) in chloroform (50 mL) was added N-bromosuccinimide (2.55 g, 14.3 mmol, 1.2 equiv). The reaction was stirred at room temperature for 15 h. Purification by column chromatography using 50% ethyl acetate in hexanes elution gave 2.64 g of the yellow solid, 90%.
Reaction SMILES: [CH3:1][N:2]1[N:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N+:12]([O-])=O)[C:3]1=[O:15].[H][H]>[Pd].C(OCC)(=O)C>[NH2:12][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:9]=1[CH:10]=[N:11][N:2]([CH3:1])[C:3]2=[O:15]
Reactant: [H][H]
Reactant: Cn1ncc2c([N+](=O)[O-])cccc2c1=O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cn1ncc2c(N)cccc2c1=O
Yield: 94 %

Procedure:
1.57 g of 2-methy-5-nitrophthalazin-1-one and 130 mg of palladium on activated carbon are suspended in 45 ml of ethyl acetate and hydrogenated with hydrogen under normal pressure. It is filtered through diatomaceous earth, and the solvent is removed in a vacuum. 1.26 g of 5-amino-2-methylphthalazin-1-one is obtained as a yellow solid.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:9]=[N:10][C:11]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:12][C:13]=1[C:14]#[C:15][CH3:16])(C)(C)C.C1CCN2C(=NCCC2)CC1>CO.O>[CH3:16][C:15]1[NH:7][C:8]2=[CH:9][N:10]=[C:11]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:12]=[C:13]2[CH:14]=1
Reactant: CC#Cc1cc(-c2ccccc2)ncc1NC(=O)OC(C)(C)C
Solvent: O
Solvent: CO
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1cc2cc(-c3ccccc3)ncc2[nH]1
Temperature: 60 °C
Reaction time: 24 h
Yield: 99.6 %

Procedure:
A solution of (6-phenyl-4-prop-1-ynylpyridin-3-yl)carbamic acid tert-butyl ester (670 mg, 2.17 mmol) in a mixture of 33 mL of methanol and 11 mL of water was treated with DBU (2.0 mL, 13.4 mmol). The resulting mixture was heated at 60° C. After 24 hours, the mixture was concentrated in vacuo, 50 mL of water was added, the mixture was sonicated, and the resulting solid was filtered. The solid was dried over P2O5 in vacuum to give 450 mg of the title product as a yellow solid (99% yield), which was used without further purification.